REFACTO AF 2000UI powder + solvent for injection medication leaflet

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 chromogenicassay. 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 hamsterovary (CHO) cells. Moroctocog alfa is a glycoprotein with 1438 amino acids with a sequence that iscomparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted) and similarpost-translational modifications to those of the plasma-derived molecule.

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

After reconstitution, 1.27 mmol (29 mg) sodium per vial or pre-filled syringe.

For the full list of excipients, see section 6.1.

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 injectionin 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

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

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’sdisease.

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

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.

When monitoring patients' factor VIII activity levels during treatment with ReFacto AF, use of thechromogenic assay is recommended. When using an in vitro thromboplastin time (aPTT)-basedone-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 referencestandard used in the assay. Also there can be significant discrepancies between assay results obtainedby aPTT-based one-stage clotting assay and the chromogenic assay. Typically, one-stage clottingassay results are 20-50% lower than the chromogenic substrate assay results. The ReFacto AFlaboratory standard can be used to correct for this discrepancy (see section 5.2). This is of importanceparticularly when changing the laboratory and/or reagents used.

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 administeredshould be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses orappropriate specific treatment may be required.

The number of units of factor VIII administered is expressed in International Units (IUs), which arerelated to the current WHO standard for factor VIII products. Factor VIII activity in plasma isexpressed 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 thequantity of factor VIII in one mL of normal human plasma.

Another moroctocog alfa product approved for use outside Europe has a different manufacturingpotency assigned that has been calibrated to the WHO International Standard using a one-stageclotting assay; this product is identified by the tradename XYNTHA. Due to the difference in methodsused 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 onfactor VIII recovery values.

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

The calculation of the required dose of factor VIII is based upon the empirical finding that 1 IU offactor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose isdetermined 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 followinginfusions of factor VIII.

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, the factor VIII activity should not fall below thegiven plasma levels (in % of normal or in IU/dl) in the corresponding period. The following table canbe used to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage/ Factor VIII level Frequency of doses (hours)/

Type of surgical procedure required (% or IU/dl) Duration of therapy (days)

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

More extensive haemarthrosis, 30-60 Repeat infusion every 12-24 hours formuscle bleeding or haematoma 3-4 days or more until pain and acutedisability are resolved.

Life-threatening haemorrhages 60-100 Repeat infusion every 8-24 hours untilthreat is resolved.

Minor surgery 30-60 Every 24 hours, at least 1 day, untilincluding tooth extraction healing is achieved.

Major surgery 80-100 Repeat infusion every 8-24 hours until(pre- and adequate wound healing, then therapypost-operative) for at least another 7 days to maintain afactor VIII activity of 30% to 60%(IU/dl).

For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially inyounger patients, shorter dose intervals or higher doses may be necessary.

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

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

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

ReFacto AF is administered by intravenous infusion over several minutes after reconstitution of thelyophilised 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.

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

Known allergic reaction to hamster protein.

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

Patients can affix one of the peel-off labels found on the vial or pre-filled syringe to document thebatch number in their diary or for reporting any side effects.

Allergic type hypersensitivity reactions have been observed with ReFacto AF. The medicinal productcontains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advisedto discontinue use of the medicinal product immediately and contact their physician. Patients should beinformed 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.

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

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low 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.

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

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

If a central venous access device (CVAD) is required, risk of CVAD-related complications includinglocal infections, bacteraemia and catheter site thrombosis should be considered (see section 4.8).

After reconstitution this medicinal product contains 1.27 mmol (29 mg) sodium per vial or pre-filledsyringe, equivalent to 1.5% of the WHO recommended maximum daily intake (RDI) of 2 g sodium foran adult. Depending on body weight of the patient and posology of ReFacto AF, patients could receivemultiple vials or pre-filled syringes. This should be taken into consideration if the patient is on a lowsalt diet.

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

Animal reproduction studies have not been conducted with factor VIII, therefore no data are availableon fertility. Because of the rare occurrence of haemophilia A in women, experience regarding the useof factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should beused during pregnancy and breast-feeding only if clearly indicated.

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

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedinfrequently for ReFacto, and may in some cases progress to severe anaphylaxis including shock (seesection 4.4).

