ESPEROCT 500UI powder + solvent for injection medication leaflet

Esperoct 500 IU powder and solvent for solution for injection

Esperoct 1 000 IU powder and solvent for solution for injection

Esperoct 1 500 IU powder and solvent for solution for injection

Esperoct 2 000 IU powder and solvent for solution for injection

Esperoct 3 000 IU powder and solvent for solution for injection

Esperoct 4 000 IU powder and solvent for solution for injection

Esperoct 5 000 IU powder and solvent for solution for injection

Esperoct 500 IU powder and solvent for solution for injection

Each powder vial contains nominally 500 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 125 IU turoctocog alfa pegol.

Esperoct 1 000 IU powder and solvent for solution for injection

Each powder vial contains nominally 1 000 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 250 IU turoctocog alfa pegol.

Esperoct 1 500 IU powder and solvent for solution for injection

Each powder vial contains nominally 1 500 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 375 IU turoctocog alfa pegol.

Esperoct 2 000 IU powder and solvent for solution for injection

Each powder vial contains nominally 2 000 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 500 IU turoctocog alfa pegol.

Esperoct 3 000 IU powder and solvent for solution for injection

Each powder vial contains nominally 3 000 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 750 IU turoctocog alfa pegol.

Esperoct 4 000 IU powder and solvent for solution for injection

Each powder vial contains nominally 4 000 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 1 000 IU turoctocog alfa pegol.

Esperoct 5 000 IU powder and solvent for solution for injection

Each powder vial contains nominally 5 000 IU turoctocog alfa pegol*.

After reconstitution, 1 mL of solution contains approximately 1 250 IU turoctocog alfa pegol.

The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specificactivity of turoctocog alfa pegol is approximately 9500 IU/mg protein.

The active substance turoctocog alfa pegol is a covalent conjugate of the protein turoctocog alfa* witha 40 kDa polyethylene glycol (PEG).

*Human factor VIII, produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO)cell line, and no additives of human or animal origin are used in the cell culture, purification,conjugation or formulation of Esperoct.

Each reconstituted vial contains 30.5 mg of sodium (see section 4.4).

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white to off-white.

The solvent is clear and colourless.

pH: 6.9.

Osmolality: 590 mOsmol/kg.

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

Esperoct can be used for all age groups.

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

During the course of treatment, appropriate determination of factor VIII activity levels is advised toguide adjustments of the dosing regimen of Esperoct, if needed. Individual patients may vary in theirresponse to factor VIII, demonstrating different half-lives and incremental recoveries. Dose based onbodyweight may require adjustment in underweight or overweight patients. In the case of majorsurgical interventions, monitoring of the factor VIII substitution therapy by measurement of plasmafactor VIII activity is necessary.

The factor VIII activity of Esperoct can be measured using the conventional factor VIII assays, thechromogenic assay and the one-stage assay.

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.

When using a one-stage clotting assay some silica based reagents should be avoided as they causeunderestimation. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importanceparticularly when changing the laboratory and/or reagents used in the assay.

The dose, dosing interval and duration of the substitution therapy depend on the severity of thefactor VIII deficiency, on the location and extent of the bleeding, on the targeted factor VIII activitylevel and the patient’s clinical condition. The number of units of factor VIII administered is expressedin International Units (IU), which is related to the current WHO concentrate standard for factor VIIIproducts. The activity of factor VIII in plasma is expressed either as percentage (relative to normalhuman plasma level) or in International Units per dL (relative to the current International Standard forfactor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one mlof human plasma.

On demand treatment and treatment of bleeding episodes

The calculation of the required dose of factor VIII is based on the empirical finding that1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by2 IU/dL.

The required dose is determined using the following formula:

Required units (IU) = 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 theclinical effectiveness in the individual case.

Guidance for the dosing of Esperoct for the on-demand treatment and treatment of bleeding episodesis provided in table 1. Plasma factor VIII activity levels should be maintained at or above thedescribed plasma levels (in IU per dL or % of normal). For treatment of bleeds a maximum singledose of Esperoct at 75 IU/kg and a maximum total dose of 200 IU/kg/24 hours may be administered.

