ADYNOVI 3000UI / 5ml powder + solvent for injection medication leaflet

ADYNOVI 250 IU/5 ml powder and solvent for solution for injection

ADYNOVI 500 IU/5 ml powder and solvent for solution for injection

ADYNOVI 1 000 IU/5 ml powder and solvent for solution for injection

ADYNOVI 2 000 IU/5 ml powder and solvent for solution for injection

ADYNOVI 3 000 IU/5 ml powder and solvent for solution for injection

ADYNOVI 250 IU/5 ml powder and solvent for solution for injection

Each vial contains nominally 250 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol,corresponding to a concentration of 50 IU/ml after reconstitution with 5 ml solvent.

ADYNOVI 500 IU/5 ml powder and solvent for solution for injection

Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol,corresponding to a concentration of 100 IU/ml after reconstitution with 5 ml solvent.

ADYNOVI 1 000 IU/5 ml powder and solvent for solution for injection

Each vial contains nominally 1 000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol,corresponding to a concentration of 200 IU/ml after reconstitution with 5 ml solvent.

ADYNOVI 2 000 IU/5 ml powder and solvent for solution for injection

Each vial contains nominally 2 000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol,corresponding to a concentration of 400 IU/ml after reconstitution with 5 ml solvent.

ADYNOVI 3 000 IU/5 ml powder and solvent for solution for injection

Each vial contains nominally 3 000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol,corresponding to a concentration of 600 IU/ml after reconstitution with 5 ml solvent.

The potency (International Units) is determined using the chromogenic assay. The specific activity of

ADYNOVI is approximately 3 800-6 000 IU/mg protein.

Rurioctocog alfa pegol (PEGylated human coagulation factor VIII (rDNA)) is a protein that has 2 332amino acids with a molecular weight of approximately 280 kDa, conjugated with a 20 kDapolyethylene glycol (PEG). It is produced by recombinant DNA technology in Chinese Hamster Ovary(CHO) cell line.

Each powder vial contains 0.45 mmol (10 mg) sodium, see section 4.4.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (powder for solution for injection).

Powder: White to off-white friable powder.

Solvent: Clear and colourless solution.

Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia A (congenitalfactor VIII deficiency).

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

The safety and efficacy of ADYNOVI in previously untreated patients have not yet been established.

No data are available.

During the course of treatment, appropriate determination of factor VIII levels is advised to guide thedose to be administered and the frequency of repeated infusions. Individual patients may vary in theirresponse to factor VIII, 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 VIII activity) is indispensable.

A field study has indicated that plasma factor VIII levels can be monitored using either a chromogenicsubstrate assay or a one stage clotting assay routinely used in clinical laboratories.

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 (World Health Organization) concentrate standard for factor VIII products.

Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) orpreferably in International Units (relative to an International Standard for factor VIII in plasma).

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

The calculation of the required dose of factor VIII is based on the empirical finding that1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The requireddose is determined using the following formula:

Required international units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5

The amount to be administered and the frequency of administration should always be oriented to theclinical effectiveness in the individual case.

In the case of the following haemorrhagic events, factor VIII activity should not fall below the givenplasma activity level (in % of normal or IU/dl) in the corresponding period.

The following Table 1 can be used to guide dosing in bleeding episodes and surgery:

Table 1: Guide for dosing in bleeding episodes and surgery

Degree of haemorrhage/type Factor VIII level Frequency of dosesof surgical procedure required (% or IU/dl) (hours)/duration of therapy (days)

Early haemarthrosis, muscle 20 - 40 Repeat injectionsbleeding or oral bleeding. every 12 to 24 hours. At least 1 day,until the bleeding episode, asindicated by pain, is resolved orhealing is achieved.

More extensive haemarthrosis, 30 - 60 Repeat injections every 12 to 24 hoursmuscle bleeding or haematoma for 3 - 4 days or more until pain andacute disability are resolved.

Life threatening haemorrhages. 60 - 100 Repeat injections every 8 to 24 hoursuntil threat is resolved.

Minor 30 - 60 Every 24 hours at least 1 day, until

Including tooth extraction. healing is achieved.

Major 80 - 100 Repeat injections every 8 to 24 hoursuntil adequate wound healing, then(pre- and postoperative) continue therapy for at leastanother 7 days to maintain afactor VIII activity of 30% to 60%(IU/dl).

