ALPROLIX 250UI powder + solvent for injection medication leaflet

ALPROLIX 250 IU powder and solvent for solution for injection

ALPROLIX 500 IU powder and solvent for solution for injection

ALPROLIX 1000 IU powder and solvent for solution for injection

ALPROLIX 2000 IU powder and solvent for solution for injection

ALPROLIX 3000 IU powder and solvent for solution for injection

ALPROLIX 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU human coagulation factor IX (rDNA), eftrenonacog alfa.

ALPROLIX contains approximately 250 IU (50 IU/mL) of human coagulation factor IX (rDNA),eftrenonacog alfa after reconstitution.

ALPROLIX 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU human coagulation factor IX (rDNA), eftrenonacog alfa.

ALPROLIX contains approximately 500 IU (100 IU/mL) of human coagulation factor IX (rDNA),eftrenonacog alfa after reconstitution.

ALPROLIX 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU human coagulation factor IX (rDNA), eftrenonacog alfa.

ALPROLIX contains approximately 1000 IU (200 IU/mL) of human coagulation factor IX (rDNA),eftrenonacog alfa after reconstitution.

ALPROLIX 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU human coagulation factor IX (rDNA), eftrenonacog alfa.

ALPROLIX contains approximately 2000 IU (400 IU/mL) of human coagulation factor IX (rDNA),eftrenonacog alfa after reconstitution.

ALPROLIX 3000 IU powder and solvent for solution for injection

Each vial contains nominally 3000 IU human coagulation factor IX (rDNA), eftrenonacog alfa.

ALPROLIX contains approximately 3000 IU (600 IU/mL) of human coagulation factor IX (rDNA),eftrenonacog alfa after reconstitution.

The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. Thespecific activity of ALPROLIX is 55-84 IU/mg protein.

Eftrenonacog alfa (recombinant human coagulation factor IX, Fc fusion protein (rFIXFc)) has 867amino acids. It is a high purity factor product produced by recombinant DNA technology in a humanembryonic kidney (HEK) cell line, without the addition of any exogenous human- or animal-derivedprotein in the cell culture, purification or final formulation.

Excipient with known effect0.3 mmol (6.4 mg) sodium per vial.

0.5 mg of polysorbate 20 per vial.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

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

Solvent: clear to colourless solution.

pH: 6.5 to 7.5

Osmolality: 255 to 345 mOsm/kg

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IXdeficiency).

ALPROLIX can be used for all age groups.

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

During the course of treatment, appropriate determination of factor IX levels is advised to guide thedose to be administered and the frequency of repeated injections. Individual patients may vary in theirresponse to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweightmay require adjustment in underweight or overweight patients. In the case of major surgicalinterventions in particular, precise monitoring of the substitution therapy by means of coagulationanalysis (plasma factor IX activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determiningfactor IX activity in patients’ blood samples, plasma factor IX activity results can be significantlyaffected by both the type of aPTT reagent and the reference standard used in the assay. This is ofimportance particularly when changing the laboratory and/or reagents used in the assay.

Measurements with a one-stage clotting assay utilising a kaolin-based aPTT reagent will likely resultin an underestimation of activity level.

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

The number of units of factor IX administered is expressed in International Units (IU), which arerelated to the current WHO standard for factor IX products. Factor IX activity in plasma is expressedeither as a percentage (relative to normal human plasma) or in International Units (relative to an

International Standard for factor IX in plasma).

One International Unit (IU) of recombinant factor IX Fc activity is equivalent to that quantity offactor IX in one mL of normal human plasma.

The calculation of the required dose of recombinant factor IX Fc is based on the empirical finding that1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1 % ofnormal activity (IU/dL). The required dose is determined using the following formula:

Required units = body weight (kg) × desired factor IX rise (%) (IU/dL) × {reciprocal of observedrecovery (IU/kg per IU/dL)}

The amount to be administered and the frequency of administration should always be oriented to theclinical effectiveness in the individual case. If a repeat dose is required to control the bleed, theprolonged half-life of ALPROLIX should be taken into account (see section 5.2). The time to peakactivity is not expected to be delayed.

