Adynovi - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 / 5ml 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.

The active substance rurioctocog alfa pegol is a covalent conjugate of the protein octocog alfa with a 20 kDa polyethylene glycol (PEG).

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Powder: White to off-white friable powder. Solvent: Clear and colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Previously untreated patients

The safety and efficacy of ADYNOVI in previously untreated patients have not yet been established. No data are available.

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

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

Posology

The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO concentrate standard for factor VIII products. Factor VIII activity in plasma 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 International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma.

On demand treatment

The calculation of the required dose of factor VIII is based on the empirical finding that

• 1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:

Required 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 the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, factor VIII activity should not fall below the given plasma 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 of surgical procedure	Factor VIII level required (% or IU/dl)	Frequency of doses (hours)/duration of therapy (days)
Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding.	20 – 40	Repeat injections every 12 to 24 hours. At least 1 day, until the bleeding episode, as indicated by pain, is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma	30 – 60	Repeat injections every 12 to 24 hours for 3 – 4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages.	60 – 100	Repeat injections every 8 to 24 hours until threat is resolved.
Surgery Minor Including tooth extraction.	30 – 60	Every 24 hours at least 1 day, until healing is achieved.
Major	80 – 100 (pre- and postoperative)	Repeat injections every 8 to 24 hours until adequate wound healing, then continue therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl).

Prophylaxis

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

Paediatric population

On demand treatment dosing in paediatric patients (12 to 18 years of age) is the same as for adult patients. Prophylactic treatment for patients from 12 to <18 years is the same as for adult patients. The long-term safety of ADYNOVI in children below 12 years has not yet been established. Adjustments of doses and administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency (see sections 5.1, 5.2).

Method of administration

ADYNOVI is for intravenous use.

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

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

4.3 Contraindications

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

Known allergic reaction to mouse or hamster protein.

4.4 Special warnings and precautions for use

Traceability

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

Hypersensitivity

Allergic type hypersensitivity reactions are possible with ADYNOVI. The medicinal product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

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

Inhibitors

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre inhibitors which are transiently present or remain consistently low titre posing less of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.

Immune tolerance induction (ITI)

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

Cardiovascular events

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

Catheter-related complications in treatment

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

Excipient related considerations

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Paediatric population

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

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).

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

Tabulated list of adverse reactions

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 completed multi-centre, prospective, open label clinical studies and 1 ongoing clinical study.

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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions reported for ADYNOVI

MedDRA Standard System Organ Class	Adverse reactions	Frequency per patient
Blood and lymphatic system disorders	Factor VIII inhibition	Uncommon (PTPs)
Immune system disorders	Hypersensitivity	Uncommon
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
	Drug eruption	Uncommon
	Urticaria	Common
Investigations	Eosinophil count increased	Uncommon
Injury, poisoning and procedural complications	Infusion related reaction	Uncommon

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

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

Description of selected adverse reactions

Hypersensitivity

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

Paediatric population

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 age having 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

No symptoms of overdose with recombinant coagulation factor VIII have been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to von Willebrand factor in the patient’s cir­culation. Activated factor VIII acts 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 fibrin and a clot can be formed. Haemophilia A is a X-chromosomal linked hereditary disorder of blood coagulation due to decreased 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 replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

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 with polyethylene glycol (PEG) reagent (MW 20 kDa). The therapeutic activity of rurioctocog alfa pegol is derived from octocog alfa, which is produced by recombinant DNA technology from a Chinese hamster ovary cell line. Octocog alfa is then covalently conjugated with the PEG reagent. The PEG moiety is conjugated to octocog alfa to increase the plasma half-life.

Clinical efficacy and safety

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 prophylactic treatment regimen to on-demand treatment and determined haemostatic efficacy in the treatment of bleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe haemophilia A received at least one infusion with ADYNOVI. Twenty-five of the 137 subjects were adolescents (12 to less than 18 years of age).

Immunogenicity

None of the subjects who participated in one or more of 6 completed clinical trials in previously treated 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 a transient FVIII inhibitor at the lowest limit of positivity (0.6 BU) during personalized prophylaxis targeting 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 IU per kg twice weekly or on-demand treatment (n = 17) with ADYNOVI at a dose of 10–60 IU per kg for 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 the starting recommended regimen without dose adjustment, and 2 subjects increased their dose to 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, a total of 101 subjects received a twice a week regimen in the prophylaxis arm, and 17 subjects were treated episodically in the on-demand arm. The median annualised bleed rate (ABR) in the on-demand treatment arm was 41.5 compared to 1.9 while on a twice a week prophylaxis regimen. The median joint ABR (Q1 ; Q3) in the on-demand arm was 38.1 (24.5 ; 44.6) compared to 0.0 (0.0 ; 2.0) while on prophylaxis, and the median spontaneous ABR was 21.6 (11.2 ; 33.2) on the on-demand arm compared to 0.0 (0.0 ; 2.2) while on prophylaxis. Results for the full-analysis population were similar to those for the per-protocol population. Of note, ABR is not comparable between different factor concentrates and between different clinical studies.