For long term prophylaxis, the recommended dose is 40 to 50 IU of ADYNOVI per kg bodyweighttwice weekly in 3 to 4 day intervals. Adjustments of doses and administration intervals may beconsidered based on achieved FVIII levels and individual bleeding tendency (see sections 5.1, pct. 5.2).

On demand treatment dosing in paediatric patients (12 to 18 years of age) is the same as for adultpatients. Prophylactic treatment for patients from 12 to <18 years is the same as for adult patients.

Currently available data in patients below 12 years are described in sections 4.8, 5.1 and 5.2.

Adjustments of doses and administration intervals may be considered based on achieved FVIII levelsand individual bleeding tendency (see sections 5.1, pct. 5.2).

ADYNOVI is for intravenous use.

The rate of administration should be determined to ensure the comfort of the patient up to a maximumof 10 ml/min.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance, to the parent molecule octocog alfa or to any of the excipientslisted in section 6.1.

Known allergic reaction to mouse or hamster protein.

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, including anaphylaxis, have been reported with ADYNOVI.

The medicinal product contains traces of mouse and hamster proteins. If symptoms of hypersensitivityoccur, patients should be advised to discontinue use of the medicinal product immediately and contacttheir physician. Patients should be informed of the early signs of hypersensitivity reactions includinghives, 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.

Immune tolerance induction (ITI)

No clinical data for use of ADYNOVI in ITI are available.

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

Catheter-related complications in treatment

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

Excipient related considerations

This medicinal product contains up to 12.42 mg sodium per vial, equivalent to 0.62% of the WHOrecommended maximum daily intake of 2 g sodium for an adult. Depending on the body weight andposology, the patient could receive more than one vial. This should be taken into consideration bypatients on a controlled sodium diet.

It is strongly recommended that every time that ADYNOVI is administered to a patient, the name andbatch number of the product are recorded in order to maintain a link between the patient and the batchof the medicinal product.

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.

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.

ADYNOVI 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 ADYNOVI. If such inhibitors occur, the condition will manifest itselfas an insufficient clinical response. In such cases, it is recommended that a specialised haemophiliacentre be contacted (see section 5.1).

The safety of ADYNOVI was evaluated in 365 previously treated patients with severe haemophilia A(factor VIII less than 1% of normal), who received at least one dose of ADYNOVI in 6 completedmulti-centre, prospective, open label clinical trials and 1 ongoing clinical trial.

The table presented below is according to the MedDRA system organ classification (System Organ

Class 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). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions reported for ADYNOVI

MedDRA Adverse reactions Frequency

Standard System Organ Class

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)*

Immune system disorders Hypersensitivity Uncommon

Anaphylactic reaction** Not known

Nervous system disorders Headache Very common

Dizziness Common

Eye disorders Ocular hyperaemia Uncommon

Vascular disorders Flushing Uncommon

Gastrointestinal disorders Diarrhoea Common

Nausea Common

Skin and subcutaneous tissue disorders Rash Common

Rash pruritic Uncommon

Urticaria Common

Investigations Eosinophil count Uncommonincreased

Injury, poisoning and procedural Infusion related reaction Uncommoncomplications

* Frequency is based on studies with all FVIII products which included patients with severehaemophilia A. PTPs = previously-treated patients.

Frequencies presented were calculated using all adverse events, related and unrelated.

** Adverse reaction identified in post-marketing surveillance.

The observed event of hypersensitivity was a mild transient non-serious rash, occurring inone 2-year-old patient who had developed a previous rash while on ADYNOVI.

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

The safety of ADYNOVI was evaluated in 38 subjects < 6 years and 34 subjects 6 to < 12 years of agehaving accumulated a total of 2 880 exposure days (EDs) and 2 975 EDs respectively. The mean (SD)age was 3.3 (1.55) and 8.1 (1.92) years respectively.

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

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII andvon Willebrand factor) with different physiological functions. When infused into a haemophilicpatient, factor VIII binds to von Willebrand factor in the patient’s circulation. Activated factor VIIIacts as a cofactor 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 sex-linked hereditary disorder of blood coagulation dueto decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internalorgans, either spontaneously or as results of accidental or surgical trauma. By replacement therapy theplasma levels of factor VIII are increased, thereby enabling a temporary correction of the factordeficiency and correction of the bleeding tendencies.