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

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

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

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

Early haemarthrosis, muscle 20-40 Repeat injection every 48 hours, until thebleeding or oral bleeding bleeding episode as indicated by pain isresolved or healing is achieved.

More extensive 30-60 Repeat injection every 24 to 48 hours untilhaemarthrosis, muscle pain and acute disability are resolved.

bleeding or haematoma

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

Minor surgery including 30-60 Repeat injection after 24 hours, as needed untiltooth extraction healing is achieved1.

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

1 In some patients and circumstances the dosing interval can be prolonged up to 48 hours (see section 5.2 forpharmacokinetic data).

For long term prophylaxis against bleeding, the recommended starting regimens are either:

* 50 IU/kg once weekly, adjust dose based on individual response or

* 100 IU/kg once every 10 days, adjust interval based on individual response. Some patients whoare well-controlled on a once every 10 days regimen might be treated on an interval of 14 days orlonger.

The highest recommended dose for prophylaxis is 100 IU/kg

There is limited experience in patients ≥65 years.

For children below the age of 12 years, higher or more frequent doses may be required, and therecommended starting dose is 50-60 IU/kg every 7 days. For adolescents of 12 years of age and above,the dose recommendations are the same as for adults. See sections 5.1 and 5.2.

The highest recommended dose for prophylaxis is 100 IU/kg

In case of self-administration or administration by a caregiver appropriate training is needed.

ALPROLIX should be injected intravenously over several minutes. The rate of administration shouldbe 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 or to any of the excipients listed in section 6.1.

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

Allergic type hypersensitivity reactions have been reported with ALPROLIX. If symptoms ofhypersensitivity occur, patients should be advised to discontinue use of the medicinal productimmediately and contact their physician. Patients should be informed of the early signs ofhypersensitivity reactions including, hives, generalised urticaria, tightness of the chest, wheezing,hypotension and anaphylaxis.

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

After repeated treatment with human coagulation factor IX products, patients should be monitored forthe development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units(BU) using appropriate biological testing.

There have been reports in the literature showing a correlation between the occurrence of a factor IXinhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluatedfor the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at anincreased risk of anaphylaxis with subsequent challenge with factor IX.

Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IXshould, according to the treating physician’s judgement, be performed under medical observationwhere proper medical care for allergic reactions could be provided.

Thromboembolism

Because of the potential risk of thrombotic complications with factor IX products, clinical surveillancefor early signs of thrombotic and consumptive coagulopathy should be initiated with appropriatebiological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or disseminatedintravascular coagulation (DIC). The benefit of treatment with ALPROLIX in these situations shouldbe weighed against the risk of these complications.

In patients with existing cardiovascular risk factors, substitution therapy with factor IX products mayincrease the cardiovascular risk.

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

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

Excipient related considerations

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially“sodium-free”. In case of treatment with multiple vials, the total sodium content should be taken intoconsideration.

Polysorbate

This medicine contains 0.5 mg of polysorbate 20 in each vial. Polysorbates may cause allergicreactions.

No interactions of ALPROLIX with other medicinal products have been reported. No interactionstudies have been performed.

Animal reproduction studies have not been conducted with ALPROLIX. A placental transfer study inmice was conducted (see section 5.3). Based on the rare occurrence of haemophilia B in women,experience regarding the use of factor IX during pregnancy and breast-feeding is not available.

Therefore, factor IX should be used during pregnancy and breast-feeding only if clearly indicated.

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

ALPROLIX.

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

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedrarely and may in some cases progress to severe anaphylaxis (including shock). In some cases, thesereactions have progressed to severe anaphylaxis, and they have occurred in close temporal associationwith development of factor IX inhibitors (see also 4.4). Nephrotic syndrome has been reportedfollowing attempted immune tolerance induction in haemophilia B patients with factor IX inhibitorsand a history of allergic reaction.

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If suchinhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, itis recommended that a specialised haemophilia centre be contacted.

There is a potential risk of thromboembolic episodes following the administration of factor IXproducts, with a higher risk for low purity preparations. The use of low purity factor IX products hasbeen associated with instances of myocardial infarction, disseminated intravascular coagulation,venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated withthromboembolic complications.