Table 1 Guidance for treatment of bleeding episodes with Esperoct

Degree of haemorrhage Factor VIII level Frequency of Duration of therapyrequired (IU/dL doses (hours)or % ofnormal)a

Mild 20-40 12-24 Until the bleeding is resolved

Early haemarthrosis, mildmuscle bleeding or mildoral bleeding

Moderate 30-60 12-24 Until the bleeding is resolved

More extensivehaemarthrosis, musclebleeding, haematoma

Severe or 60-100 8-24 Until the threat is resolvedlife-threateninghaemorrhagesa The required dose is determined using the following formula:

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

Perioperative management

The dose level and dosing intervals for surgery depend on the procedure and local practice. Amaximum single dose of Esperoct at 75 IU/kg and a maximum total dose of 200 IU/kg/24 hours maybe administered.

The frequency of doses and duration of therapy should always be individually adjusted based onindividual clinical response.

Table 2 includes general recommendation for dosing of Esperoct for perioperative management.

Consideration should be given to maintain a factor VIII activity at or above the target range.

Table 2 Guidance for dosing of Esperoct for perioperative management

Type of surgical Factor VIII Frequency of doses (hours) Duration of therapyprocedure level required(%) (IU/dL)a

Minor surgery 30-60 Within one hour before Single dose or repeat injection

Including tooth surgery every 24 hours for at least 1 dayextraction until healing is achieved

Repeat after 24 hours ifnecessary

Major surgery 80-100 Within one hour before Repeat injection every 8 to(pre- and surgery to achieve factor VIII 24 hours as necessary untilpost-operative) activity within the target adequate wound healing isrange achieved

Repeat every 8 to 24 hours to Consider to continue therapy formaintain factor VIII activity another 7 days to maintain awithin the target range factor VIII activity of 30% to60% (IU/dL)a The required dose is determined using the following formula:

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

The recommended dose for adults is 50 IU of Esperoct per kg body weight every 4 days.

Adjustments of doses and administration intervals may be considered based on achieved factor VIIIlevels and individual bleeding tendency.

The recommended dose in adolescents (12 years and above) is the same as for adults.

The recommended dose for prophylaxis in children below 12 years is 65 IU per kg body weight(50-75 IU/kg) administered twice weekly. Adjustments of doses and administration intervals may beconsidered based on achieved factor VIII levels and individual bleeding tendency.

For more details on paediatrics, see sections 4.4, 5.1 and 5.2.

Esperoct is for intravenous use.

Esperoct should be administered by intravenous injection (over approximately 2 minutes) afterreconstitution of the powder with 4 mL supplied solvent (sodium chloride 9 mg/mL (0.9%) solutionfor injection).

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.

Known allergic reaction to hamster protein.

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 are possible with Esperoct. The product contains traces ofhamster proteins, which in some patients may cause allergic reactions. If symptoms of hypersensitivityoccur, patients should be advised to immediately discontinue the use of the medicinal product andcontact their physician. Patients should be informed of the early signs of hypersensitivity reactionsincluding 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 first 50exposure 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 titreposing 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.

Decreased factor VIII activity in previously treated patients

From post marketing reports, a decreased factor VIII activity in the absence of detectable factor VIIIinhibitors has been reported in previously treated patients (PTPs). The decreased factor VIII activitywas observed at time of switching to Esperoct and may, in some cases, have been associated with anti-

PEG antibodies. Appropriate determination of factor VIII activity upon switching should beconsidered.

See section 4.8 for additional information.

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, the risk of CVAD-related complicationsincluding local infections, bacteraemia and catheter site thrombosis should be considered.

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

Decreased factor VIII incremental recovery in previously untreated patients

In 31 out of 59 previously untreated patients (PUPs), decreased factor VIII incremental recovery (IR)has been observed in the absence of detectable factor VIII inhibitors in clinical trials. Out of these, 14patients had only a single measurement of low IR, while 17 patients had 2 or more consecutively low

IRs occurring within 5 to 10 EDs. Decreased IR was temporary and returned to > 0.6 (IU/dL)/(IU/kg)between 15 to 70 EDs. The decreased IR was observed with increasing anti-PEG IgG titers in PUPswithout inhibitors to factor VIII. Consecutive low IR could potentially be associated with reducedefficacy during this time period. Monitoring of paediatric patients, including monitoring of post dosefactor VIII activity, is recommended. If a bleeding is not controlled with the recommended dose of

Esperoct and/or the expected Factor VIII activity levels are not attained in the absence of FVIIIinhibitors, consider adjusting the dose, dosing frequency or discontinuing the product.