Rurioctocog alfa pegol, is a pegylated recombinant human factor VIII with an extended half-life.

Rurioctocog alfa pegol is a covalent conjugate of octocog alfa consisting of 2 332 amino acids withpolyethylene glycol (PEG) reagent (MW 20 kDa). The therapeutic activity of rurioctocog alfa pegol isderived from octocog alfa, which is produced by recombinant DNA technology from a Chinesehamster ovary cell line. Octocog alfa is then covalently conjugated with the PEG reagent. The PEGmoiety is conjugated to octocog alfa to increase the plasma half-life.

The safety, efficacy, and pharmacokinetics of ADYNOVI were evaluated in a pivotal multi-centre,open-label, prospective clinical trial that compared the efficacy of a twice weekly prophylactictreatment regimen to on-demand treatment and determined haemostatic efficacy in the treatment ofbleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe haemophilia Areceived at least one infusion with ADYNOVI. Twenty-five of the 137 subjects were adolescents(12 to less than 18 years of age).

None of the subjects who participated in one or more of 6 completed clinical trials in previouslytreated patients (PTPs) developed persistent neutralizing (inhibitory) antibodies against FVIII of ≥ 0.6

BU/mL (based on the Nijmegen modification of the Bethesda assay). One patient developed atransient FVIII inhibitor at the lowest limit of positivity (0.6 BU) during personalized prophylaxistargeting a FVIII level of 8-12%.

From an ongoing study in previously untreated patients < 6 years with severe hemophilia A,preliminary reports on 9 cases of FVIII inhibitor development associated with treatment with

ADYNOVI were received.

Prophylactic treatment

Subjects received either prophylactic treatment (n = 120) with ADYNOVI at a dose of 40-50 IUper kg twice weekly or on-demand treatment (n = 17) with ADYNOVI at a dose of 10-60 IU per kgfor a 6-month period. The median dosing interval was 3.6 days and the mean dose (SD)was 48.7 (4.4) IU/kg. One hundred eighteen of 120 (98%) prophylaxis subjects remained on thestarting recommended regimen without dose adjustment, and 2 subjects increased their doseto 60 IU/kg during prophylaxis due to bleeding in target joints.

In the per-protocol population, i.e. dosed according to the protocol specific dosing requirements, atotal of 101 subjects received a twice a week regimen in the prophylaxis arm, and 17 subjects weretreated episodically in the on-demand arm. The median annualised bleed rate (ABR) in the on-demandtreatment arm was 41.5 compared to 1.9 while on a twice a week prophylaxis regimen. The medianjoint ABR (Q1 ; Q3) in the on-demand arm was 38.1 (24.5 ; 44.6) compared to 0.0 (0.0 ; 2.0) while onprophylaxis, and the median spontaneous ABR was 21.6 (11.2 ; 33.2) on the on-demand armcompared to 0.0 (0.0 ; 2.2) while on prophylaxis. Results for the full-analysis population were similarto those for the per-protocol population. Of note, ABR is not comparable between different factorconcentrates and between different clinical trials.

Forty out of 101 subjects (40%) experienced no bleeding episodes, 58 out of 101 subjects (57%)experienced no joint bleeding episodes, and 58 out of 101 subjects (57%) experienced no spontaneousbleeding episodes in the prophylaxis arm. All subjects in the on-demand arm experienced a bleedingepisode, including a joint or spontaneous bleeding episode.

Treatment of bleeding episodes

A total of 518 bleeding episodes were treated with ADYNOVI in the per-protocol population. Ofthese, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 157 (n=61 subjects)occurred in the prophylaxis arm. The median dose per infusion to treat all bleeding episodes in theper-protocol population was 32.0 (Interquartile Range (IQR): 21.5) IU per kg. Overall, 95.9% ofbleeding episodes were controlled with 1 to 2 infusions and 85.5% were controlled withonly 1 infusion. Of the 518 bleeding episodes, 96.1% were rated excellent (full relief of pain andcessation of objective signs of bleeding after a single infusion) or good (definite pain relief and/orimprovement in signs of bleeding after a single infusion) in their response to treatment with

ADYNOVI.

