This information is intended for use by health professionals

1. Name of the medicinal product

ReFacto AF 250 IU powder and solvent for solution for injection

ReFacto AF 500 IU powder and solvent for solution for injection

ReFacto AF 1000 IU powder and solvent for solution for injection

ReFacto AF 2000 IU powder and solvent for solution for injection

ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe

ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe

ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe

ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe

ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe

2. Qualitative and quantitative composition

ReFacto AF 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 62.5 IU moroctocog alfa.

ReFacto AF 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 125 IU moroctocog alfa.

ReFacto AF 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 250 IU moroctocog alfa.

ReFacto AF 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 500 IU moroctocog alfa.

ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe

Each pre-filled syringe contains nominally 250 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 62.5 IU moroctocog alfa.

ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe

Each pre-filled syringe contains nominally 500 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 125 IU moroctocog alfa.

ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe

Each pre-filled syringe contains nominally 1000 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 250 IU moroctocog alfa.

ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe

Each pre-filled syringe contains nominally 2000 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 500 IU moroctocog alfa.

ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe

Each pre-filled syringe contains nominally 3000 IU* moroctocog alfa**.

After reconstitution, each mL of solution contains approximately 750 IU moroctocog alfa.

* The potency (International Units) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of ReFacto AF is 7,600-13,800 IU/mg protein.

** Human coagulation factor VIII produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Moroctocog alfa is a glycoprotein with 1438 amino acids with a sequence that is comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted) and similar post-translational modifications to those of the plasma-derived molecule.

The manufacturing process for ReFacto was modified to eliminate any exogenous human- or animal-derived protein in the cell culture process, purification, or final formulation; and at the same time the invented name was changed to ReFacto AF.

Excipient with known effect:

After reconstitution, 1.23 mmol (29 mg) sodium per vial or pre-filled syringe

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection

Powder and solvent for solution for injection

White to off-white cake/powder

Clear, colourless solvent

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection in pre-filled syringe

Powder and solvent for solution for injection in pre-filled syringe

White to off-white cake/powder in top chamber of the pre-filled syringe

Clear, colourless solvent in bottom chamber of the pre-filled syringe

4. Clinical particulars
4.1 Therapeutic indications

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

ReFacto AF is appropriate for use in adults and children of all ages, including newborns.

ReFacto AF does not contain von Willebrand factor, and hence is not indicated in von Willebrand's disease.

4.2 Posology and method of administration

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

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.

When monitoring patients' factor VIII activity levels during treatment with ReFacto AF, use of the chromogenic assay is recommended. When using an in vitro thromboplastin time (aPTT)-based one-stage clotting assay for determining factor VIII activity in patients' blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one-stage clotting assay and the chromogenic assay. Typically, one-stage clotting assay results are 20-50% lower than the chromogenic substrate assay results. The ReFacto AF laboratory standard can be used to correct for this discrepancy (see section 5.2). This is of importance particularly when changing the laboratory and/or reagents used.

Posology

The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of bleeding, and on the patient's clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required.

The number of units of factor VIII administered is expressed in International Units (IUs), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for factor VIII in plasma). One IU of factor VIII activity is equivalent to the quantity of factor VIII in one mL of normal human plasma.

Another moroctocog alfa product approved for use outside Europe has a different manufacturing potency assigned that has been calibrated to the WHO International Standard using a one-stage clotting assay; this product is identified by the tradename XYNTHA. Due to the difference in methods used to assign product potency of XYNTHA and ReFacto AF, 1 IU of the XYNTHA product (one-stage assay calibrated) is approximately equivalent to 1.38 IU of the ReFacto AF product (chromogenic assay calibrated). If a patient normally treated with XYNTHA is prescribed ReFacto AF, the treating physician may consider adjustment of dosing recommendations based on factor VIII recovery values.

Based on their current regimen, individuals with haemophilia A should be advised to bring an adequate supply of factor VIII product for anticipated treatment when travelling. Patients should be advised to consult with their healthcare provider prior to travel.