Excipient-related considerations

This medicinal product contains 30.5 mg sodium per reconstituted vial, equivalent to 1.5% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

No interactions of human coagulation factor VIII (rDNA) with other medicinal products have beenreported.

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.

Esperoct 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 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).

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions hasbeen observed.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with Esperoct. If such inhibitors occur, the condition will manifest itself asan insufficient clinical response. In such cases, it is recommended that a specialised haemophiliacentre is contacted.

The frequencies of adverse reactions as observed across six clinical studies in a total of 270 PTPs and81 PUPs with severe haemophilia A (< 1% endogenous factor VIII activity) and no history ofinhibitors are listed in table 3. The categories of adverse reactions presented in table 3 is according tothe 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), veryrare (< 1/10 000); not known (cannot be estimated from the available data).

Table 3 Frequency of adverse drug reactions in clinical studies

System Organ Class Preferred term Frequency (PTPs) Frequency (PUPs)

Blood and lymphatic Factor VIII inhibition* Uncommon Very common**system disorders

Skin and subcutaneous Pruritus Common -tissue disorders Erythema Common Common

Rash Common Common

General disorders and Injection site reaction*** Common Commonadministration siteconditions

Immune system disorders Drug hypersensitivity - Common

Hypersensitivity Uncommon -

Investigations Coagulation factor VIII Not known**** -level decreased

* The confirmed factor VIII inhibitor patient was identified by an initial inhibitor test result of ≥ 0.6 Bethesda units (BU) confirmed in asecond sample taken no more than 2 weeks later.

** Covering confirmed factor VIII inhibitor patients in patients at risk (with at least 10 exposure days).

*** Preferred terms included in injection site reactions: Injection site reaction, Vessel puncture site haematoma, Infusion site reaction,

Injection site erythema, Injection site rash, Vessel puncture site pain, and Injection site swelling.

**** Based on post marketing reports.

Factor VIII inhibitors

One confirmed case of factor VIII inhibitor occurred in an 18 year-old previously treated patient onprophylactic treatment with Esperoct. The patient had a factor VIII gene intron 22 inversion and wasat a high risk of developing factor VIII inhibitors.

There is no indication of an increased risk of factor VIII inhibitor development with treatment of

Esperoct as compared to other factor VIII products.

Anti-drug antibodies

There was one case of persistent anti-drug antibodies concomitant with the confirmed case offactor VIII inhibitors (see Factor VIII inhibitors above). Three patients had transiently positive testresults for anti-drug antibodies after administration of Esperoct but no correlation with adverse eventscould be established.

Anti-PEG antibodies

During the clinical study programme, thirty-seven patients had pre-existing anti-PEG antibodiesbefore administration of Esperoct. Twenty of the 37 patients were negative for anti-PEG antibodiespost administration of Esperoct. Seventeen patients developed transient low titre anti-PEG antibodies.

No correlation with adverse events could be established.

From post-marketing reporting, occurrence of anti-PEG-antibodies has also been observed at time ofswitching to Esperoct. In some patients anti-PEG antibodies may have been associated with lower thanexpected level of FVIII activity.

No difference in the safety profile was observed between previously treated children and adultpatients.

In some PUPs, temporary decreased factor VIII IR has been observed in the absence of detectablefactor VIII inhibitors (see section 4.4 for more details).

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 recombinant coagulation factor VIII have been reported.

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

Turoctocog alfa pegol is a purified recombinant human factor VIII (rFVIII) product with a 40 kDapolyethylene-glycol (PEG) conjugated to the protein. The PEG is attached to the O-linked glycan inthe truncated B-domain of rFVIII (turoctocog alfa). The mechanism of action of turoctocog alfa pegolis based on the replacement of the deficient or absent factor VIII in patients with haemophilia A.

When turoctocog alfa pegol is activated by thrombin at the site of injury, the B-domain containing the

PEG moiety and the a3-region are cleaved off, thus generating activated recombinant factor VIII(rFVIIIa) which is similar in structure to native factor VIIIa.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von

Willebrand factor) with different physiological functions. When injected into a haemophiliac patient,factor VIII binds to von Willebrand factor in the patient’s circulation. Activated factor VIII acts as acofactor for activated factor IX, accelerating the conversion of factor X to activated factor X.

Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrinand a clot can be formed. Haemophilia A is a X-linked hereditary disorder of blood coagulation due todecreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs,either spontaneously or as results of accidental or surgical trauma. By factor VIII replacement therapythe plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factordeficiency and correction of the bleeding tendencies.