Paediatric population < 12 years of age

A total of 66 PTPs with severe haemophilia A were dosed (32 subjects aged < 6 years and 34 subjectsaged 6 to < 12 years) in the paediatric study. The prophylactic regimen was 40 to 60 IU/kg of

ADYNOVI twice a week. The mean dose (SD) was 54.3 (6.3) IU/kg and the median frequency ofinfusions per week was 1.87. The median overall ABR was 2.0 (IQR: 3.9) for the 65 subjects in theper-protocol population and the median ABRs for spontaneous and joint bleeding episodes wereboth 0 (IQR: 1.9). Twenty four out of 65 subjects (37%) experienced no bleeding episodes, 47 outof 65 subjects (72%) experienced no joint bleeding episodes, and 43 out of 65 subjects (66%)experienced no spontaneous bleeding episodes on prophylaxis.

Of the 70 bleeding episodes observed during the paediatric study, 82.9% were controlledwith 1 infusion and 91.4% were controlled with 1 or 2 infusions. Control of bleeding was ratedexcellent (full relief of pain and cessation of objective signs of bleeding after a single infusion) orgood (definite pain relief and/or improvement in signs of bleeding after a single infusion) in 63 outof 70 (90.0%) bleeding episodes.

Perioperative management (surgical prophylaxis)

A total of 21 major surgical procedures and 5 additional minor surgeries were performed and assessedin 21 unique subjects in the surgery study. For major surgeries, the preoperative loading dose rangedfrom 36 IU/kg to 109 IU/kg (median: 63 IU/kg); and postoperative total dose ranged from 186 IU/kgto 1 320 IU/kg (median: 490 IU/kg). The median total dose for major surgeries was 553 IU/kg(range: 248-1 394 IU/kg) and the median total dose of minor surgeries was 106 IU/kg (range: 76-132 IU/kg).

Perioperative haemostatic efficacy was rated as excellent (blood loss less than or equal to thatexpected for the same type of procedure performed in a non-haemophilic patient, and required bloodcomponents for transfusions less than or similar to that expected in non-haemophilic population) forall 26 (21 major, 5 minor) procedures. The median (IQR) observed intraoperative blood loss (n = 14)was 10.0 (20.0) ml compared to the predicted average blood loss (n = 14) of 150.0 (140.0) ml formajor orthopaedic surgeries.

The European Medicines Agency has deferred the obligation to submit results of studies with

ADYNOVI in one or more subsets of the paediatric population in the treatment of congenitalfactor VIII deficiency. See 4.2 for information on paediatric use.

Long-term prophylaxis treatment in paediatric and adult subjects

The long-term safety and efficacy of ADYNOVI in prophylaxis and treatment of bleeding episodeswas evaluated in 216 paediatric and adult PTPs with severe haemophilia A who had either previouslyparticipated in other ADYNOVI studies or were naïve to ADYNOVI. In the treated population,subjects received a fixed-dose twice-weekly regimen of 40 to 50 IU/kg if aged ≥ 12 years or of 40 to60 IU/kg if aged < 12 years. The dose was adjusted up to 80 IU/kg twice weekly if required tomaintain FVIII trough levels of > 1%. Subjects that opted for a personalized (pharmacokinetically-tailored) prophylactic regimen received doses up to 80 IU/kg per infusion that targeted FVIII troughlevels of ≥ 3% at least twice weekly. ABR per prophylactic regimen, bleeding site and etiology arepresented in Table 3.

Table 3: Annualized bleed rate (ABR) by prophylactic regimen (ITT population)

Twice-Weekly Every 5 Days Every 7 Days PK- tailoreda(N=186) (N=56) (N=15) (N=25)

Bleeding Site Etiology

Mean[Point Estimate- 95% Confidence Interval]

Overall 2.2 [1.85 - 2.69] 2.1 [1.54 - 2.86] 2.7 [1.44 -5.20] 2.6 [1.70 - 4.08]

Joint 1.2 [0.96 - 1.58] 1.1 [0.81 - 1.55] 2.0 [0.90 - 4.62] 1.4 [0.91 - 2.17]

Spontaneous 1.2 [0.92 - 1.56] 1.3 [0.87 - 2.01] 1.8 [0.78- 4.06] 1.0 [0.54 - 1.71]

Point estimates and 95% confidence intervals obtained from a generalized linear model fitting a negative binomial distribution withlogarithmic link function.

Subjects receiving doses in multiple regimens are included in summaries for multiple regimens.

Includes all subjects in the study (adults and paediatric subjects < 18 years. For Twice Weekly and PK-tailored dosing no subjects < 12years were included in Every 5 & 7 Days dosing.