Previously Treated Patients (PTPs): A total of 153 patients with severe haemophilia B were observedin phase III clinical studies and an extension study. Adverse events were monitored for a total of561 subject-years. The total number of exposure days was 26,106 with a median of 165 (range 1 to528) exposure days per subject.

Previously Untreated Patients (PUPs): A total of 33 patients with severe haemophilia B were observedin one clinical study. Adverse events were monitored for a total of 57.51 subject-years. The totalnumber of exposure days was 2,233 with a median of 76 (range 1 to 137) exposure days per subject.

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

Term Level).

Frequencies have been evaluated according to the following convention: very common (≥1/10);common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare(<1/10,000), not known (cannot be estimated from the available data). The table lists adverse reactionsreported in the clinical studies and identified in post-marketing use.

Table 2: Adverse reactions reported for ALPROLIX

MedDRA System Organ Class Adverse reactions Frequencycategory

Blood and lymphatic system disorders Factor IX inhibition Common1

Immune system disorders Hypersensitivity Common1

Anaphylactic reaction Not known

Anaphylactic shock Not known

Metabolism and nutrition disorders Decreased appetite Uncommon

Nervous system disorders Headache Common

Dizziness Uncommon

Dysgeusia Uncommon

Cardiac disorders Palpitations Uncommon

Vascular disorders Hypotension Uncommon

Gastrointestinal disorders Paraesthesia oral Common

Breath odour Uncommon

Renal and urinary disorders Obstructive uropathy Common

Haematuria Uncommon

Renal colic Uncommon

General disorders and administration site Injection site erythema Commonconditions Fatigue Uncommon

Infusion site pain Uncommon1 Frequency based on occurrence in PUPs study. Both events of factor IX inhibition and hypersensitivityoccurred in a single PUP in Study IV. See Description of selected adverse reactions.

Throughout the clinical study program, one patient (previously untreated) in Study IV developed alow titer factor IX inhibitor associated with hypersensitivity (see section 5.1). In post-marketingexperience, factor IX inhibitor development and hypersensitivity (including anaphylaxis) have beenobserved.

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

For extent and age characterisation of the safety database in children see section 5.1.

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

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

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04

Factor IX is a single chain glycoprotein with a molecular mass of about 55,000 Dalton. It is a vitamin-

K dependent coagulation factor. Factor IX is activated by factor XIa in the intrinsic coagulationpathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, incombination with activated factor VIII, activates factor X. Activated factor X converts prothrombininto thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed.

Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels offactor IX and results in bleeding into joints, muscles or internal organs, either spontaneously or as aresult of accidental or surgical trauma. By replacement therapy the plasma level of factor IX isincreased thereby enabling a temporary correction of the factor deficiency and correction of thebleeding tendencies.

ALPROLIX (eftrenonacog alfa) is a long-acting, fully recombinant, fusion protein comprising humancoagulation factor IX covalently linked to the Fc domain of human immunoglobulin G1, and producedby recombinant DNA technology.

The Fc region of human immunoglobulin G1 binds with the neonatal Fc receptor. This receptor isexpressed throughout life as part of a naturally occurring pathway that protects immunoglobulins fromlysosomal degradation by cycling these proteins back into circulation, resulting in their long plasmahalf-life.

The safety, efficacy, and pharmacokinetics of ALPROLIX were evaluated in 2 multinational, open-label, pivotal studies in previously treated patients (PTPs); a phase 3 study in adults and adolescents,referred to as Study I and a phase 3 paediatric study, referred to as Study II (see Paediatric population).

The safety and efficacy of ALPROLIX was also evaluated in previously untreated patients (PUPs)with severe haemophilia B (Study IV), see Paediatric population.

Study I compared the efficacy of each of 2 prophylactic treatment regimens (fixed weekly intervalwith dosing of 50 IU/kg, and individualised interval with 100 IU/kg starting every 10 days) to ondemand treatment. The study enrolled a total of 123 previously treated male patients (12 to 71 years ofage) with severe haemophilia B (≤2% endogenous FIX activity). All patients received treatment with

ALPROLIX and were followed for up to 77 weeks.