On demand treatment

The calculation of the required dose of factor VIII is based upon the empirical finding that 1 IU of 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 units (IU) = body weight (kg) x desired factor VIII rise (% or IU/dl) x 0.5 (IU/kg per IU/dl), where 0.5 IU/kg per IU/dl represents the reciprocal of the recovery generally observed following infusions of factor VIII.

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, the factor VIII activity should not fall below the given plasma levels (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide 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 every 12-24 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 infusion every 12-24 hours for 3-4 days or more until pain and acute disability are resolved.

Life-threatening haemorrhages

60-100

Repeat infusion every 8-24 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 post-operative)

Repeat infusion every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl).

Prophylaxis

For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

Paediatric population

The need for an increased dose relative to that used for adults and older children should be anticipated when treating younger children (less than 6 years of age) with ReFacto AF (see section 5.2).

Elderly population

Clinical studies did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualised.

Renal or hepatic impairment

Dose adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

Method of administration

Intravenous use.

ReFacto AF is administered by intravenous infusion over several minutes after reconstitution of the lyophilised powder for injection with sodium chloride 9 mg/mL (0.9%) solution for injection (provided). The rate of administration should be determined by the patient's comfort level.

Appropriate training is recommended for non-healthcare professionals administering the product.

For reconstitution instructions prior to administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known allergic reaction to hamster protein.

4.4 Special warnings and precautions for use

Hypersensitivity

Allergic type hypersensitivity reactions have been observed with ReFacto AF. The medicinal product contains traces of 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 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.

Reports of lack of effect

Reports of lack of effect, mainly in prophylaxis patients, have been received in the clinical trials and in the post-marketing setting for ReFacto. The reported lack of effect with ReFacto has been described as bleeding into target joints, bleeding into new joints or a subjective feeling by the patient of new onset bleeding. When prescribing ReFacto AF it is important to individually titrate and monitor each patient's factor level in order to ensure an adequate therapeutic response (see section 4.8).

It is strongly recommended that every time ReFacto AF is administered to a patient, the name on the carton and batch number of the product are recorded in order to maintain a link between the patient and the batch number of the medicinal product. Patients can affix one of the peel-off labels found on the vial or pre-filled syringe to document the batch number in their diary or for reporting any side effects.

Cardiovascular events

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

Catheter-related complications

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 (see section 4.8).

Sodium content

After reconstitution this medicinal product contains 1.23 mmol (29 mg) sodium per vial or pre-filled syringe, to be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions of recombinant coagulation factor VIII products with other medicinal products have been reported.

4.6 Fertility, pregnancy and lactation

Animal reproduction studies have not been conducted with factor VIII, therefore no data are available on fertility. Because of 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 breast-feeding only if clearly indicated.

4.7 Effects on ability to drive and use machines

ReFacto AF 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 infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently for ReFacto, and may in some cases progress to severe anaphylaxis including shock (see section 4.4).

Trace amounts of hamster protein may be present in ReFacto AF. Very rarely, development of antibodies to hamster protein has been observed, but there were no clinical sequelae. In a study of ReFacto, twenty of 113 (18%) previously treated patients (PTPs) had an increase in anti-CHO antibody titre, without any apparent clinical effect.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ReFacto AF (see section 5.1). 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.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). The table lists adverse reactions reported in the clinical trials with ReFacto or ReFacto AF. The frequencies are based on all causality treatment emergent adverse events in pooled clinical trials with 715 subjects (591 PTPs, 124 previously untreated patients (PUPs)).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Very common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Blood and lymphatic system disorders