ITT = intent to treat; N = Number of subjects included in the analysisa Targeting FVIII activity trough levels of ≥3% of normal

Of note, ABR is not comparable between different factor concentrates and between different clinicaltrials.

Long-term haemostatic efficacy was evaluated in 910 bleeding episodes treated with ADYNOVI andwas rated excellent or good in 88.5% of bleeding episodes. Across age categories and for both thefixed-dose and the PK-tailored dose regimen, >85% of bleed treatments were rated excellent or good.

The majority of bleeding episodes were treated with one (74.0%) or two (15.4%) infusions.

Personalized prophylaxis PROPEL clinical trial in adolescents and adult subjects

The safety and efficacy of ADYNOVI was evaluated in a prospective, randomized, open-labelmulti-centre study in 121 (115 randomized) adolescents (12-18 years old) and adult PTPs with severehaemophilia A for a 12-month treatment period. The study compared 2 PK-guided prophylactic dosingregimens of ADYNOVI that targeted Factor VIII trough levels of 1-3% dosed twice weekly (N=57) or8-12% dosed every other day (N=58), by assessing the proportions of subjects achieving a total ABRof 0 in the second 6-month study period.

The average prophylactic doses administered in the 1-3% and 8-12 % trough arms were 3 866.1 IU/kgper year [mean (SD) infusions/week = 2.3 (0.58)] and 7 532.8 IU/kg per year [(mean (SD)infusions/week = 3.6 (1.18)], respectively. After dose adjustment during the first 6-month period ofprophylaxis, median trough levels in the second 6-month period (based on the one-stage clotting assayand calculated to the end of the planned infusion interval) ranged from 2.10 IU/dL to 3.00 IU/dL in the1-3% trough level arm and from 10.70 IU/dL to 11.70 IU/dL in the 8-12 % trough level arm,demonstrating that dosing in the 2 prophylaxis regimens was generally adequate to achieve andmaintain the desired FVIII trough levels.

The primary endpoint of the study, proportion of subjects who had a total ABR of 0 during the second6-month period, was not reached in the ITT patient population (p= 0.0545) but was reached in the per-protocol population (p = 0.0154). The proportions of randomized subjects with total ABRs,spontaneous ABRs and spontaneous annualized joint bleeding rates (AJBRs) of 0 during the second 6-month study period in the Per Protocol population are presented in Table 4.

Table 4: Annualized bleed rate (ABR) of 0, second 6-month study period

Proportion of Subjects Without Bleedings in 6 Months[Point Estimate- 95% Confidence Interval]

ITT Population1-3% Trough Level (N=57) 8-12% Trough Level (N=58)

Total ABR of 0 0.421 [0.292; 0.549] 0.621[0.491; 0.750]

Spontaneous ABR of 0 0.596 [0.469; 0.724] 0.760 [0.645; 0.875]

Spontaneous AJBR of 0 0.649 [0.525; 0.773] 0.850 [0.753; 0.947]

ABR = Annualized bleeding rate. AJBR = Annualized joint bleeding rate.

Annualized bleeding rate determined by dividing the number of bleeds by observation period in years.

Proportion of Subjects Without Bleedings in 6 Months [Point

Estimate- 95% Confidence Interval]

Per Protocol Population1-3% Trough Level (N=52) 8-12% Trough Level (N=43)

Total ABR of 0 0.404 [0.270; 0.549] 0.674 [0.515; 0.809]

Spontaneous ABR of 0 0.596 [0.451; 0.730] 0.814 [0.666; 0.916]

Spontaneous AJBR of 0 0.654 [0.509; 0.780] 0.907 [0.779; 0.974]

ABR = Annualized bleeding rate. AJBR = Annualized joint bleeding rate.

Per-protocol population = all subjects who completed the second 6 months of prophylactic treatment and had no majordeviations from the protocol affecting the study results.

Annualized bleeding rate determined by dividing the number of bleeds by observation period in years.

Of note, ABR is not comparable between different factor concentrates and between different clinicaltrials.

Total ABRs, spontaneous ABRs and spontaneous AJBRs during the second 6-month study period arepresented in Table 5.