Out of 123 subjects who completed Study I, 93 were enrolled in Study III (extension study) withmedian total follow-up time of 6.5 years.

Of note, Annualised Bleeding Rates (ABR) are not comparable between different factor concentratesand between different clinical studies.

Prophylaxis fixed weekly and individualised intervals

Median weekly dose for subjects in the fixed weekly arm was 45.17 IU/kg (interquartile range (IQR)38.1 -53.7) in Study I. The corresponding median ABR in subjects evaluable for efficacy were 2.95(IQR: 1.01-4.35) and remained similar throughout Study III (1.85 (IQR: 0.76-4.0)). Subjects had amedian of 0.38 (IQR: 0.00-1.43) spontaneous joint bleeds in Study III.

For subjects in the individualised interval arm, the median dosing interval was 12.53 days (IQR: 10.4-13.4) in Study I. The corresponding median ABR was 1.38 (IQR: 0.00-3.43) and remained similarthroughout Study III (1.85 (IQR: 0.76-4.0)).

Dosing intervals and factor consumption remained similar in Study III (extension study) compared to

Study I for both prophylactic regimens.

No bleeding episodes were experienced in 42% of subjects while on individualised prophylaxis and in23% of subjects while on weekly prophylaxis. There was a lower proportion of subjects inindividualised interval prophylaxis with ≥1 target joint at baseline than in weekly prophylaxis (27.6%and 57.1%, respectively).

Treatment of bleeding

Of the 636 bleeding events observed during Study I, 90.4% were controlled with 1 injection andoverall 97.3% with 2 or fewer injections. The median average dose per injection to treat a bleedingepisode was 46.07 (IQR: 32.86-57.03) IU/kg. The median overall dose to treat a bleeding episode was51.47 IU/kg (IQR: 35.21-61.73) in the weekly prophylaxis arm, 49.62 IU/kg (IQR: 35.71-94.82) in theindividualised interval prophylaxis arm and 46.58 IU/kg (IQR: 33. 33-59.41) in the on-demandtreatment arm.

Perioperative management (surgical prophylaxis)

A total of 35 major surgical procedures were performed and assessed in 22 subjects (21 adults andadolescents, and 1 paediatric patient <12 years of age) in Study I and Study III. Of the 35 majorsurgeries, 28 surgeries (80.0%) required a single pre-operative dose to maintain haemostasis duringsurgery. The median average dose per injection to maintain haemostasis during surgery was94.7 IU/kg (range: 49 to 152 IU/kg). The total dose on the day of surgery ranged from 49 to 341 IU/kgand the total dose in the 14-day perioperative period ranged from 60 to 1947 IU/kg.

The haemostatic response was rated as excellent or good in 100% of major surgeries.

Study II enrolled a total of 30 previously treated male paediatric patients with severe haemophilia B(≤2% endogenous FIX activity). Patients were less than 12 years of age (15 were <6 years of age and15 were 6 to <12 years of age). All patients received treatment with ALPROLIX and were followedfor up to 52 weeks.

All of the 30 patients were treated with ALPROLIX on a prophylactic dosing regimen starting with50-60 IU/kg every 7 days, with adjustment of dose to a maximum of 100 IU/kg and dosing interval toa minimum of once weekly and a maximum of twice weekly. Out of 30 patients having completed

Study II, 27 enrolled to Study III (extension study). The median time on Study II+III was 2.88 yearsand median number of exposure days was 166.

Study IV enrolled 33 previously untreated paediatric patients (PUPs) with severe haemophilia B (≤2%endogenous FIX activity). The median age at enrolment was 0.6 years (range 0.08 to 2 years); 78.8%of subjects were less than 1 year old. The overall median number of weeks on ALPROLIX was83.01 (range 6.7 to 226.7 weeks), and the overall median number of EDs was 76 days (range 1 to 137days).