Clinical efficacy during prophylaxis and treatment of bleeding episodes

The clinical efficacy of Esperoct for prophylaxis and treatment of bleeds was investigated in sevenprospective, multi-centre clinical studies. All patients had severe haemophilia A.

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

Prophylaxis in adults/adolescents

The efficacy of Esperoct for prophylaxis and treatment of bleeds was evaluated in an open-label,non-controlled study in adolescents and adult patients with severe haemophilia A ages 12 years andabove. The prophylactic effect of Esperoct was demonstrated with a dosing at 50 IU per kg bodyweight every 4 days or every 3-4 days (twice weekly) in 175 patients. The median annualizedbleeding rate (ABR) in adults and adolescents receiving Esperoct was 1.18 (Interquartile range IQR:0.00;4.25), whereas the spontaneous ABR was 0.00 (IQR: 0.00;1.82), traumatic ABR was 0.00 (IQR:0.00;1.74) and joint ABR was 0.85 (IQR: 0.00;2.84). When including imputations, (replacing missingdata for withdrawn patients with a substituted value) the estimated mean ABR for all bleeds was3.70 (95% CI: 2.94;4.66). Of the 175 adults/adolescents on prophylaxis, 70 (40%) did not have anybleeds. The mean annual consumption for prophylaxis was 4 641 IU/kg.

Adults/adolescents who had a low bleeding rate of 0-2 bleeding episodes during the last 6 months andhad obtained at least 50 doses of Esperoct had the option of being randomised to prophylaxis treatmentevery 7 days (75 IU/kg every 7 days) or every 4 days (50 IU/kg every 4 days). A total of 55 of the 120eligible patients chose to be randomised (17 to the every 4 days dosing and 38 to the 75 IU every7 days). The ABR for randomised patients was 1.77 (0.59;5.32) for treatment every 4 days and 3.57(2.13;6.00) for once weekly prophylaxis. Nine of these patients reverted back to prophylaxis every4 days during the randomised study phase. Overall, including all extensions parts, 31 of 61 patients onevery 7 days prophylaxis switched back to every 4 days treatment.

Prophylaxis in previously treated patients (PTPs) (below 12 years)

The efficacy and safety of Esperoct for prophylaxis and on-demand treatment of bleeding episodeswere evaluated in an open-label, single-arm, non-controlled study in 68 children below 12 years withsevere haemophilia A. The prophylactic effect of Esperoct was demonstrated with a mean prophylacticdose of 64.7 IU per kg body weight twice weekly. The median and estimated mean annualizedbleeding rate in children below 12 years receiving Esperoct twice weekly was 1.95 and 2.13 (95% CI:1.48;3.06), whereas the spontaneous ABR was 0.00 and 0.58 (95% CI: 0.24;1.40), traumatic ABR was0.00 and 1.52 (95% CI: 1.07;2.17) and joint ABR was 0.00 and 1.03 (95% CI: 0.59;1.81), respectively.

Of the 68 children below 12 years on prophylaxis, 29 (42.6%) did not have any bleeds.

The mean annual consumption for prophylaxis was 6 475 IU/kg.

Due to the long duration of the study, several patients crossed the age-group to which they wereinitially enrolled: some < 6 years also contributed to the age category of 6-11 years and some 6-11 years age group had progressed to the adolescent age category. Main efficacy results in patients< 12 years separated by main and extension phase are summarised in table 4.

Table 4 Annualised Bleeding Rate (ABR) in the paediatric PTPs study by actual age-groups (main and extension phase) - full analysis set

Main Phase Extension Phase

Age of patient* 0-5 years 6-11 years 0-5 years 6-11 years(N=34) (N=34) (N=27) (N=53)

Number of bleeds 30 32 41 134

Mean treatment period(years) 0.46 0.51 4.79 4.86

Total ABR

Poisson-estimated mean 1.94 1.84 0.32 0.52(95% CI) (1.12; 3.36) (1.08; 3.13) (0.15; 0.66) (0.35; 0.78)

Median 1.94 1.94 0.22 0.21(IQR) (0.00; 2.08) (0.00; 2.08) (0.00; 0.44) (0.00; 0.64)

*some patients contributed to both age groups

Prophylaxis in previously untreated patients (PUPs) (below 6 years)

The efficacy and safety of Esperoct were evaluated in a multi-national, non-randomised, open labelphase 3 study. Pre-prophylaxis (optional on-demand treatment for bleeding episodes and/or dosing of60 IU/kg at intervals longer than a week until the subject reached 20 exposure days (EDs) or turned24 months of age) and prophylaxis treatment of bleeds were evaluated in 81 PUPs below 6 years withsevere haemophilia A. Of the total 81 patients, 55 patients started on pre-prophylaxis and 42 of thosepatients then switched to prophylaxis. In total, 69 patients received prophylaxis with a meanprophylactic dose of 68.9 IU per kg body weight twice weekly.