Table 5: Annualized bleed rate (ABR) second 6-month study period(ITT Population)1-3% Trough Level (N=57) 8-12% Trough Level (N=53)

Median Mean (SD) Median Mean (SD)

Total ABR 2.0 3.6 (7.5) 0.0 1.6 (3.4)

Spontaneous ABR 0.0 2.5 (6.6) 0.0 0.7 (1.7)

Spontaneous AJBR 0.0 2.0 (6.4) 0.0 0.5 (1.7)

ABR = Annualized bleeding rate. AJBR = Annualized joint bleeding rate.

Annualized bleeding rate determined by dividing the number of bleeds by observation period in years.

Per Protocol Population1-3% Trough Level (N=52) 8-12% Trough Level (N=43)

Median Mean (SD) Median Mean (SD)

Total ABR 2.0 2.4 (3.2) 0.0 2.1 (4.2)

Spontaneous ABR 0.0 1.6 (2.6) 0.0 0.8 (2.4)

Spontaneous AJBR 0.0 1.0 (1.8) 0.0 0.7 (2.2)

ABR = Annualized bleeding rate. AJBR = Annualized joint bleeding rate.

Per-protocol population = all subjects who completed the second 6 months of prophylactic treatment and had no majordeviations from the protocol affecting the study results.

Annualized bleeding rate determined by dividing the number of bleeds by observation period in years.

A total of 242 bleeding episodes in 66 subjects were treated with ADYNOVI; 155 bleeds in40 subjects in the 1-3% trough level arm and 87 bleeds in 26 subjects in the 8-12% trough level arm.

The majority of bleeds (86.0%, 208/242) were treated with 1 or 2 infusions; and bleed treatment atresolution of the bleeding episode was rated excellent or good in 84.7% (205/242) of bleeds.

The pharmacokinetics (PK) of ADYNOVI were evaluated in a crossover study with octocog alfain 26 subjects (18 adults and 8 adolescents) and in 22 subjects (16 adults and 6 adolescents)after 6 months of treatment with ADYNOVI. Plasma factor VIII activity was measured by theone stage clotting assay and chromogenic assay.

ADYNOVI has an extended half-life of 1.4 to 1.5-fold compared to recombinant human coagulationfactor VIII (octocog alfa) in the adolescent and adult population, as determined based on one stageclotting and chromogenic assays, respectively. An increase in AUC and a decrease in clearance ascompared to the parent molecule, octocog alfa, were also observed. Incremental recovery wascomparable with both products. The change in PK parameters was similar in both the adult andadolescent populations and between one-stage clotting and chromogenic substrate assays.

Paediatric pharmacokinetics

Pharmacokinetic parameters calculated from 39 subjects less than 18 years of age (intent-to-treatanalysis) are available for 14 children (2 to less than 6 years), 17 older children (6 to lessthan 12 years) and 8 adolescent subjects (12 to < 18 years of age). The half-life extension in thepaediatric population was 1.3 to 1.5 fold using both the one stage clotting and chromogenic assays.

The mean clearance (based on body weight) of ADYNOVI was higher and the mean half-life waslower in children less than 12 years of age than adults.

A higher dose may be required in children less than 12 years of age, see section 4.2.

Table 6: Pharmacokinetic parameters using the chromogenic assay (Arithmetic mean ± SD)

ADYNOVI ADYNOVI ADYNOVI ADYNOVI

Adults Adolescents Paediatric Paediatric(18 years and (12-<18 years) patients patients

PK parameters older) N = 8 (6-<12 years) (< 6 years)

N = 18 Dose: N = 17 N = 14

Dose: 45 ± 5 IU/kg Dose: Dose:

45 ± 5 IU/kg 50 ± 10 IU/kg 50 ± 10 IU/kg

Design Individual PK with full samplinga Population PK with sparse samplingb

Terminal15.01 ± 3.89 13.80 ± 4.01 11.93 ± 2.58 12.99 ± 8.75half--life [h]

MRT [h] 19.70 ± 5.05 17.73 ± 5.44 17.24 ± 3.73 18.74 ± 12.60

CL [mL/(kg·h)]d 2.16 ± 0.75 2.58 ± 0.84 2.80 ± 0.67 3.49 ± 1.21

Incrementalnac nacrecovery 2.87 ± 0.61 2.34 ± 0.62(2.19± 0.40) (1.90 ± 0.27)[(IU/dL)/(IU/kg)]

AUC0-Inf 2 589 ± 848 1 900 ± 841 2 259 ± 514 2 190 ± 1 593[IU·h/dL]