FVIII inhibition (PUPs)*

FVIII inhibition (PTPs)* +

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Decreased appetite

Nervous system disorders

Headache

Dizziness

Neuropathy peripheral; somnolence; dysgeusia

Cardiac disorders

Angina pectoris; tachycardia; palpitations

Vascular disorders

Haemorrhage; haematoma

Hypotension; thrombophlebitis; flushing

Respiratory, thoracic and mediastinal disorders

Cough

Dyspnoea

Gastrointestinal disorders

Diarrhoea; vomiting; abdominal pain; nausea

Skin and subcutaneous tissue disorders

Urticaria; rash; pruritus

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia

General disorders and administration site conditions

Pyrexia

Chills; catheter site related reaction

Asthenia; injection site reaction; injection site pain; injection site inflammation

Investigations

Antibody test positive; Anti-factor VIII antibody test positive

Aspartate aminotransferase increased; alanine aminotransferase increased; blood bilirubin increased; blood creatinine phosphokinase increased

* Frequency is based on studies which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients

+ see section 5.1 for further information

Paediatric population

One event of cyst in an 11-year old patient and one event described as confusion in a 13-year old patient have been reported as possibly related to ReFacto AF treatment.

Safety of ReFacto AF was evaluated in studies that included both previously treated adults and previously treated children and adolescents (n=18, aged 12-16 years in a study and n=49, aged 7-16 years in a supporting study), with a tendency for higher frequencies of adverse reactions in children aged 7-16 years as compared to adults. Additional safety experience in children has been accrued through studies that encompassed both previously treated (n=18 aged <6 years and n=19 aged 6 to <12 years) and previously untreated (n=23 aged <6 years) patients and which supports a safety profile similar with that observed in adult patients.

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.

United Kingdom

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517,

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

4.9 Overdose

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

ReFacto AF contains B-domain deleted recombinant coagulation factor VIII (moroctocog alfa). It is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. ReFacto AF has functional characteristics comparable to those of endogenous factor VIII. Factor VIII activity is greatly reduced in patients with haemophilia A, and, therefore, replacement therapy is necessary.

When infused into a haemophiliac patient, factor VIII binds to the von Willebrand factor present 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 is formed. Haemophilia A is a sex-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 a result 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.

Clinical efficacy

The data in the table below relates to PUP and PTP data from ReFacto AF studies in patients <12 years.

Consumption and efficacy results in paediatric population

PTPs

<6 years

PTPs

6 to <12 years

PUPs

<6 years

Dose by weight (IU/kg) per prophylaxis infusion a

median (min, max)

N=14

36 IU/kg

(28, 51)

N=13

32 IU/kg

(21, 49)

N=22

46 IU/kg

(17,161)

Total ABR all subjects b

median (min, max)

--

--

N=23

3.17

(0.0, 39.5)

Total ABR for subjects who reported following an On Demand regimen at Baseline c

median (min, max)

N=5

41.47

(1.6, 50.6)

N=9

25.22

(0.0, 46.6)

--

Total ABR for subjects who reported following a Prophylaxis regimen at Baseline c

median (min, max)

N=13

1.99

(0.0, 11.2)

N=9

5.55

(0.0, 13.0)

--

Dose by weight (IU/kg) per bleeding episode for bleed treatment

median (min, max)

N=13

35 IU/kg

(28, 86)

N=14

33 IU/kg

(17, 229)

N=21

55 IU/kg

(11, 221)

% of bleeds treated successfully with ≤ 2 infusions

98.7%

98.8%

96.7%

a The dose and frequency of ReFacto AF prescribed throughout the study were at the investigator's discretion as per local standard of care.

b Subjects in the PUP study were not required to follow a regular continuous prophylaxis treatment; however, with the exception of one subject (with only on demand (OD) treatment) the majority of subjects took regular prophylaxis infusions. Several began with OD infusions but switched to prophylaxis treatment during their participation, and some had only sporadic prophylaxis infusions.

c Subjects in the PTP study reported their FVIII treatment modality (prophylaxis or on demand) at baseline and were not required to maintain this modality as a condition of study participation. The dose and frequency of ReFacto AF prescribed throughout the study were at the investigator's discretion as per local standard of care.