The prophylactic effect of Esperoct in PUPs below 6 years with severe haemophilia A wasdemonstrated with a median and estimated mean annualized bleeding rate of 1.35 and 1.76 (95% CI:1.26;2.46).

The mean annual consumption for the 69 PUPs on prophylaxis was 5 395 IU/kg.

Main efficacy results in PUPs on prophylaxis separated by main and extension phase are summarisedin table 5.

Table 5 Annualised Bleeding Rate (ABR) in the paediatric PUPs study (main and extensionphase) - full analysis set

Main Phase Extension Phase(N=69) (N=55)

Number of bleeds 124 223

Mean treatment period (years) 0.60 2.83

Total ABR

Poisson-estimated mean (95% CI) 2.98(2.16; 4.10) 1.43 (0.98; 2.10)

Median (IQR) 2.49(0.00; 5.22) 0.73 (0.00; 2.57)

In the study, a total of 56 adverse reactions in 43 of 81 patients and a total of 80 serious adverse eventsin 48 patients were reported after exposure to Esperoct.

In 31 out of 59 PUPs without inhibitors, temporary decreased factor VIII IR has been observed afterexposure to Esperoct. There were 17 PUPs with consecutive measurements of decreased IR, all ofthese subjects had anti-PEG IgG antibodies. An association between anti-PEG antibodies and low IRcannot be excluded.

Clinical efficacy of Esperoct in treatment of bleeding episodes and during on-demand treatment

The efficacy of Esperoct in the treatment of bleeding episodes was demonstrated for all PTP agegroups. The vast majority of bleeds treated with Esperoct were of mild/moderate severity.

The overall haemostatic success rate for the treatment of bleeds in PTPs was 84.4%.

The haemostatic success rates per age groups in PTPs were 89.4% (0−5 years), 82.6% (6−11 years),78.9% (12−17 years) and 84.9% (≥ 18 years), respectively; and 94.2% of all bleeds were resolved with1−2 injections.

The efficacy of Esperoct in the treatment of bleeding episodes was demonstrated in PUPs < 6 years ofage. The overall haemostatic success rate was 91.9%; and 93.3% of the successfully treated bleedswere resolved with 1−2 injections.

In the pivotal study, 12 patients above 18 years of age chose to stay on on-demand treatment. In thesepatients, 1 270 bleeds were treated with an average treatment dose of 37.5 IU/kg (20−75 IU/kg). 97%of the total bleeds were effectively treated with 1-2 injections of Esperoct.

Clinical efficacy of Esperoct during surgery

Haemostatic effect of Esperoct in surgical procedures was assessed in four studies, of which one was adedicated surgery study.

In the dedicated surgery study, 49 major surgeries were performed in 35 previously treated adolescentand adult patients. On the day of surgery, patients received a pre-surgery mean dose of 55.7 IU/kg(range: 27.2−86.2 IU/kg) and post-surgery mean dose was 30.7 IU/kg (range: 10.1−58.8 IU/kg). Theoverall haemostatic success rate of Esperoct during major surgery was 95.9%, with the haemostaticefficacy rated as excellent or good in 47 of 49 major surgeries performed.

In two studies with previously treated children (aged < 12 years), 24 patients underwent 46 surgeries,of which only 1 surgery was categorized as major, with a successful haemostatic response. The minorsurgeries in these patients were without any complications though haemostatic efficacy and FVIIIlevels were not monitored during these surgeries. In 26 previously untreated children (aged < 6 years)in the PUP study, a successful haemostatic effect was reported for all 4 major surgeries, and 25 of the30 minor surgeries. Esperoct was administered at the investigators’ discretion in accordance with thedosing recommendations.