Prophylaxis individualised regimen

In Study II the median average weekly dose of ALPROLIX was 59.40 IU/kg (interquartile range,52.95 to 64.78 IU/kg) for subjects <6 years of age and 57.78 IU/kg (interquartile range, 51.67 to65.01 IU/kg) for subjects 6 to <12 years of age. The median dosing interval overall was 6.99 days(interquartile range, 6.94 to 7.03) with no difference in the median dosing interval between agecohorts. With the exception of one patient whose last prescribed dose was 100 IU/kg every 5 days, theother 29 patients last prescribed doses were up to 70 IU/kg every 7 days. No bleeding episodes wereexperienced in 33% of paediatric subjects. Dosing intervals and factor consumption remained similarin Study III compared to Study II.

Median annualised bleeding rates in subjects <12 years of age evaluable for efficacy were 1.97(interquartile range 0.00 to 3.13) in Study II and remained similar throughout Study III (extensionstudy).

In PUPs (Study IV) the median average weekly dose of ALPROLIX was 57.96 IU/kg (interquartilerange 52.45 to 65.06 IU/kg) and the median average dosing interval was 7 days (interquartile range6.95 to 7.12 days). Dosing intervals and factor consumption remained similar in Study IV compared to

Study II and III. For PUPs receiving prophylactic treatment, 8 (28.6 %) of the subjects experienced nobleeding episodes. The overall median ABR for subjects in the prophylactic treatment regimen was1.24 (interquartile range 0.0 to 2.49).

Treatment of bleeding episodes

Of the 60 bleeding events observed during Study II, 75% were controlled with 1 injection, and overall91.7% of bleeding episodes were controlled with 2 or fewer injections. The median average dose perinjection to treat a bleeding episode was 63.51 (interquartile range, 48.92 to 99.44) IU/kg. The medianoverall dose to treat a bleeding episode was 68.22 IU/kg (interquartile range, 50.89 to 126.19).

Of the 58 bleeding events observed in PUPs receiving prophylactic treatment in Study IV, 87.9% werecontrolled with 1 injection, and overall 96.6% of bleeding episodes were controlled with 2 or fewerinjections. The median average dose per injection to treat a bleeding episode was 71.92 IU/kg(interquartile range 52.45 to 100.81 IU/kg). The median overall dose to treat a bleeding episode was78.74 IU/kg (interquartile range 53.57 to 104.90 IU/kg).

All pharmacokinetic studies with ALPROLIX were conducted in previously treated patients withsevere haemophilia B. Data presented in this section were obtained by one-stage clotting assay with asilica-based aPTT reagent calibrated against factor IX plasma standards.

Pharmacokinetic properties were evaluated in 22 subjects (≥19 years) receiving ALPROLIX (rFIXFc).

Following a washout period of at least 120 hours (5 days), the subjects received a single dose of50 IU/kg. Pharmacokinetic samples were collected pre-dose and then subsequently at 11 time pointsup to 240 hours (10 days) post-dose. Pharmacokinetic parameters of the non-compartmental analysisafter 50 IU/kg dose of ALPROLIX are presented in Table 3.

Table 3: Pharmacokinetic parameters of ALPROLIX (50 IU/kg dose)

ALPROLIX

Pharmacokinetic parameters1 (95% CI)

N=220.92

Incremental Recovery (IU/dL per IU/kg)(0.77-1.10)

AUC/Dose 31.58(IU*h/dL per IU/kg) (28.46-35.05)46.10

Cmax (IU/dL)(38.56-55.11)3.17

CL (mL/h/kg)(2.85-3.51)t (h) 77.60½(70.05-85.95)2 5.03t½α (h)(3.20-7.89)2 82.12t½β (h)(71.39-94.46)95.82

MRT (h)(88.44-106.21)303.4

Vss (mL/kg)(275.1-334.6)11.22

Time to 1% (days)2(10.20-12.35)1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)2 These pharmacokinetic parameters obtained from the compartmental analysis

Abbreviations: CI = confidence interval; Cmax= maximum activity; AUC = area under the FIX activity time curve; t1/2 =terminal half-life; t½α = distribution half-life; t½β = elimination half-life; CL = clearance; Vss = volume of distribution atsteady-state; MRT = mean residence time.