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 spontaneous bleeding episodes in the prophylaxis arm. All subjects in the on-demand arm experienced a bleeding episode, 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. Of these, 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 the per-protocol population was 32.0 (Interquartile Range (IQR): 21.5) IU per kg. Overall, 95.9% of bleeding episodes were controlled with 1 to 2 infusions and 85.5% were controlled with only 1 infusion. Of the 518 bleeding episodes, 96.1% were rated excellent (full relief of pain and cessation of objective signs of bleeding after a single infusion) or good (definite pain relief and/or improvement 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 subjects aged 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 of infusions per week was 1.87. The median overall ABR was 2.0 (IQR: 3.9) for the 65 subjects in the per-protocol population and the median ABRs for spontaneous and joint bleeding episodes were both 0 (IQR: 1.9). Twenty four out of 65 subjects (37%) experienced no bleeding episodes, 47 out of 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 controlled with 1 infusion and 91.4% were controlled with 1 or 2 infusions. Control of bleeding was rated excellent (full relief of pain and cessation of objective signs of bleeding after a single infusion) or good (definite pain relief and/or improvement in signs of bleeding after a single infusion) in 63 out of 70 (90.0%) bleeding episodes.

Perioperative management (surgical prophylaxis)

A total of 21 major surgical procedures and 5 additional minor surgeries were performed and assessed in 21 unique subjects in the surgery study. For major surgeries, the preoperative loading dose ranged from 36 IU/kg to 109 IU/kg (median: 63 IU/kg); and postoperative total dose ranged from 186 IU/kg to 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: 76132 IU/kg).

Perioperative haemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the same type of procedure performed in a non-haemophilic patient, and required blood components for transfusions less than or similar to that expected in non-haemophilic population) for all 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 for major 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 congenital factor 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 episodes was evaluated in 216 paediatric and adult PTPs with severe haemophilia A who had either previously participated 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 lU/kg if aged > 12 years or of 40 to 60 IU/kg if aged < 12 years. The dose was adjusted up to 80 IU/kg twice weekly if required to maintain 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 trough levels of > 3% at least twice weekly. ABR per prophylactic regimen, bleeding site and etiology are presented in Table 3.

Table 3: Annualized Bleed Rate (ABR) by Prophylactic Regimen (ITT Population)
Bleeding Site Etiology	Twice-Weekly (N=186)	Every 5 Days (N=56)	Every 7 Days (N=15)	PK- tailoureda (N=25)
	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 with logarithmic link function. Subjects receiving doses in multiple regimens are included in summaries for multiple regimens. ITT = intent to treat; N = Number of subjects included in the analysis a Targeting FVIII activity trough levels of >3% of normal

Of note, ABR is not comparable between different factor concentrates and between different clinical studies

Long-term haemostatic efficacy was evaluated in 910 bleeding episodes treated with ADYNOVI and was rated excellent or good in 88.5% of bleeding episodes. Across age categories and for both the fixed-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-label multi-centre study in 121 (115 randomized) adolescents (12–18 years old) and adult PTPs with severe haemophilia A for a 12 months treatment period. The study compared 2 PK-guided prophylactic dosing regimens of ADYNOVI that targeted Factor VIII trough levels of 1–3% dosed twice weekly (N=57) or 8–12% dosed every other day (N=58), by assessing the proportions of subjects achieving a total ABR of 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/kg per 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 of prophylaxis, median trough levels in the second 6-month period (based on the one-stage clotting assay and calculated to the end of the planned infusion interval) ranged from 2.10 IU/dL to 3.00 IU/dL in the 1–3% 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 and maintain the desired FVIII trough levels.

The primary endpoint of the study, proportion of subjects who had a total ABR of 0 during the second 6 month period, was not reached in the ITT patient population (p= 0.0545) but was reached in the perprotocol 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 Population
	1–3% 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 = Annualizedjoint 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 Population
	1–3% 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-protocolpopulation = all subjects who completed the second 6 months of prophylactic treatment and had no major deviations 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 clinical studies

Total ABRs, spontaneous ABRs and spontaneous AJBRs during the second 6-month study period are presented 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 = Annualizedjoint bleeding rate. Annualized bleeding rate determined by dividing the number of bleeds by observation period in years .
	Per Protocol Population
	1–3% 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 = Annualizedjoint bleeding rate. Per-protocolpopulation = all subjects who completed the second 6 months of prophylactic treatment and had no major deviations 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 in 40 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 at resolution of the bleeding episode was rated excellent or good in 84.7% (205/242) of bleeds.

5.2 Pharmacokinetic properties

The pharmacokinetics (PK) of ADYNOVI were evaluated in a crossover study with octocog alfa in 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 the one stage clotting assay and chromogenic assay.