Abbreviations: ABR = annualised bleeding rate

Factor VIII inhibition

Previously Treated Patients

Within a pooled dataset of 591 PTPs treated with ReFacto (1 clinical study) or ReFacto AF (6 clinical studies), there were 10 (1.7%) confirmed factor VIII inhibitor cases (1 high-titre (≥ 5 BU/mL), 9 low-titre (< 5 BU/mL)).

In a clinical study with ReFacto AF in previously treated patients (PTPs) (factor VIII:C ≤ 2%) , the incidence of factor VIII inhibitors was the primary safety endpoint. Two clinically silent, low-titre, transient inhibitors were observed in 94 patients with a median exposure of 76 exposure days (ED, range 1-92), corresponding to 2.2% of the 89 patients with at least 50 ED. In a supporting study of ReFacto AF, 1 de novo and 2 recurrent inhibitors (all low-titre, central laboratory determination) were observed in 110 patients (PTPs) (factor VIII:C ≤ 2%); median exposure of 58 ED (range 5-140) and 98 patients had at least 50 ED to ReFacto AF. Ninety-eight (98) of the original 110 patients continued treatment in a second supportive study and had subsequent extended exposure to ReFacto AF with a median of 169 additional ED (range 9-425). One (1) additional low-titre de novo inhibitor was observed.

In a clinical study of PTPs with haemophilia A (factor VIII:C ≤ 2%) undergoing major surgery, 1 low-titre inhibitor was observed in 30 patients who received treatment with ReFacto AF.

In a clinical study with ReFacto in PTPs (factor VIII:C < 2%), 1 high-titre inhibitor was observed in 113 patients.

In a clinical study with ReFacto AF in paediatric (<12 years of age, N=37) PTPs (FVIII:C <1%), the percentage of patients with clinically significant inhibitor development was the primary safety outcome. No patient met the protocol-defined criteria of clinically significant FVIII inhibition. Transient, low-titre FVIII inhibitor development was observed in 2 patients (<6 years of age). Both patients showed a dip in recovery at the same visit (ED 10 – 15), the inhibitor test was positive, with subsequent return to expected recovery. Neither patient experienced any clinical manifestation of FVIII inhibition and did not receive specific treatment for the event.

Immune Tolerance Induction

Data on immune tolerance induction (ITI) have been collected in patients with haemophilia A who had developed inhibitors to factor VIII. As part of the pivotal trial with ReFacto in PUPs, ITI data from 25 patients were reviewed (15 with high titres, 10 with low titres). Of these 25 patients, 20 had a decrease in inhibitor titres to < 0.6 BU/mL, of whom initially 11 of 15 had high titres (≥ 5 BU/mL) and 9 of 10 had low titres. Out of 6 patients who developed low titre inhibitors but did not receive ITI, 5 had similar titre decreases. No long-term outcome is available.

5.2 Pharmacokinetic properties

Pharmacokinetic properties of ReFacto, derived from a cross-over study of ReFacto and a plasma-derived FVIII concentrate, using the chromogenic substrate assay (see section 4.2), in 18 previously treated patients are listed in the table below.

Pharmacokinetic parameter estimates for ReFacto in previously treated patients with haemophilia A

PK parameter

Mean

SD

Median

AUCt (IU·h/mL)

19.9

4.9

19.9

t1/2 (h)

14.8

5.6

12.7

CL (mL/h·kg)

2.4

0.75

2.3

MRT (h)

20.2

7.4

18.0

recovery

(IU/dl increase in FVIII:C per IU/kg FVIII given)

2.4

0.38

2.5

Abbreviations: AUCt = area under the plasma concentration-time curve from zero to the last measurable concentration; t½ = half-life; CL = clearance; FVIII:C = FVIII activity; MRT = mean residence time

In a study in which the potency of ReFacto AF, ReFacto and FVIII activity in patient plasma were measured using the chromogenic substrate assay, ReFacto AF was shown to be bioequivalent to ReFacto. The ratios of geometric least-square means of ReFacto AF-to-ReFacto were 100.6%, 99.5% and 98.1% for recovery, AUCt and AUC (area under the plasma concentration curve from time zero to infinity), respectively. The corresponding 90% confidence intervals about the ratios of ReFacto AF to ReFacto geometric means were within the bioequivalence window of 80% to 125%, demonstrating bioequivalence of ReFacto AF to ReFacto.