The elimination half-life (82 hours) is influenced by the Fc region, which in animal models was shownto be mediated by neonatal Fc receptor cycling pathways.

A population pharmacokinetic model was developed based on FIX activity data from 161 subjects ofall ages (2-76 years of age) weighing between 12.5 kg to 186.7 kg in three clinical studies (12 subjectsin a phase 1/2a study, 123 subjects in Study I and 26 subjects in Study II). The estimate of CL for atypical 70 kg adult is 2.30 dL/h and steady-state volume of distribution is 194.8 dL, respectively. Theobserved mean (SD) activity time profile following a single dose of ALPROLIX in patients withsevere haemophilia B is shown below (see Table 4).

Table 4: The Observed Mean (SD) FIX activity [IU/dL] following a single dose of ALPROLIX1(rFIXFc) for patients ≥ 12 years of Age

Dose10 mins 1h 3h 6h 24h 48h 96h 144h 168h 192h 240h 288h(IU/kg)52.9 34.5 28.7 25.1 15.1 9.7 5.0 3.4 3.2 2.6 2.150 NA(30.6) (7.3) (6.7) (5.1) (3.9) (3.0) (1.6) (1.1) (1.9) (1.0) (0.9)112 77.1 36.7 21.8 10.1 4.81 2.86 2.30100 NA NA NA NA(24) (12.8) (8.0) (4.8) (2.6) (1.67) (0.98) (0.94)1 See section 4.2; NA: Not available

Pharmacokinetic parameters of ALPROLIX were determined for adolescents in Study I(pharmacokinetic sampling was conducted pre-dose followed by assessment at multiple time points upto 336 hours (14 days) post-dose) and for children in Study II (pharmacokinetic sampling wasconducted pre-dose followed by assessment at 7 time points up to 168 hours (7 days) post-dose).

Table 5 presents the pharmacokinetic parameters calculated from the paediatric data of 35 subjects lessthan 18 years of age.

Table 5: Comparison of PK Parameters of ALPROLIX (rFIXFc) by Age Category

Study II Study I<6 years 6 to <12 years 12 to <18 years

PK Parameters1 (2, 4) (6, 10) (12, 17)

N = 11 N = 13 N = 11

IR 0.5989 0.7170 0.8470(IU/dL per IU/kg) (0.5152, 0.6752) (0.6115, 0.8407) (0.6767, 1.0600)

AUC/Dose22.71 28.53 29.50(IU*h/dL per(20.32, 25.38) (24.47, 33.27) (25.13, 34.63)

IU/kg)t (h) 66.49 70.34 82.22½ (55.86, 79.14) (60.95, 81.17) (72.30, 93.50)83.65 82.46 93.46

MRT (h)(71.76, 97.51) (72.65, 93.60) (81.77, 106.81)4.365 3.505 3.390

CL (mL/h/kg)(3.901, pct. 4.885) (3.006, 4.087) (2.888, 3.979)

Vss (mL/kg) 365.1 289.0 316.8(316.2, 421.6) (236.7, 352.9) (267.4, 375.5)1PK parameters derived from noncompartmental analysis are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; IR = incremental recovery; AUC = area under the FIX activity timecurve; t1/2 = terminal half-life; MRT = mean residence time; CL = clearance; Vss = volume of distribution atsteady-state

Non-clinical data reveal no special hazard for humans based on thrombogenicity test in rabbits(Wessler stasis model) and repeated dose toxicity studies (which included assessment of local toxicity,male reproductive organs and electrocardiographic parameters) in rats and monkeys. Studies toinvestigate genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development havenot been conducted. In a placental transfer study, eftrenonacog alfa (rFIXFc) has been shown to crossthe placenta in small amounts in mice.

Sucrose

Histidine

Mannitol

Polysorbate 20

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Sodium chloride

Water for injections

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

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

Unopened vial4 years

During the shelf-life, the product may be stored at room temperature (up to 30 °C) for a single periodnot exceeding 6 months. The date that the product is removed from refrigeration should be recordedon the carton. After storage at room temperature, the product may not be returned to the refrigerator.

