ALTUVOCT 500UI powder + solvent for injection medication leaflet

ALTUVOCT 250 IU powder and solvent for solution for injection

ALTUVOCT 500 IU powder and solvent for solution for injection

ALTUVOCT 750 IU powder and solvent for solution for injection

ALTUVOCT 1 000 IU powder and solvent for solution for injection

ALTUVOCT 2 000 IU powder and solvent for solution for injection

ALTUVOCT 3 000 IU powder and solvent for solution for injection

ALTUVOCT 4 000 IU powder and solvent for solution for injection

ALTUVOCT 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU efanesoctocog alfa. ALTUVOCT contains approximately83 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU efanesoctocog alfa. ALTUVOCT contains approximately167 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 750 IU powder and solvent for solution for injection

Each vial contains nominally 750 IU efanesoctocog alfa. ALTUVOCT contains approximately250 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 1 000 IU powder and solvent for solution for injection

Each vial contains nominally 1 000 IU efanesoctocog alfa. ALTUVOCT contains approximately333 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 2 000 IU powder and solvent for solution for injection

Each vial contains nominally 2 000 IU efanesoctocog alfa. ALTUVOCT contains approximately667 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 3 000 IU powder and solvent for solution for injection

Each vial contains nominally 3 000 IU efanesoctocog alfa. ALTUVOCT contains approximately1 000 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

ALTUVOCT 4 000 IU powder and solvent for solution for injection

Each vial contains nominally 4 000 IU efanesoctocog alfa. ALTUVOCT contains approximately1 333 IU/mL of human coagulation factor VIII efanesoctocog alfa after reconstitution.

Potency is determined using an activated partial thromboplastin time (aPTT)-based one-stage clottingassay with Actin-FSL reagent.

Efanesoctocog alfa [human coagulation factor VIII (rDNA)] is a protein that has 2 829 amino acids.

Efanesoctocog alfa is produced by recombinant DNA technology in a human embryonic kidney(HEK) cell line. No raw materials of human or animal origin are used in the manufacturing process.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: lyophilized, white to off-white powder or cake

Solvent: clear, colourless solutionpH: 6.5 to 7.2

Osmolality: 586 to 688 mOsm/kg

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

ALTUVOCT can be used for all age groups.

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

After proper training in the correct injection technique (see section 6.6 and package leaflet), a patientmay self-inject ALTUVOCT, or the patient’s caregiver may administer it, if their physiciandetermines that it is appropriate.

Individual patients may vary in their response to factor VIII, demonstrating different half-lives andrecoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients.

Monitoring of factor VIII levels for the purpose of dose adjustment is usually not necessary duringroutine prophylaxis. In case of major surgery or life-threatening bleeds, determination of factor VIIIlevels is required to guide the dose and frequency of repeated injections.

When using an in vitro thromboplastin-time (aPTT)-based one-stage clotting assay for determiningfactor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantlyaffected by both the type of aPTT reagent and the reference standard used in the assay. Also there canbe significant discrepancies between assay results obtained by aPTT-based one-stage clotting assayand the chromogenic assay according to Ph. Eur. This is of importance particularly when changing thelaboratory and/or reagents used in the assay.

It is recommended to use a validated one-stage clotting assay to determine plasma factor VIII activityof ALTUVOCT. Throughout the clinical development an Actin-FSL-based one-stage clotting assaywas used.

According to the findings of a comparative analysis of clinical study samples, results obtained using achromogenic assay should be divided by 2.5 to approximate the patient’s factor VIII activity (seesection 4.4). In addition, a field study comparing different aPTT reagents indicated approximately2.5-fold higher factor VIII activity levels when using Actin-FS instead of Actin-FSL in the one-stageclotting assay and approximately 30% lower results when using SynthASil.

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 factor VIII administered is expressed in International Units (IU), which arerelated to the current WHO concentrate standard for factor VIII products. Factor VIII activity inplasma is expressed either as a percentage (relative to normal human plasma) or preferably in

International Units (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity is equivalent to that quantity of factor VIII in one mL of normal humanplasma.