In total, 129 single-dose pharmacokinetic (PK) profiles of Esperoct were evaluated in 86 patients(including 24 paediatric patients of 0 to below 12 years).

All pharmacokinetic studies with Esperoct were conducted in previously treated patients with severehaemophilia A (factor VIII < 1%). Patients received a single dose of 50 IU/kg, and blood sampleswere collected prior to dosing and at multiple time points up to 96 hours after dosing.

The half-life of Esperoct was 1.6 fold longer compared to non-PEGylated factor VIII products inadults.

A total of 108 single dose pharmacokinetic profiles at 50 IU/kg Esperoct were evaluated in69 patients. The single dose pharmacokinetic parameters are comparable between young children (0 tobelow 6 years) and older children (6 to below 12 years), and between adolescents (12 to 17 years) andadults (18 years and above).

As expected incremental recovery appeared to be lower while body weight adjusted clearanceappeared to be higher in children compared to adults and adolescents. In general, there was a trend ofincreasing incremental recovery and decreasing clearance (mL/h/kg) with age. This corresponds to ahigher volume of distribution per kilo body weight in children compared to adults (table 6).

The single dose pharmacokinetic parameters determined after 28 weeks of prophylactic treatment with

Esperoct were consistent with the initial pharmacokinetic parameters.

Single-dose pharmacokinetic parameters of Esperoct are listed in table 6.

Table 6 Single-dose pharmacokinetic parameters of Esperoct 50 IU/kg in PTPs by ageusing the chromogenic assay (geometric mean [CV%])

PK Parameter 0 to below 6 to below 12 to below 18 years and6 years 12 years 18 years above(N=13) (N=11) (N=3) (N=42)

Number of profiles 13 11 5 79

IR (IU/dL) per 1.80 (29) 1.99 (25) 2.79 (12) 2.63 (22)(IU/kg)a

Maximum 101.2 (28) 119.6 (25) 133.2 (9) 134.4 (23)factor VIII activity(IU/dL)at1/2 (hours) 13.6 (20) 14.2 (26) 15.8 (43) 19.9 (34)

P K Parameter 0 to below 6 to below 12 to below 18 years and6 years 12 years 18 years above(N=13) (N=11) (N=3) (N=42)

AUCinf 2 147 (47) 2 503 (42) 3 100 (44) 3 686 (35)(IU*hour/dL)

CL (mL/hour/kg) 2.6 (45) 2.4 (40) 1.5 (43) 1.4 (32)

Vss (mL/kg) 44.2 (34) 41.2 (25) 33.4 (10) 37.7 (27)

MRT (hours) 17.0 (22) 17.3 (31) 21.7 (45) 25.2 (29)b

Abbreviations: AUC = area under the factor VIII activity time profile; t1/2 = terminal half-life; MRT = mean residence time; CL = clearance;

Vss = volume of distribution at steady-state; IR = Incremental recovery.a Incremental recovery and factor VIII were assessed 30 min post-dosing for patients 12 years and above and 60 min post-dosing (firstsample) for children below 12 years.b Calculation based on 67 profiles.

In the paediatric PUP trial, IR was assessed in 46 patients below 6 years of age after firstadministration, with a geometric mean (CV%) of 1.76 (34) [IU/dL]/[IU/kg]. In 17 out of 59 PUPswithout inhibitors, consecutive measurements (i.e., 2 or more) of temporary decreased IR occurredwithin 5 to 10 EDs (see section 4.4 for more details).

The mean trough FVIII activity for PTPs and PUPs by age are summarised in table 7.

Table 7 Estimated mean trough FVIII activity in PTPs and PUPs by age

PTPs PTPs PUPs

Trough FVIII activity 60 IU/kg Esperoct 50 IU/kg Esperoct 60 IU/kgprophylaxis twice prophylaxis every 4th Esperoctweekly day prophylaxistwice weekly

Age groups at baseline 0- 6- 12-17 years ≥ 18 years 0-5 years5 years 11 years

Number of patients 31 34 23 143 81contributing to theanalysis

Number of trough values 144 161 112 722 355included in the analysis

Number of trough values 62 43 16 107 128abelow LLOQ

Mixed model resultsb:

Mean trough FVIII 1.2 2.0 2.7 3.0 1.5activity (IU/dL) 0.8; 1.6 1.5; 2.7 1.8; 4.0 2.6; 3.5 1.1; 1.995% CI

Abbreviations: LLOQ = lower limit of quantificationa Plasma activities below lower limit of quantification (LLOQ) of 0.009 IU/mL are set to half of LLOQ (0.0045 IU/mL).b Mixed model on the log-transformed plasma FVIII activities with age group as fixed effect and patient as a random effect. Separatemodelling is done for each prophylaxis treatment (i.e. for each dosing frequency). The trough level is presented back-transformed to thenatural scale.