ADYNOVI has an extended half-life of 1.4 to 1.5-fold compared to recombinant human coagulation factor VIII (octocog alfa) in the adolescent and adult population, as determined based on one stage clotting and chromogenic assays, respectively. An increase in AUC and a decrease in clearance as compared to the parent molecule, octocog alfa, were also observed. Incremental recovery was comparable with both products. The change in PK parameters was similar in both the adult and adolescent 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-treat analysis) are available for 14 children (2 to less than 6 years), 17 older children (6 to less than 12 years) and 8 adolescent subjects (12 to < 18 years of age). The half-life extension in the paediatric 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 was lower 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) _____________­_________________

PK parameters	ADYNOVI Adults (18 years and older) N = 18 Dose: 45 ± 5 lU/kg	ADYNOVI Adolescents (12-<18 years) N = 8 Dose: 45 ± 5 IU/kg	ADYNOVI Paediatric patients (6-<12 years) N = 17 Dose: 50 ± 10 lU/kg	ADYNOVI Paediatric patients (< 6 years) N = 14 Dose: 50 ± 10 IU/kg
Design	Individual PK with full sampling3		Population PK wit	h sparse samplingb
Terminal half–life [h]	15.01 ± 3.89	13.80 ± 4.01	11.93 ± 2.58	12.99 ± 8.75
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
Incremental recovery [(IU/dL)/(IU/kg)]	2.87 ± 0.61	2.34 ± 0.62	nac (2.19± 0.40)	nac (1.90 ± 0.27)
AUCo-Inf [IU-h/dL]	2 589± 848	1 900 ± 841	2259±514	2 190 ± 1 593
Vss [dL/kg]	0.40 ± 0.09	0.54 ± 0.22	0.46 ± 0.04	0.54 ± 0.03
Cmax [IU/dL]	145 ± 29	117 ± 28	nac (130±24)	nac (117± 16)
Abbreviations: Cmax: maximum observed time; CL: clearance; Vss: body weight ad		activity; AUC: area under the curve; MRT: mean residence justed 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/(kgJi) for subject 122001 in age group 12 to < 18 years was not included in the analysis of clearance.

5.3 Preclinical safety data

In the repeat dose toxicity study in Cynomologous monkey, two animals showed vacuolation in the kidney in the mid dose group (350IU/kg). The vacuolations did not recover after 2 weeks. The human relevance 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 conducted with ADYNOVI. Thus it was not possible to conclude on the potential risks of PEG accumulation in various 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder

Mannitol

Trehalose dihydrate

Histidine

Glutathione

Sodium chloride

Calcium chloride dihydrate

Tris(hydroxymet­hyl)aminometha­ne

Polysorbate 80

Solvent

Sterilised water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial

2 years.

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

After reconstitution

Chemical and physical in-use stability has been demonstrated for 3 hours at a temperature not above 30 °C. From a microbiological point of view, unless the method of reconstitution precludes the risk 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.

6.4 Special precautions for storage

Store refrigerated (2°to 8 °C).

Do not freeze.

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

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

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

6.5 Nature and contents of container

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 rubber stopper, containing 5 ml of sterilised water for injections.

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 vial

and a device for reconstitution (BAXJECT II Hi-Flow).

• – ADYNOVI in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in

a sealed blister, with the powder vial and the solvent vial preassembled for reconstitution.

6.6 Special precautions for disposal and other handling

The reconstituted medicinal product should be inspected visually for particulate matter and discolouration prior to administration. The solution should be clear or slightly opalescent. Solutions that are cloudy or have deposits should not be used.

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 the reconstitution 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 the inside (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 the solvent 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 touch the exposed purple plastic spike.

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

  
  

Administration

• •     Visually inspect the reconstituted solution for particulate matter and discolouration prior to

• administration.

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 steps

• 1. Remove the blue cap from the BAXJECT II Hi-Flow device (Figure E). Do not draw air into the syringe. Connect the syringe to the BAXJECT II Hi-Flow. Use of a Luer-lock syringe is recommended.

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

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

A separate BAXJECT II Hi-Flow device is required to reconstitute each vial of ADYNOVI with the 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 of the 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 blister

• 1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent vials preassembled with the system for reconstitution) from the refrigerator and let it reach room temperature (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 from the blister.

• 4. Place the powder vial on a flat surface with the solvent vial on top (Figure 1). The solvent vial has 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 the solvent vial with the other hand until the system is fully collapsed and the solvent flows down into 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 reconstituted solution will pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should be clear, colourless and free from particles.

Figure 1 Figure 2 Figure 3

Administration

• • Visually inspect the reconstituted solution for particulate matter and discolouration prior to

administration.

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 steps

• 1. Remove the blue cap from the BAXJECT III device. Do not draw air into the syringe. Connect the syringe to the BAXJECT III device. Use of a Luer-lock syringe is recommended.

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

• 3. Disconnect the syringe; attach a suitable needle and inject intravenously. If a patient is to receive more than one vial of ADYNOVI, the contents of multiple vials may be drawn into the same 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 of the 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 local requirements.

7. MARKETING AUTHORISATION HOLDER

Baxalta Innovations GmbH

Industriestrasse 67

A-1221 Vienna

Austria

8. MARKETING AUTHORISATION NUMBER(S)

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 08 January 2018