For the dose of 50 IU factor VIII per kg body weight, the expected in vivo plasma recovery infactor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula:

Estimated increment of factor VIII (IU/dL or % of normal) = 50 IU/kg x 2 (IU/dL per IU/kg)

ALTUVOCT dosing for the on-demand treatment, control of bleeding episodes and perioperativemanagement is provided in Table 1.

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

Degree of haemorrhage/ Type Recommended dose Additional informationof surgical procedure

Early haemarthrosis, muscle Single dose of 50 IU/kg For minor and moderate bleedingbleeding or oral bleeding episodes occurring within 2 to 3 daysafter a prophylactic dose, a lower doseof 30 IU/kg dose may be used.

An additional dose of 30 or 50 IU/kgafter 2 to 3 days may be considered.

More extensive haemarthrosis, Single dose of 50 IU/kg Additional doses of 30 or 50 IU/kgmuscle bleeding or haematoma every 2 to 3 days may be considereduntil bleeding is resolved.

Life threatening haemorrhages Single dose of 50 IU/kg Additional doses of 30 or 50 IU/kgevery 2 to 3 days may be administereduntil the threat is resolved.

Minor surgery including tooth Single dose of 50 IU/kg An additional dose of 30 or 50 IU/kgextraction after 2 to 3 days may be considered.

Degree of haemorrhage/ Type Recommended dose Additional informationof surgical procedure

Major surgery Single dose of 50 IU/kg Additional doses of 30 or 50 IU/kgevery 2 to 3 days may be administeredas clinically needed until adequatewound healing is achieved.

For resumption of prophylaxis (if applicable) after treatment of a bleed, it is recommended to allow aninterval of at least 72 hours between the last 50 IU/kg dose for treatment of a bleed and resumingprophylaxis dosing. Thereafter, prophylaxis can be continued as usual on the patient’s regular dosingschedule.

The recommended dosing for routine prophylaxis for adults and children is 50 IU/kg of ALTUVOCTadministered once weekly.

There is limited experience in patients ≥ 65 years. The dosing recommendations are the same as forpatients < 65 years.

The dosing recommendations are the same as for adults.

The entire ALTUVOCT dose should be injected intravenously over 1 to 10 minutes, based on thepatient’s comfort level.

For instructions on dilution 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 the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Allergic type hypersensitivity reactions are possible with ALTUVOCT. 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 shock, standard medical treatment for shock should be implemented.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in themanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulinsdirected against the factor VIII pro-coagulant activity, which are quantified in Bethesda Units (BU)per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to theseverity of the disease as well as the exposure to factor VIII, this risk being highest within the first50 exposure days but continues throughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titresposing 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 forthe development of inhibitors by appropriate clinical observations and laboratory tests. If the expectedfactor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriatedose, testing for factor VIII inhibitor presence should be performed. In patients with high levels ofinhibitor, 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 ofhaemophilia and factor VIII inhibitors.

Monitoring laboratory tests

If the chromogenic assay or the one-stage clotting assay with Actin-FS reagent are used, divide theresult by 2.5 to approximate the patient’s factor VIII activity level (see section 4.2). Of note, thisconversion factor only represents an estimate (mean chromogenic assay/one-stage clotting assay

Actin-FSL ratio: 2.53; SD: 1.54; Q1: 1.98; Q3: 2.96; N=3 353).

In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increasethe 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.

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

No interaction studies have been performed.

Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrenceof haemophilia A in women, experience regarding the use of factor VIII during pregnancy andbreast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactationonly if clearly indicated.

ALTUVOCT has no or negligible influence on the ability to drive and use machines.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinjection 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).

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with ALTUVOCT (see section 5.1). If such inhibitors occur, the conditionmay manifest itself as an insufficient clinical response. In such cases, it is recommended that aspecialised haemophilia centre be contacted.