Vss [dL/kg] 0.40 ± 0.09 0.54 ± 0.22 0.46 ± 0.04 0.54 ± 0.03nac nac

Cmax [IU/dL] 145 ± 29 117 ± 28(130 ± 24) (117 ± 16)

Abbreviations: Cmax: maximum observed activity; AUC: area under the curve; MRT: mean residencetime; CL: clearance; Vss: body weight adjusted volume of distribution at steady-state,a Individual PK with 12 post-infusion samples.b Population PK model with 3 post-infusion samples based on randomized drawing schedule.c NA, Not applicable, as Incremental Recovery and Cmax in children were determined by individual

PK. Results for Incremental Recovery and Cmax determined by individual PK in parenthesis.d The clearance value of 12.18 ml/(kg·h) for subject 122001 in age group 12 to < 18 years was notincluded in the analysis of clearance.

In the repeat dose toxicity study in Cynomolgus monkey, two animals showed vacuolation in thekidney in the mid dose group (350 IU/kg). The vacuolations did not recover after 2 weeks. The humanrelevance of kidney vacuolation observed in the preclinical study is unknown.

Nonclinical data are limited to 1 month exposure and no studies in juvenile animals were conductedwith ADYNOVI. Thus, it was not possible to conclude on the potential risks of PEG accumulation invarious tissues/organs relevant for chronic use of ADYNOVI in the paediatric population.

No studies on genotoxicity, carcinogenicity or reproductive toxicity have been performed with

ADYNOVI.

Mannitol (E421)

Trehalose dihydrate

Histidine

Glutathione

Sodium chloride

Calcium chloride dihydrate (E509)

Tris(hydroxymethyl)aminomethane

Polysorbate 80 (E433)

Water for injections

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

Unopened vial2 years.

Before opening the medicinal product may be stored at room temperature (up to 30 °C) for a period ofup to 3 months. The end of the 3-month storage at room temperature should be recorded on theproduct carton. This date should never exceed the one initially mentioned on the outer carton. At theend of this period the product shall not be put back in the refrigerator, but shall be used or discarded.

Chemical and physical in-use stability has been demonstrated for 3 hours at a temperature notabove 30 °C. From a microbiological point of view, unless the method of reconstitution precludes therisk of microbial contamination, the product should be used immediately. If not used immediately,in-use storage times and conditions are the responsibility of the user. Do not refrigerate.

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

Do not freeze.

ADYNOVI with BAXJECT II Hi-Flow device: Keep the vial in the outer carton in order to protectfrom light.

ADYNOVI in BAXJECT III system: Keep the sealed blister in the outer carton in order to protectfrom light.

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

Type I glass vial, closed with a chlorobutyl rubber stopper, containing 250 IU, 500 IU, 1 000 IU,2 000 IU or 3 000 IU of powder.

Type I glass vial, closed with a chlorobutyl or bromobutyl rubber stopper, containing 5 ml of water forinjections.

The medicinal product is provided in one of the following configurations:

- ADYNOVI with BAXJECT II Hi-Flow device: Each pack contains a powder vial, a solvent vialand a device for reconstitution (BAXJECT II Hi-Flow).

- ADYNOVI in BAXJECT III system: Each pack contains a ready to use BAXJECT III system ina sealed blister, with the powder vial and the solvent vial preassembled for reconstitution.

The reconstituted medicinal product should be inspected visually for particulate matter anddiscolouration prior to administration. The solution should be clear or slightly opalescent. Do not usesolutions that are cloudy or have deposits.

After reconstitution, the solution has a pH of 6.7 to 7.3. The osmolality is ≥ 380 mOsmol/kg.

Preparation and reconstitution using the BAXJECT II Hi-Flow device

For reconstitution use only the solvent vial and the reconstitution device provided in the pack.1. Use antiseptic technique (clean and low-germ conditions) and a flat work surface during thereconstitution procedure.2. Allow the vials of powder and solvent to reach room temperature (between 15 °C and 25 °C)before use.3. Remove plastic caps from the powder and solvent vials.4. Clean rubber stoppers with an alcohol wipe and allow to dry prior to use.5. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching theinside (Figure A). Do not remove the device from the package.6. Turn the package over. Press straight down to fully insert the clear plastic spike through thesolvent vial stopper (Figure B).7. Grip the BAXJECT II Hi-Flow package at its edge and pull the package off the device(Figure C). Do not remove the blue cap from the BAXJECT II Hi-Flow device. Do not touchthe exposed purple plastic spike.

