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 surgery including tooth extraction

30-60

Every 24 hours, at least 1 day, until healing is achieved.

Major surgery

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

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the 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 the batch number in their diary or for reporting any side effects.

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 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 the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 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 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).

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 1.27 mmol (29 mg) sodium per vial or pre-filled syringe, equivalent to 1.5% of the WHO recommended maximum daily intake (RDI) of 2 g sodium for an adult. Depending on body weight of the patient and posology of ReFacto AF, patients could receive multiple vials or pre-filled syringes. This should be taken into consideration if the patient is on a low salt 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. 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.

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 765 subjects.

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 with all FVIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients

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. 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

4.9. Overdose

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