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

Term Level). Frequencies of adverse reactions are based on Phase 3 clinical studies in 277 previouslytreated patients (PTPs) with severe haemophilia A, of which 161 (58.2%) were adults (18 years of ageand older), 37 (13.4%) were adolescents (12 to < 18 years of age), and 79 (28.5%) were children underthe age of 12 years.

Adverse drug reactions (ADRs) (summarized in Table 2) were reported in 111 (40.1%) of the 277subjects treated with routine prophylaxis or on-demand therapy.

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 ALTUVOCT in clinical studies

MedDRA system organ class Adverse reactions Frequency category

Nervous system disorders Headache1 Very common

Gastrointestinal disorders Vomiting Common

Skin and subcutaneous tissue disorders Eczema Common

Rash2 Common

Urticaria3 Common

Musculoskeletal and connective tissue disorders Arthralgia Very common

Pain in extremity Common

Back pain Common

General disorders and administration site Pyrexia Commonconditions Injection site reaction4 Uncommon1 Headache, including migraine.2 Rash, including rash maculo papular.3 Urticaria, including urticaria papular.4 Injection site reaction, including injection site haematoma and injection site dermatitis.

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

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.

No symptoms of overdose with human coagulation factor VIII (rDNA) have been reported.

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

Efanesoctocog alfa is replacement factor VIII therapy. Activated factor VIII acts as a cofactor foractivated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor Xconverts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can beformed. Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreasedlevels of functional factor VIII:C and results in bleeding into joints, muscles or internal organs, eitherspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levelsof factor VIII are increased, thereby enabling a temporary correction of the factor deficiency andcorrection of the bleeding tendencies.

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

ALTUVOCT (efanesoctocog alfa) or recombinant coagulation Factor VIII Fc-Von Willebrand Factor-

XTEN is a recombinant fusion protein that temporarily replaces the missing coagulation Factor VIIIneeded for effective haemostasis.

Efanesoctocog alfa is a FVIII protein that is designed not to bind endogenous VWF in order toovercome the half-life limit imposed by FVIII-VWF interactions. The D’D3 domain of VWF is theregion that interacts with FVIII. Appending the D’D3 domain of VWF to a rFVIII-Fc fusion proteinprovides protection and stability to FVIII and prevents FVIII interaction with endogenous VWF, thusovercoming the limitation on FVIII half-life imposed by VWF clearance.

The Fc region of human immunoglobulin G1 (IgG1) binds to the neonatal Fc receptor (FcRn). FcRn ispart of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins byrecycling them back into circulation and thus prolonging the plasma half-life of the fusion protein.

Efanesoctocog alfa contains 2 XTEN polypeptides, which further increase its pharmacokinetics (PK).

The natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN polypeptide,inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN is inserted inbetween the D’D3 domain and Fc.

The safety, efficacy, and pharmacokinetics of ALTUVOCT have been evaluated in two multi-centre,prospective, open-label Phase 3 clinical studies (one study in adults and adolescents [XTEND-1] andone paediatric study in children < 12 years of age [XTEND-Kids, see Paediatric population]) inpreviously treated patients (PTPs) with severe haemophilia A (< 1% endogenous FVIII activity or adocumented genetic mutation consistent with severe haemophilia A). The long-term safety andefficacy of ALTUVOCT is also being evaluated in a long-term extension study.

All studies evaluated the efficacy of routine prophylaxis with a weekly dose of 50 IU/kg anddetermined haemostatic efficacy in the treatment of bleeding episodes and during perioperativemanagement in subjects undergoing major or minor surgical procedures. Furthermore, the efficacy of

ALTUVOCT prophylaxis compared with previous prophylactic factor VIII was also evaluated in anintra-subject comparison in subjects who had participated in a prospective observational study(OBS16221) prior to enrolment in the XTEND-1 study.

Clinical efficacy during routine prophylaxis in adults/adolescents

The completed adult and adolescent study (XTEND-1) enrolled a total of 159 PTPs (158 male and1 female subjects) with severe haemophilia A. Subjects were aged 12 to 72 years and included25 adolescent subjects aged 12 to 17 years. All 159 enrolled subjects received at least one dose of

ALTUVOCT and were evaluable for efficacy. A total of 149 subjects (93.7%) completed the study.