In a cross-over pharmacokinetic study, the pharmacokinetic parameters for ReFacto AF were determined at baseline and followed up in 25 previously treated patients (≥ 12 years) after repeated administration of ReFacto AF for six months. The ratios of geometric least-square means of month 6-to-baseline pharmacokinetic were 107%, 100% and 104% for recovery, AUCt and AUC, respectively. The corresponding 90% confidence intervals about the ratios of month 6-to-baseline for the above pharmacokinetic parameters were within the equivalence window of 80% to 125%. This indicates no time-dependent changes in the pharmacokinetic properties of ReFacto AF.

In the same study, in which the drug potency of ReFacto AF and a full-length recombinant factor VIII (FLrFVIII) comparator, and the FVIII activity measured in patient plasma samples were all determined using the same one-stage clotting assay at a central laboratory, ReFacto AF was shown to be pharmacokinetically equivalent to FLrFVIII in 30 previously treated patients (≥ 12 years) using the standard bioequivalence approach.

In PUPs, pharmacokinetic parameters of ReFacto were evaluated using the chromogenic assay. These patients (n=59; median age 10 ± 8.3 months) had a mean recovery at Week 0 of 1.5 ± 0.6 IU/dl per IU/kg (range 0.2 to 2.8 IU/dl per IU/kg) which was lower than that obtained in PTPs treated with ReFacto at Week 0 with a mean recovery of 2.4 ± 0.4 IU/dl per IU/kg (range 1.1 to 3.8 IU/dl per IU/kg). In the PUPs, the mean recovery was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dl per IU/kg. Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of 8.0 ± 2.2 hours.

In a ReFacto AF study of 19 PUPs, the recovery at the beginning of the study in the 17 children aged 28 days to less than 2 years was 1.32 ± 0.65 IU/dl per IU/kg and in the 2 children aged 2 to <6 years were 1.7 and 1.8 IU/dl per IU/kg. Except in cases where inhibitors were detected, the mean recovery was stable over time (6 visits during a 2-year period) and individual values ranged from 0 (in presence of inhibitor) to 2.7 IU/dl per IU/kg.

In a study of 37 paediatric PTPs, the pharmacokinetic parameters of ReFacto AF observed after a 50 IU/kg dose are shown in the table below.

Mean ± SD FVIII Pharmacokinetic Parameters after Single 50 IU/kg Dose in Paediatric PTPs

PK parameter

Number of subjects

Meana ± SD

Recovery, IU/dl per IU/kg

Aged <6 years

Aged 6 to <12 years

17

19

1.7 ± 0.4

2.1 ± 0.8

Cmax, IU/mLb

19

0.9 (45)

AUCinf, IU∙h/mLb

14

9.9 (41)

t½, hb

14

9.1 ± 1.9

CL, mL/h/kgb

14

4.4 (30)

Vss, mL/kgb

14

56.4 (15)

a Geometric mean (geometric CV%) for all, except for arithmetic mean ±SD for incremental recovery and t½.

b Patients aged 6 to <12 years only.

Abbreviations: Cmax = maximum observed plasma concentration; CV = coefficient of variation; AUCinf = area under the plasma concentration-time profile from time zero extrapolated to infinite time; t½ = terminal half-life; CL = clearance; Vss = steady-state volume of distribution.

5.3 Preclinical safety data

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

No investigations on carcinogenic potential or toxicity to reproduction have been conducted.

6. Pharmaceutical particulars
6.1 List of excipients

Powder

Sucrose

Calcium chloride dihydrate

L-Histidine

Polysorbate 80

Sodium chloride

Solvent

Sodium chloride

Water for injections

6.2 Incompatibilities

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

Only the provided infusion set is to be used, because treatment failure can occur as a consequence of human-coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf life

3 years.