Only pre-dose measurements collected at steady state for the given prophylaxis treatment are included in the analyses.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity.

Sodium chloride

L-Histidine

Sucrose (E 473)

Polysorbate 80 (E 433)

L-Methionine

Calcium chloride dihydrate

Sodium hydroxide (for pH adjustment) (E 524)

Hydrochloric acid (for pH adjustment) (E 507)

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts or reconstituted with injection solutions other than the provided sodium chloride solvent.

The reconstituted product should not be administered in the same tubing or container with othermedicinal products.

Unopened vial (before reconstitution):

3 years when stored in a refrigerator (2 °C - 8 °C).

During the shelf life the product may be kept:

* at room temperature (≤ 30 °C) for a single period no longer than 1 yearor

* above room temperature (> 30 °C up to 40 °C) for a single period no longer than 3 months

Once the product has been stored outside of the refrigerator, the product must not be returned forstorage in the refrigerator.

Record the beginning of storage outside refrigerator and the storage temperature in the space providedon the carton.

After reconstitution (500 IU, 1 000 IU, 1 500 IU, 2 000 IU, 3 000 IU)

Chemical and physical in-use stability have been demonstrated for:

* 24 hours when stored in a refrigerator (2 °C - 8 °C) or

* 4 hours at ≤ 30 °C or

* 1 hour between ˃ 30 °C and 40 °C, only if the product was stored above room temperature(˃ 30 °C up to 40 °C) before reconstitution for no longer than 3 months.

After reconstitution (4 000 IU, 5 000 IU)

Chemical and physical inuse stability have been demonstrated for:

* 24 hours when stored in a refrigerator (2 °C - 8 °C) or

* 4 hours at ≤ 30 °C.

From a microbiological point of view, the product should be used immediately after reconstitution. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of theusers and would normally not be recommended for longer than as stated above, unless reconstitutionhas taken place in controlled and validated aseptic conditions.

The reconstituted solution should be stored in the vial.

Store in a refrigerator (2 °C - 8 °C). Do not freeze.

Store in the original package in order to protect from light.

Applicable for 500 IU, 1 000 IU, 1 500 IU, 2 000 IU, 3 000 IU

For storage at room temperature (≤ 30 °C or up to 40 °C) and storage conditions after reconstitution ofthe medicinal product, see section 6.3.

Applicable for 4 000 IU, 5 000 IU

For storage at room temperature (≤ 30 °C) and storage conditions after reconstitution of the medicinalproduct see section 6.3.

Each pack of Esperoct contains:

- 1 glass vial (type I) with powder closed with a chlorobutyl rubber stopper, an aluminium sealwith a plastic snap-off cap- 1 sterile vial adapter for reconstitution- 1 pre-filled syringe of 4 mL solvent with backstop (polypropylene), a rubber plunger(bromobutyl) and a rubber tip cap (bromobutyl)- 1 plunger rod (polypropylene).

Esperoct is to be administered intravenously after reconstitution of the powder with the solventsupplied in the syringe. After reconstitution the solution appears as a clear and colourless liquid free ofvisible particles. The reconstituted medicinal product should be inspected visually for particulatematter and discolouration prior to administration. The solution should be clear and colourless. Do notuse solutions that are cloudy or have deposits.

For instructions on reconstitution of the medicinal product before administration, see the packageleaflet.

The rate of administration should be determined by the patient’s comfort level over approximately2 minutes.

An infusion set (butterfly needle with tubing), sterile alcohol swabs, gauze pads and plasters will alsobe needed. These devices are not included in the Esperoct package.

Always use an aseptic technique.

After the injection, safely dispose of the syringe with the infusion set and the vial with the vial adapter.

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

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/19/1374/001

EU/1/19/1374/002

EU/1/19/1374/003

EU/1/19/1374/004

EU/1/19/1374/005

EU/1/19/1374/006

EU/1/19/1374/007

Date of first authorisation: 20 June 2019

Date of latest renewal: 09 February 2024

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

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