The efficacy of weekly 50 IU/kg ALTUVOCT as routine prophylaxis was evaluated as estimated bythe mean annualized bleeding rate (ABR) (Table 3) and by comparing the ABR during on-studyprophylaxis vs. the ABR during pre-study factor VIII prophylaxis (Table 4). A total of 133 adults andadolescents, who had been receiving factor VIII prophylaxis prior to study enrolment, were assignedto receive ALTUVOCT for routine prophylaxis at a dose of 50 IU/kg once weekly (QW) for 52 weeks(Arm A). An additional 26 subjects, who were on pre-study episodic (on-demand) treatment withfactor VIII, received episodic (on-demand) treatment with ALTUVOCT at doses of 50 IU/kg for26 weeks, followed by routine prophylaxis at a dose of 50 IU/kg once weekly for 26 weeks (Arm B).

Overall, 115 subjects received at least a total number of 50 exposure days in Arm A and 17 subjectscompleted at least 25 exposure days of routine prophylaxis in Arm B.

Table 3: Summary of Annualized bleeding rate (ABR) with ALTUVOCT prophylaxis,

ALTUVOCT on-demand treatment, and after switch to ALTUVOCT prophylaxis insubjects ≥ 12 years of age

Arm A Arm B Arm B

Endpoint1 Prophylaxis2 On demand3 Prophylaxis3

N = 133 N = 26 N = 26

Bleeds

Mean ABR (95% CI)4 0.71 (0.52; 0.97) 21.41 (18.81; 24.37) 0.70 (0.33; 1.49)

Median ABR (IQR) 0.00 (0.00; 1.04) 21.13 (15.12; 27.13) 0.00 (0.00; 0.00)

Subjects with zero bleeds, % 64.7 0 76.9

Spontaneous bleeds

Mean ABR (95% CI)4 0.27 (0.18; 0.41) 15.83 (12.27; 20.43) 0.44 (0.16; 1.20)

Median ABR (IQR) 0.00 (0.00; 0.00) 16.69 (8.64; 23.76) 0.00 (0.00; 0.00)

Subjects with zero bleeds, % 80.5 3.8 84.6

Joint bleeds

Mean ABR (95% CI)4 0.51 (0.36; 0.72) 17.48 (14.88; 20.54) 0.62 (0.25; 1.52)

Median ABR (IQR) 0.00 (0.00; 1.02) 18.42 (10.80; 23.90) 0.00 (0.00; 0.00)

Subjects with zero bleeds, % 72.2 0 80.81 All analyses of bleeding endpoints are based on treated bleeds.2 Subjects assigned to receive ALTUVOCT prophylaxis for 52 weeks.3 Subjects assigned to receive ALTUVOCT for 26 weeks.4 Based on negative binomial model.

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to75th percentile.

An intra-subject comparison of ABRs during on-study and pre-study prophylaxis demonstrated astatistically significant reduction of 77% in ABR during routine prophylaxis with ALTUVOCTcompared to pre-study factor VIII prophylaxis (see Table 4).

Table 4: Intra-Subject comparison of Annualized bleeding rate (ABR) with ALTUVOCTprophylaxis versus pre-study factor VIII prophylaxis in subjects ≥ 12 years of age

On-study prophylaxis with Pre-study standard of

ALTUVOCT care50 IU/kg QW factor VIII prophylaxis2

Endpoint (N = 78) (N = 78)

Median Observation Period 50.09 (49.07; 51.18) 50.15 (43.86; 52.10)(weeks)(IQR)

Bleeds

Mean ABR (95% CI)1 0.69 (0.43; 1.11) 2.96 (2.00; 4.37)

Reduction in ABR, % (95% CI) 77 (58; 87)p-value <0.0001

Subjects with zero bleeds, % 64.1 42.3

Median ABR (IQR) 0.00 (0.00; 1.04) 1.06 (0.00; 3.74)1 Based on negative binomial model.2 Prospective observational study (OBS16221).

