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.

Each vial contains nominally 250 IU*, 500 IU*, 1000 IU* or 2000 IU* moroctocog alfa**

ReFacto AF 250 IU: After reconstitution, each ml of solution contains approximately 62.5 IU/ml moroctocog alfa.

ReFacto AF 500 IU: After reconstitution, each ml of the solution contains approximately 125 IU/ml moroctocog alfa.

ReFacto AF 1000 IU: After reconstitution, each ml of the solution contains approximately 250 IU/ml moroctocog alfa.

ReFacto AF 2000 IU: After reconstitution, each ml of the solution contains approximately 500 IU/ml 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. Bdomain deleted) and similar posttranslational modifications to those of the plasma-derived molecule.

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

Excipients:

After reconstitution, 1.23 mmol (29 mg) sodium per vial.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White to off-white cake/powder.

Clear, colourless solvent.

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.

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

Posology

The labelled potency of ReFacto AF is based on the European Pharmacopoeial chromogenic substrate assay, in which the manufacturing potency standard has been calibrated to the WHO International Standard using the chromogenic substrate assay. When monitoring patients' factor VIII activity levels during treatment with ReFacto AF, use of the European Pharmacopoeial chromogenic substrate assay is strongly recommended. The chromogenic assay yields results which are higher than those observed with use of the one-stage clotting 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).

Another moroctocog alfa product approved for use outside Europe has a different potency assigned using a manufacturing potency standard 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 (onestage 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.

The dosage 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 International Units (relative to an International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dosage 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 incremental 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:

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. 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. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

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 dosage intervals or higher doses may be necessary.

Patients using factorVIII replacement therapy are to be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if factor VIII inhibitors are present. Data from clinical trials indicated that if inhibitors are present at levels less than 10 Bethesda Units (BUs), administration of additional antihaemophilic factor may neutralise the inhibitors. In patients with levels of inhibitor above 10 BU, 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 patients with haemophilia (see section 4.4).

Special populations

Renal or hepatic impairment

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

Paediatric patients

Safety and efficacy studies with ReFacto have been performed both in previously treated children and adolescents (n=31, ages 8-18 years) and in previously untreated neonates, infants and children (n=101, ages < 1-52 months).

The need for an increased dose relative to that used for adults and older children should be anticipated when treating younger children with ReFacto AF. In a study of ReFacto in children less than 6 years of age, pharmacokinetic analysis revealed half-life and recovery less than that observed in older children and adults (see section 5.2). During the clinical trials, children less than 6 years of age on a prophylaxis regimen used an average dose of 50 IU/kg of ReFacto and experienced an average of 6.1 bleeding episodes per year. Older children and adults on a prophylaxis regimen used an average dose of 27 IU/kg and experienced an average of 10 bleeding episodes per year. In a clinical trial setting the mean dose per infusion of ReFacto for bleeding episodes in children less than 6 years of age was higher than the mean dose administered to older children and adults (51.3 IU/kg and 29.3 IU/kg, respectively).

Method of administration

ReFacto AF is administered by intravenous injection 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.

In the interest of patients, it is recommended that every time ReFacto AF is administered, the name and batch number of the product should be recorded.

For reconstitution instructions prior to administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity to hamster proteins.

As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. The product contains traces of hamster proteins. Patients should be informed of the early signs of hypersensitivity reactions (including hives, generalised urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. If allergic or anaphylactic reactions occur, administration of ReFacto AF is to be discontinued immediately, and an appropriate treatment must be initiated. In case of shock, the current medical standards for treatment of shock are to be observed. Patients are to be advised to discontinue use of the product and contact their physician or seek immediate emergency care, depending on the type and severity of the reaction, if any of these symptoms occur.

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 (BUs) per ml of plasma using the Nijmegen modification of the Bethesda assay. The risk of developing inhibitors is correlated to the exposure to factor VIII, this risk being highest within the first 20 exposure days. Inhibitors have been observed in previously treated patients receiving factor VIII products, including ReFacto AF. Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development. Patients treated with recombinant coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests (see also section 4.8).