The product may be removed from refrigerated storage for one single period of maximum 3 months at room temperature (up to 25°C). At the end of this period of room temperature storage, the product must not be returned to refrigerated storage, but is to be used or discarded.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 3 hours at temperatures up to 25°C.

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection

The product does not contain a preservative, and the reconstituted product should be used immediately, or within 3 hours after reconstitution. Other in-use storage times and conditions are the responsibility of the user.

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection in pre-filled syringe

The product does not contain a preservative, and the reconstituted product should be used immediately, or within 3 hours after reconstitution or removal of the grey tip cap. Other in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection in pre-filled syringe

Store and transport refrigerated (2°C - 8°C). Do not freeze.

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

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

6.5 Nature and contents of container

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection

250 IU, 500 IU, 1000 IU or 2000 IU powder in a 10 mL vial (type 1 glass) with a stopper (butyl) and a flip-off seal (aluminium) and 4 mL of solvent in a pre-filled syringe (type 1 glass) with a plunger stopper (butyl), a tip-cap (butyl) and a sterile vial adapter reconstitution device, a sterile infusion set, alcohol swabs, a plaster and a gauze pad.

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection in pre-filled syringe

250 IU, 500 IU, 1000 IU, 2000 IU or 3000 IU lyophilised powder in top chamber and 4 mL of solvent in bottom chamber of the pre-filled syringe (type 1 glass) with butyl rubber plungers and closure, one plunger rod for assembly, a polypropylene vented sterile cap, a sterile infusion set, alcohol swabs, a plaster and a gauze pad.

Pack size of 1.

6.6 Special precautions for disposal and other handling

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection

The vial of lyophilised product powder for injection must be reconstituted with the supplied solvent [sodium chloride 9 mg/mL (0.9%) solution] from the pre-filled syringe using the sterile vial adapter reconstitution device. The vial should be gently rotated until all of the powder is dissolved. Please see package leaflet, section 3, for additional information on reconstitution and administration.

After reconstitution, the solution is drawn back into the syringe. The solution will be clear or slightly opalescent and colourless. The solution is to be discarded if visible particulate matter or discolouration is observed.

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection in pre-filled syringe

The lyophilised powder in the top chamber of the pre-filled syringe must be reconstituted with the solvent [sodium chloride 9 mg/mL (0.9%) solution] in the bottom chamber of the pre-filled syringe. The pre-filled syringe should be gently rotated until all of the powder is dissolved. Please see package leaflet, section 3, for additional information on reconstitution and administration.

After reconstitution, the solution will be clear or slightly opalescent and colourless. The solution is to be discarded if visible particulate matter or discolouration is observed.

The product, when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This is to be considered during the preparation and administration of the product, including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations in section 6.3 be followed closely.

Any unused product or waste material is to be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Bruxelles

Belgium

8. Marketing authorisation number(s)

ReFacto AF

250 IU powder and solvent for solution for injection: EU/1/99/103/001

500 IU powder and solvent for solution for injection: EU/1/99/103/002

1000 IU powder and solvent for solution for injection: EU/1/99/103/003

2000 IU powder and solvent for solution for injection: EU/1/99/103/004

250 IU powder and solvent for solution for injection in pre-filled syringe: EU/1/99/103/009

500 IU powder and solvent for solution for injection in pre-filled syringe: EU/1/99/103/006

1000 IU powder and solvent for solution for injection in pre-filled syringe: EU/1/99/103/007

2000 IU powder and solvent for solution for injection in pre-filled syringe: EU/1/99/103/008

3000 IU powder and solvent for solution for injection in pre-filled syringe: EU/1/99/103/005

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 13 April 1999

Date of latest renewal: 15 April 2014

10. Date of revision of the text

08/2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

Ref: RF 12_0