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to75th percentile.

An intra-subject comparison (N = 26) of ABR during the first 26 weeks of on-demand ALTUVOCTtreatment versus ABR in the following 26 weeks on weekly ALTUVOCT prophylaxis (Arm B)showed a clinically important bleeding reduction of 97% for the weekly prophylactic regimen and anincrease of subjects with zero bleeds from 0 to 76.9%.

Efficacy in control of bleeding

In the adult and adolescent study (XTEND-1), a total of 362 bleeding episodes were treated with

ALTUVOCT, most occurring during on-demand treatment in Arm B. The majority of bleedingepisodes were localized in joints. Response to the first injection was assessed by subjects at least8 hours after treatment. A 4-point rating scale of excellent, good, moderate, and no response was usedto assess response. Efficacy in control of bleeding episodes in subjects ≥ 12 years of age issummarized in Table 5. Control of bleeding episodes was similar across the treatment arms.

Table 5: Summary of efficacy in control of bleeding in subjects ≥ 12 years of age

Number of bleeding episodes (N = 362)

Number of injections to treat 1 injection 350 (96.7)bleeding episode, N (%) 2 injections 11 (3.0)> 2 injections 1 (0.3)

Median total dose to treat ableeding episode (IU/kg) (IQR) 50.93 (50.00; 51.85)

Number of evaluable injections (N = 332)

Response to treatment of a Excellent or good 315 (94.9)bleeding episode, N (%) Moderate 14 (4.2)

No response 3 (0.9)

Perioperative management of bleeding

Perioperative haemostasis was assessed in 49 major surgeries in 41 subjects (32 adults and9 adolescents and children) across Phase 3 studies. Of the 49 major surgeries, 48 surgeries required asingle pre-operative dose to maintain haemostasis during surgery; for 1 major surgery during routineprophylaxis, no pre-operative loading dose was administered on the day of/or before surgery. Themedian dose per pre-operative injection was 50 IU/kg (range 12.7 - 84.7). The mean (SD) totalconsumption and number of injections during the perioperative period (from the day before surgeryuntil Day 14 after surgery) were 171.85 (51.97) IU/kg and 3.9 (1.4), respectively.

The clinical evaluation of haemostatic response during major surgery was assessed using a 4-pointscale of excellent, good, moderate, or poor/none. The haemostatic effect of ALTUVOCT was rated as“excellent” or “good” in 48 of 49 surgeries (98%). No surgery had an outcome rated as “poor/none” or“missing”.

Types of major surgeries assessed include major orthopaedic procedures such as joint arthroplasties(joint replacements of knee, hip, and elbow), joint revisions and ankle fusion. Other major surgeriesincluded molar extractions, dental restoration and tooth extraction, circumcision, resection of vascularmalformation, hernia repair, and rhinoplasty/mentoplasty. An additional 25 minor surgeries wereevaluated; haemostasis was reported as “excellent” in all available cases.

Immunogenicity was evaluated during clinical studies with ALTUVOCT in previously treated adultsand children diagnosed with severe haemophilia A. Inhibitor development to ALTUVOCT was notdetected in clinical studies.

During Phase 3 clinical studies (median treatment duration 96.3 weeks), 4/276 (1.4%) of evaluablepatients developed transient treatment-emergent anti-drug antibodies (ADA). No evidence of ADAimpact on pharmacokinetics, efficacy or safety was observed.

Routine prophylaxis

The efficacy of weekly 50 IU/kg ALTUVOCT as routine prophylaxis in children < 12 years wasevaluated as estimated by the mean ABR. A total of 74 children (38 children < 6 years of age and36 children 6 to < 12 years of age) were enrolled to receive ALTUVOCT for routine prophylaxis at adose of 50 IU/kg intravenously once weekly for 52 weeks. In all 74 subjects, routine prophylaxisresulted in an overall mean ABR (95% CI) of 0.9 (0.6; 1.4) and a median (Q1; Q3) ABR of 0 (0; 1.0)for treated bleeds.