The product should not be used beyond the expiry date printed on the vial or six months afterremoving the carton from refrigeration, whichever is earlier.

Chemical and physical stability has been demonstrated for 6 hours when stored at room temperature(up to 30 °C). If the product is not used within 6 hours, it must be discarded. From a microbiologicalpoint 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. Protect product fromdirect sunlight.

Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the vial in the outer carton in order to protectfrom 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 chlorobutyl rubber stopper

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

- a plunger rod

- a sterile vial adapter for reconstitution

- a sterile infusion set

- alcohol swab(s)

- plaster(s)

- gauze pad(s).

Pack size of 1.

The powder for injection in each vial must be reconstituted with the supplied solvent (sodium chloridesolution) 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.

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

This product is for single use only.

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

Instructions for preparation and administration

The procedure below describes the preparation and administration of ALPROLIX.

ALPROLIX is administered by intravenous (IV) injection after dissolving the powder for injectionwith the solvent supplied in the pre-filled syringe. ALPROLIX pack contains:

A) 1 Powder vial

B) 5 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

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

Wash your hands before opening the pack.

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

Check the expiry date on the ALPROLIX carton. Do not use if the product has expired.

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

3. Place the vial on a clean flat surface. Removethe plastic flip-top cap from the vial.

4. Wipe the top of the vial with one of the alcoholswabs (F) provided in the pack and allow to airdry. Do not touch the top of the vial or allow itto touch anything else once wiped.

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

6. Place the vial on a flat surface. Hold the vialadapter in its protective cap and place itsquarely over the top of the vial. Press downfirmly until the adapter snaps into place on topof the vial, with the adapter spike penetratingthe vial stopper.

7. Attach the plunger rod (C) to the solventsyringe by inserting the tip of the plunger rodinto the opening in the syringe plunger. Turnthe plunger rod firmly clockwise until it issecurely seated in the syringe plunger.

8. Break off the white, tamper-resistant, plasticcap from the solvent syringe by bending theperforation cap until it snaps off. Set the capaside by placing it with the top down on a flatsurface. Do not touch the inside of the cap orthe syringe tip.

9. Lift the protective cap away from the adapterand discard.

10. Connect the solvent syringe to the vial adapterby inserting the tip of the syringe into theadapter opening. Firmly push and turn thesyringe clockwise until it is securely connected.

11. Slowly depress the plunger rod to inject all thesolvent into the ALPROLIX vial.

12. With the syringe still connected to the adapterand the plunger rod pressed down, gently swirlthe vial until the powder is dissolved.

Do not shake.

13. The final solution must be inspected visually before administration. The solution should appearclear to slightly opalescent (pearl-like) and colourless. Do not use the solution if cloudy orcontains visible particles.

14. Ensuring that the syringe plunger rod is stillfully pressed down, invert the vial. Slowly pullon the plunger rod to draw back all the solutionthrough the vial adapter into the syringe.

Note: If you use more than one vial of

ALPROLIX per injection, each vial should beprepared separately as per the previousinstructions (steps 1 to 13) and the solventsyringe should be removed, leaving the vialadapter in place. A single large luer locksyringe may be used to draw back the preparedcontents of each of the individual vials.

15. Detach the syringe from the vial adapter bygently pulling and turning the syringecounterclockwise.

16. Discard the vial and the adapter.

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

After preparation, ALPROLIX can be stored at room temperature for up to 6 hours beforeadministration. After this time, the prepared ALPROLIX should be discarded. Protect from directsunlight.

Administration (Intravenous Injection):

ALPROLIX 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 thetubing. Attach the syringe with the prepared ALPROLIX solutionto 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 otheralcohol swab provided in the pack.

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

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

5. After completing the injection and removing the needle, you shouldfold 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 anappropriate medical waste container as these materials may hurt others if not disposed of properly. Donot reuse equipment.

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/16/1098/001

EU/1/16/1098/002

EU/1/16/1098/003

EU/1/16/1098/004

EU/1/16/1098/005

Date of first authorisation: 12 May 2016

Date of latest renewal: 11 February 2021

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

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