8. Turn the system over so that the solvent vial is on top. Quickly insert the purple plastic spikefully into the powder vial stopper by pushing straight down (Figure D). The vacuum will drawthe solvent into the powder vial.

9. Swirl gently until the powder is completely dissolved. Do not refrigerate after reconstitution.

Figure A Figure B Figure C

Figure D Figure E Figure F

- Visually inspect the reconstituted solution for particulate matter and discolouration prior toadministration.o The appearance of the reconstituted solution is clear and colourless.o Do not use if particulate matter or discolouration is observed.

- Administer as soon as possible, but no later than 3 hours after reconstitution.

Administration steps1. Remove the blue cap from the BAXJECT II Hi-Flow device (Figure E). Do not draw air intothe syringe. Connect the syringe to the BAXJECT II Hi-Flow. Use of a Luer-lock syringe isrecommended.

2. Turn the system upside down (powder vial now on top). Draw the reconstituted solution into thesyringe by pulling the plunger back slowly (Figure F).

3. Disconnect the syringe; attach a suitable needle and inject intravenously. If a patient is toreceive more than one vial of ADYNOVI, the contents of multiple vials may be drawn into thesame syringe.

A separate BAXJECT II Hi-Flow device is required to reconstitute each vial of ADYNOVI withthe solvent.

4. Administer over a period of up to 5 minutes (maximum infusion rate 10 ml per min).

It is strongly recommended that every time ADYNOVI is administered, the name and batch number ofthe product are recorded. Peel-off labels are provided on the powder vial.

Reconstitution with the BAXJECT III system

Do not use if the lid is not completely sealed on the blister1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solventvials preassembled with the system for reconstitution) from the refrigerator and let it reach roomtemperature (between 15 °C and 25 °C).

2. Wash your hands thoroughly using soap and warm water.3. Open the ADYNOVI blister by peeling away the lid. Remove the BAXJECT III system fromthe blister.4. Place the powder vial on a flat surface with the solvent vial on top (Figure 1). The solvent vialhas a blue stripe. Do not remove the blue cap until instructed in a later step.5. With one hand holding the powder vial in the BAXJECT III system, press down firmly on thesolvent vial with the other hand until the system is fully collapsed and the solvent flows downinto the powder vial (Figure 2). Do not tilt the system until the transfer is complete.

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved(Figure 3). Be sure that the powder is completely dissolved, otherwise not all reconstitutedsolution will pass through the device filter. The product dissolves rapidly (usually in lessthan 1 minute). After reconstitution the solution should be clear, colourless and free fromparticles.

Figure 1 Figure 2 Figure 3

Figure 4 Figure 5

- Visually inspect the reconstituted solution for particulate matter and discolouration prior toadministration.o The appearance of the reconstituted solution is clear and colourless.o Do not use if particulate matter or discolouration is observed.

- Administer as soon as possible, but no later than 3 hours after reconstitution.

Administration steps1. Remove the blue cap from the BAXJECT III device (Figure 4). Do not draw air into thesyringe. Connect the syringe to the BAXJECT III device. Use of a Luer-lock syringe isrecommended.

2. Turn the system upside down (powder vial now on top). Draw the reconstituted solution into thesyringe by pulling the plunger back slowly (Figure 5).

3. Disconnect the syringe; attach a suitable needle and inject intravenously. If a patient is toreceive more than one vial of ADYNOVI, the contents of multiple vials may be drawn into thesame syringe.

4. Administer over a period of up to 5 minutes (maximum infusion rate 10 ml per min).

It is strongly recommended that every time ADYNOVI is administered, the name and batch number ofthe product are recorded. Peel-off labels are provided on the blister.

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

Baxalta Innovations GmbH

Industriestrasse 67

A-1221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/17/1247/003

EU/1/17/1247/004

EU/1/17/1247/007

EU/1/17/1247/008

EU/1/17/1247/011

EU/1/17/1247/012

EU/1/17/1247/013

EU/1/17/1247/014

EU/1/17/1247/015

EU/1/17/1247/016

Date of first authorisation: 08 January 2018

Date of latest renewal: 09 November 2022

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

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