A sensitivity analysis (N = 73), excluding one subject who did not receive the weekly prophylaxistreatment as specified in the protocol for an extended period, showed a mean ABR (95% CI) of 0.6(0.4; 0.9) for treated bleeds [median (Q1; Q3) 0 (0; 1.0)]. 47 children (64.4%) experienced no bleedingepisode that required treatment. The mean ABR (95% CI) for treated spontaneous bleeds was 0.2 (0;0.3) [median (Q1; Q3) 0 (0; 0)]. For treated joint bleeds, the mean ABR (95% CI) was 0.3 (0.2; 0.6)and the median (Q1; Q3) was 0 (0; 0).

Control of bleeding

The efficacy in control of bleeding in children < 12 years of age was assessed in the paediatric study,excluding one subject who did not receive the weekly prophylaxis treatment as specified in theprotocol for an extended period. A total of 43 bleeding episodes were treated with ALTUVOCT.

Bleeding was resolved with a single 50 IU/kg injection of ALTUVOCT in 95.3% of bleedingepisodes. The median (Q1; Q3) total dose to treat a bleeding episode was 52.6 IU/kg (50.0; 55.8).

The pharmacokinetics (PK) of ALTUVOCT were evaluated in the Phase 3 studies XTEND-1 and

XTEND-Kids, enrolling 159 adults and adolescents, and 74 children < 12 years old, respectively,receiving weekly intravenous injections of 50 IU/kg. Among children < 12 years old, 37 subjects had

ALTUVOCT single dose PK profiles available.

Efanesoctocog alfa has demonstrated a half-life that is about 4-fold longer compared to standard half-life factor VIII products and about 2.5- to 3-fold longer compared to extended half-life factor VIIIproducts. PK parameters following a single dose of ALTUVOCT are presented in Table 6. The PKparameters were based on plasma factor VIII activity measured by the aPTT-based one-stage clottingassay. After a single dose of 50 IU/kg, ALTUVOCT exhibited high sustained factor VIII activity withprolonged half-life across age cohorts. There was a trend of increasing AUC, and decreasingclearance, with increasing age in the paediatric cohorts. The PK profile at steady state (week 26) wascomparable with the PK profile obtained after the first dose.

Table 6: Pharmacokinetic parameters following a single dose of ALTUVOCT by age(one-stage clotting assay using Actin-FSL)

PK parameters

Mean (SD) Paediatric study Adult and adolescent study1 to < 6 years 6 to < 12 years 12 to < 18 years Adults

N = 18 N = 18 N = 25 N = 134

AUC0-tau, IU*h/dL 6 800 (1 120)b 7 190 (1 450) 8 350 (1 550) 9 850 (2 010)at½z, h 38.0 (3.72) 42.4 (3.70) 44.6 (4.99) 48.2 (9.31)

CL, mL/h/kg 0.742 (0.121) 0.681 (0.139) 0.582 (0.115) 0.493 (0.121)a

Vss, mL/kg 36.6 (5.59) 38.1 (6.80) 34.9 (7.38) 31.0 (7.32)a

MRT, h 49.6 (5.45) 56.3 (5.10) 60.0 (5.54) 63.9 (10.2)a

Cmax, IU/dL 143 (57.8) 113 (22.7) 118 (24.9) 133 (33.8)

Incremental Recovery, 2.81 (1.1) 2.24 (0.437) 2.34 (0.490) 2.64 (0.665)

IU/dL per IU/kga Calculation based on 128 profiles.b N = 17

AUC0-tau = area under the activity-time curve over the dosing interval, CL = clearance, MRT = meanresidence time, SD = standard deviation, t½z = terminal half-life, Vss = volume of distribution at steadystate, Cmax = maximum activity

In XTEND-1, ALTUVOCT at steady state maintained normal to near normal (> 40 IU/dL) factor VIIIactivity for a mean (SD) of 4.1 (0.7) days with once weekly prophylaxis in adults. The factor VIIIactivity over 10 IU/dL was maintained in 83.5% of adults and adolescent subjects throughout thestudy. In children < 12 years, weekly ALTUVOCT at steady state maintained normal to near normal(> 40 IU/dL) factor VIII activity for 2 to 3 days and > 10 IU/dL factor VIII activity for approximately7 days (see Table 7).

