Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
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.
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.
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.
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). |
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.
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).
Clinical studies did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualised.
Dose adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.
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.
No symptoms of overdose have been reported with recombinant coagulation factor VIII products.
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.
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.
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 (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.
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.
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.
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