Trace amounts of hamster protein may be present in ReFacto AF. Very rarely, development ofantibodies 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-CHOantibody titre, without any apparent clinical effect.

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

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: verycommon (≥ 1/10); common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). The table listsadverse reactions reported in the clinical trials with ReFacto or ReFacto AF. The frequencies are basedon all causality treatment emergent adverse events in pooled clinical trials with 765 subjects.

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

System Organ Class Very common Common Uncommon≥ 1/10 ≥ 1/100 ≥ 1/1,000 toto < 1/10 < 1/100

Blood and lymphatic FVIII inhibition FVIII inhibitionsystem disorders (PUPs)* (PTPs)*

Immune system Anaphylactic reactiondisorders

Metabolism and Decreased appetitenutrition disorders

Nervous system Headache Dizziness Neuropathy peripheral;disorders somnolence; dysgeusia

Cardiac disorders Angina pectoris; tachycardia;palpitations

Vascular disorders Haemorrhage; Hypotension; thrombophlebitis;haematoma flushing

Respiratory, thoracic Cough Dyspnoeaand mediastinaldisorders

Gastrointestinal Diarrhoea; vomiting;disorders abdominal pain; nausea

Skin and subcutaneous Urticaria; rash; pruritus Hyperhidrosistissue disorders

Musculoskeletal and Arthralgia Myalgiaconnective tissuedisorders

General disorders and Pyrexia Chills; catheter site Asthenia; injection site reaction;administration site related reaction injection site pain; injection siteconditions inflammation

Investigations Antibody test positive; Aspartate aminotransferase

Anti-factor VIII increased; alanineantibody test positive aminotransferase increased;blood bilirubin increased; bloodcreatinine phosphokinaseincreased

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

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

Safety of ReFacto AF was evaluated in studies that included both previously treated adults andpreviously treated children and adolescents (n=18, aged 12-16 years in a study and n=49, aged 7-16years in a supporting study), with a tendency for higher frequencies of adverse reactions in childrenaged 7-16 years as compared to adults. Additional safety experience in children has been accruedthrough 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 profilesimilar with that observed in adult patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

ReFacto AF contains B-domain deleted recombinant coagulation factor VIII (moroctocog alfa). It is aglycoprotein 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 VIIIactivity is greatly reduced in patients with haemophilia A, and, therefore, replacement therapy isnecessary.

When infused into a haemophiliac patient, factor VIII binds to the von Willebrand factor present in thepatient’s circulation.

Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor Xto activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then convertsfibrinogen into fibrin, and a clot is formed. Haemophilia A is a sex-linked hereditary disorder of bloodcoagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, musclesor internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacementtherapy, the plasma levels of factor VIII are increased, thereby enabling a temporary correction of thefactor deficiency and correction of the bleeding tendencies.

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 PTPs PUPs<6 years 6 to <12 years <6 years

Dose by weight (IU/kg) per N=14 N=13 N=22prophylaxis infusion a 36 IU/kg 32 IU/kg 46 IU/kgmedian (min, max) (28, 51) (21, 49) (17,161)

Total ABR all subjects b N=23median (min, max) -- -- 3.17(0.0, 39.5)

Total ABR for subjects whoreported following an On Demand N=5 N=9regimen at Baseline c 41.47 25.22 --median (min, max) (1.6, 50.6) (0.0, 46.6)

Total ABR for subjects whoreported following a Prophylaxis N=13 N=9regimen at Baseline c 1.99 5.55 --median (min, max) (0.0, 11.2) (0.0, 13.0)

Dose by weight (IU/kg) perbleeding episode for bleed N=13 N=14 N=21treatment 35 IU/kg 33 IU/kg 55 IU/kgmedian (min, max) (28, 86) (17, 229) (11, 221)% of bleeds treated successfullywith ≤ 2 infusions 98.7% 98.8% 96.7%a The dose and frequency of ReFacto AF prescribed throughout the study were at theinvestigator’s discretion as per local standard of care.b Subjects in the PUP study were not required to follow a regular continuous prophylaxistreatment; 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 infusionsbut switched to prophylaxis treatment during their participation, and some had only sporadicprophylaxis infusions.c Subjects in the PTP study reported their FVIII treatment modality (prophylaxis or ondemand) at baseline and were not required to maintain this modality as a condition of studyparticipation. The dose and frequency of ReFacto AF prescribed throughout the study were atthe investigator’s discretion as per local standard of care.