Table 7: Pharmacokinetic parameters at steady state of ALTUVOCT by age (one-stageclotting assay using Actin-FSL)

PK parameters

Mean (SD) Paediatric studya Adult and adolescent studya1 to < 6 years 6 to < 12 years 12 to < 18 years Adults

N = 37 N = 36 N = 24 N = 125

Peak, IU/dL 136 (48.9) 131 (36.1) 124 (31.2) 150 (35.0)(N = 35) (N = 35) (N = 124)

Incremental Recovery, 2.22 (0.83) 2.10 (0.73) 2.25 (0.61) 2.64 (0.61)

IU/dL per IU/kg (N = 35) (N = 35) (N = 22) (N = 120)

Time to 40 IU/dL, h 68.0 (10.5)b 80.6 (12.3)b 81.5 (12.1)c 98.1 (20.1)c

Time to 20 IU/dL, h 109 (14.0)b 127 (14.5)b 130 (15.7)c 150 (27.7)c

Time to 10 IU/dL, h 150 (18.2)b 173 (17.1)b 179 (20.2)c 201 (35.7)c

Trough, IU/dL 10.9 (19.7) 16.5 (23.7) 9.23 (4.77) 18.0 (16.6)(N = 36) (N = 22) (N = 123)a Steady state peak, trough and incremental recovery were computed using available measurements atweek 52/end of study PK sampling visit.b Time to factor VIII activity was predicted using a population PK model for paediatric patients.c Time to factor VIII activity was predicted using a population PK model for adult patients.

Peak = 15 min post dose at steady state, Trough = predose factor VIII activity value at steady state,

SD = standard deviation

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies in ratsand monkeys (including measurements of safety pharmacology) and an in vitro haemocompatibilitystudy. Studies to investigate genotoxicity, carcinogenicity toxicity to reproduction or embryo-foetaldevelopment have not been conducted.

Sucrose

Calcium chloride dihydrate (E 509)

Histidine

Arginine hydrochloride

Polysorbate 80 (E 433)

Water for injections

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

Only the provided adapter and infusion set should be used because treatment failure can occur as aconsequence of coagulation factor VIII adsorption to the internal surface of some injection equipment.

Unopened vial4 years

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

The medicinal product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

Each pack of ALTUVOCT 250 IU, 500 IU, 750 IU 1 000 IU, 2 000 IU, 3 000 IU and 4 000 IU powderand solvent for solution for injection contains:

- a glass vial (type I) with powder and chlorobutyl rubber stopper- a sterile vial adapter for reconstitution- a pre-filled glass syringe of 3 mL solvent with a bromobutyl rubber plunger stopper- a plunger rod- a sterile infusion set

ALTUVOCT is to be administered intravenously after reconstitution of the powder with the solventsupplied in the syringe. The vial should be gently swirled until all of the powder is dissolved. Afterreconstitution the solution should be clear and colourless to slightly opalescent. Do not use solutionsthat are cloudy or have deposits.

Always use an aseptic technique.

Additional information on reconstitution

ALTUVOCT is administered by intravenous injection after dissolving the powder for injection withthe solvent supplied in the pre-filled syringe. ALTUVOCT pack contains:

A. Powder B. 3 mL C. Plunger D. Vial E. Infusion setvial solvent in rod adaptorpre-filledsyringe

You will also need sterile alcohol swabs (F). This device is not included in the ALTUVOCT package.

To draw up the solution from multiple vials into a single syringe you may use a separate large syringe(G). If a large syringe is not available, follow steps 6 to 8 to administer the solution from each syringe.