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.

In the interest of patient safety, it is recommended that every time ReFacto AF is administered, the name on the carton and batch number of the product are recorded. Patients can affix one of the peel-off labels found on the vial to document the batch number in their diary or for reporting any side effects.

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

No interaction studies have been performed.

Animal reproduction studies have not been conducted with factor VIII. 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 lactation only if clearly indicated.

No studies on the effects on the ability to drive and use machines have been performed.

Factor VIII inhibition

The occurrence of neutralising antibodies (inhibitors) to factor VIII is well known in the treatment of patients with haemophilia A. As with all coagulation factor VIII products, patients are to be monitored for the development of inhibitors that are to be titrated in Bethesda Units (BUs) using the Nijmegen modification of the Bethesda assay. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

In a clinical study with ReFacto AF in previously treated patients (PTPs), 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; median exposure of 58 ED (range 5-140) and 98 patients had at least 50 ED to ReFacto AF. Ninetyeight (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. The frequency of inhibitors observed in these studies is within the expected range.

In a clinical study with ReFacto in PTPs, 1 inhibitor was observed in 113 patients. Also, there have been spontaneous post-marketing reports of hightitre inhibitors involving previously treated patients.

There are no clinical data on previously untreated patients (PUPs) with ReFacto AF. However, clinical trials are planned in previously untreated patients (PUPs) with ReFacto AF. In a clinical trial, 32 out of 101 (32%) previously untreated patients (PUPs) treated with ReFacto developed inhibitors: 16 out of 101 (16%) with a titre> 5 BU and 16 out of 101 (16%) with a titre 5 BU. The median number of exposure days up to inhibitor development in these patients was 12 (range 3-49). Of the 16 patients with high titres, 15 received immune tolerance (IT) treatment. Of the 16 patients with low titres, IT treatment was started in 10. IT had an efficacy of 73% for patients with high titres and 90% for those with low titres. For all 101 treated PUPs, regardless of inhibitor development, the median number of exposure days is 197 (range 1-1299).

Adverse reactions based on experience from clinical trials with ReFacto or ReFacto AF are presented in the table below by system organ class. These frequencies have been estimated on a per-patient basis and are described using the following categories: very common (1/10); common (1/100 to <1/10); and uncommon (1/1,000 to <1/100).

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

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 previously treated children and adolescents (n=18, age 1216 in a study and n=49, age 716 in a supporting study). Although a limited number of children have been studied, there is a tendency for higher frequencies of adverse events in children aged 7-16 as compared to adults. A clinical trial evaluating use of moroctocog alfa (AFCC) in children less than 6 years of age is on going.

The following adverse events have also been reported for ReFacto: paraesthesia, fatigue, blurred vision, acne, gastritis, gastroenteritis, and pain.

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%) PTPs had an increase in anti-CHO antibody titre, without any apparent clinical effect.

If any reaction takes place that is thought to be related to the administration of ReFacto AF, the rate of infusion is to be decreased or the infusion stopped, as dictated by the response of the patient (see section 4.4).

No case of overdose has been reported.

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

ReFacto AF contains Bdomain 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 sexlinked 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.

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.

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 K-value, AUC_t 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 followedup 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 6to-baseline pharmacokinetic were 107%, 100% and 104% for K-value, AUC_t 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 incremental 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 Kvalue 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 incremental 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.

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.

Powder

Sucrose

Calcium chloride dihydrate

L-Histidine

Polysorbate 80

Sodium chloride

Solvent

Sodium chloride

Water for injections

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.

Unopened powder vial

2 years.

After reconstitution

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

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.

Store and transport refrigerated (2°C - 8°C). Do not freeze, in order to prevent damage to the pre-filled syringe.

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.

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

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

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 (aluminum) 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.

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.

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.

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.

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

Wyeth Europa Ltd.

Huntercombe Lane South

Taplow, Maidenhead

Berkshire, SL6 0PH

United Kingdom

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

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

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

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

Date of first authorisation: 13 Apr 1999

Date of last renewal: 15 Apr 2009

15 April 2009

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