Abbreviations: ABR = annualised bleeding rate

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

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

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 previouslytreated 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 19.9t1/2 (h) 14.8 5.6 12.7

CL (mL/h·kg) 2.4 0.75 2.3

MRT (h) 20.2 7.4 18.0recovery(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 measurableconcentration; 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 weremeasured 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 zeroto infinity), respectively. The corresponding 90% confidence intervals about the ratios of ReFacto AFto ReFacto geometric means were within the bioequivalence window of 80% to 125%, demonstratingbioequivalence of ReFacto AF to ReFacto.

In a cross-over pharmacokinetic study, the pharmacokinetic parameters for ReFacto AF weredetermined at baseline and followed up in 25 previously treated patients (≥ 12 years) after repeatedadministration of ReFacto AF for six months. The ratios of geometric least-square means of month6-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 forthe above pharmacokinetic parameters were within the equivalence window of 80% to 125%. Thisindicates 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 determinedusing the same one-stage clotting assay at a central laboratory, ReFacto AF was shown to bepharmacokinetically equivalent to FLrFVIII in 30 previously treated patients (≥ 12 years) using thestandard bioequivalence approach.

In PUPs, pharmacokinetic parameters of ReFacto were evaluated using the chromogenic assay. Thesepatients (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) andranged from 1.5 to 1.8 IU/dl per IU/kg. Population pharmacokinetic modeling using data from44 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 aged28 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 yearswere 1.7 and 1.8 IU/dl per IU/kg. Except in cases where inhibitors were detected, the mean recoverywas stable over time (6 visits during a 2-year period) and individual values ranged from 0 (in presenceof 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 17 1.7 ± 0.4

Aged 6 to <12 years 19 2.1 ± 0.8

Cmax, IU/mLb 19 0.9 (45)

AUCinf, IU∙h/mLb 14 9.9 (41)t b½, h 14 9.1 ± 1.9

CL, mL/h/kgb 14 4.4 (30)

V bss, mL/kg 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 = areaunder the plasma concentration-time profile from time zero extrapolated to infinite time; t½ = terminal half-life; CL = clearance; Vss = steady-state volume of distribution.

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

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

Sucrose

Calcium chloride dihydrate

L-Histidine

Polysorbate 80

Sodium chloride

Sodium chloride

Water for injections

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

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

3 years.

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

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

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

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

The product does not contain a preservative, and the reconstituted product should be usedimmediately, or within 3 hours after reconstitution or removal of the grey tip cap. Other in-use storagetimes 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 injectionin 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.

ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection250 IU, 500 IU, 1000 IU or 2000 IU powder in a 10 mL vial (type 1 glass) with a stopper (butyl) and aflip-off seal (aluminum) and 4 mL of solvent in a pre-filled syringe (type 1 glass) with a plungerstopper (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 injectionin pre-filled syringe250 IU, 500 IU, 1000 IU, 2000 IU or 3000 IU lyophilised powder in top chamber and 4 mL of solventin bottom chamber of the pre-filled syringe (type 1 glass) with butyl rubber plungers and closure, oneplunger rod for assembly, a polypropylene vented sterile cap, a sterile infusion set, alcohol swabs, aplaster and a gauze pad.

Pack size of 1.

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 adapterreconstitution device. The vial should be gently rotated until all of the powder is dissolved. Please seepackage 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 slightlyopalescent and colourless. The solution is to be discarded if visible particulate matter or discolourationis observed.

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

The lyophilised powder in the top chamber of the pre-filled syringe must be reconstituted with thesolvent [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 packageleaflet, section 3, for additional information on reconstitution and administration.

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

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

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/99/103/001

EU/1/99/103/002

EU/1/99/103/003

EU/1/99/103/004

EU/1/99/103/009

EU/1/99/103/006

EU/1/99/103/007

EU/1/99/103/008

EU/1/99/103/005

Date of first authorisation: 13 April 1999

Date of latest renewal: 15 April 2014

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

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