F. Alcohol swabs G. Large Syringe

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

Wash your hands before opening the pack.

Reconstitution1. Prepare the vial

a. Remove the vial cap

Hold the powder vial (A) on a clean flat surface and remove theplastic cap.

b. Clean vial top

Wipe the top of the vial with an alcohol swab.

After cleaning, ensure nothing touches the top of the vial.

c. Open vial adapter package

Peel off the protective paper lid from the vial adapter package (D).

Do not touch the vial adapter, or remove it from its package.

d. Attach vial adapter

Place the vial adapter package squarely over the top of the vial.

Press down firmly until the adapter snaps into place. The spike willpenetrate the vial stopper.

2. Prepare the syringe

a. Attach plunger rod

Insert the plunger rod (C) into the 3 mL syringe (B). Turn the plungerrod clockwise until it is securely attached.

b. Remove syringe cap

Snap off the top part of white 3 mL syringe cap at the perforations andset aside.

Do not touch the inside of cap or the syringe tip.

3. Attach syringe to vial

a. Remove vial adapter package

Lift the package away from the vial adapter and dispose.

b. Attach syringe to vial adapter

Hold the vial adapter at the lower end. Place the syringe tip onto thetop of the vial adapter. Turn the syringe clockwise to securely attach.

4. Dissolve the powder and solvent

a. Add solvent to vial

Slowly press the plunger rod to inject all the solvent into the vial.

b. Dissolve powder

With your thumb on the plunger rod, gently swirl the vial untilpowder is dissolved.

Do not shake.

c. Inspect solution

Inspect the solution before administration. It should be clear and colourless.

Do not use the solution if cloudy or contains visible particles.

5. If using multiple vials

If your dose requires multiple vials, follow the steps below (5a and 5b) otherwise skip tostep 6.

a. Repeat 1 to 4

Repeat steps 1 to 4 with all vials until you have prepared enoughsolution for your dose.

Remove the 3 mL syringes from each vial (see step 6b), leaving thesolution in each vial.

b. Using large syringe (G)

For each vial, attach the large syringe (G) to the vial adapter (see step3b) and perform step 6, to combine the solution from each vial intothe large syringe. In case you only need part of an entire vial, use thescale on the syringe to see how much solution you withdraw.

6. Draw solution into syringe

a. Draw back solution

Point the syringe up. Slowly pull the plunger rod to draw all thesolution into the syringe.

b. Detach syringe

Detach the syringe from the vial by holding the vial adapter. Turn thesyringe anticlockwise to detach.

It is recommended to use ALTUVOCT immediately after reconstitution (see section 6.3).

Administration7. Prepare for injection

a. Remove tubing cap

Open infusion set (E) packaging (do not use if damaged).

Remove the tubing cap.

Do not touch the exposed end of the tubing set.

b. Attach syringe

Attach prepared syringe to the end of the infusion set tubing byturning the syringe clockwise.

c. Prepare injection site

If needed apply a tourniquet. Wipe injection site with an alcoholswab (F).

d. Remove air from syringe and tubing

Remove air by pointing the syringe up and gently pressing theplunger rod. Do not push the solution through the needle.

Injecting air into the vein can be dangerous.

8. Inject solution

a. Insert needle

Remove protective needle cover.

Insert the needle into a vein and remove the tourniquet if used.

You may use a plaster to hold the plastic wings of the needle in place at the injection siteto prevent movement.

b. Inject solution

The prepared solution should be injected intravenously over 1 to 10 minutes, based on thepatient’s comfort level.

9. Dispose safely

a. Remove needle

Remove the needle. Fold over the needle protector; it should snapinto place.

b. Safe disposal

Ensure all used components in the provided kit (other than packaging) is safely dispose of in amedical waste container.

Do not reuse equipment.

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

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/24/1824/001

EU/1/24/1824/002

EU/1/24/1824/003

EU/1/24/1824/004

EU/1/24/1824/005

EU/1/24/1824/006

EU/1/24/1824/007

Date of first authorisation: 17 June 2024

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

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