Refacto (Antihemophilic Factor (Recombinant)) - Indications and Dosage

INDICATIONS AND USAGE

ReFacto^® Antihemophilic Factor (Recombinant) is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia).

ReFacto is indicated for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown.

ReFacto can be of a significant therapeutic value for treatment of hemophilia A in certain patients with inhibitors to factor VIII⁶. In clinical studies of ReFacto, patients who developed inhibitors on study continued to manifest a clinical response when inhibitor titers were < 10 BU. When an inhibitor is present, the dosage requirement of factor VIII is variable. The dosage can be determined only by a clinical response and by monitoring of circulating factor VIII levels after treatment (see DOSAGE AND ADMINISTRATION).

ReFacto does not contain von Willebrand factor and therefore is not indicated in von Willebrand's disease.

INSTRUCTIONS FOR USE

Patients should follow the specific reconstitution and administration procedures provided by their physicians. The procedures below are provided as general guidelines for the reconstitution and administration of ReFacto.

RECONSTITUTION

Always wash your hands before performing the following procedures. Aseptic technique should be used during the reconstitution procedure.

ReFacto^® Antihemophilic Factor (Recombinant) is administered by intravenous (IV) infusion after reconstitution with the supplied Sodium Chloride Diluent.

1. Allow the vials of lyophilized ReFacto and diluent to reach room temperature.
2. Remove the plastic flip-top caps from the ReFacto vial and the diluent vial to expose the central portions of the rubber stoppers.
3. Wipe the tops of both vials with the alcohol swab provided, or use another antiseptic solution, and allow to dry.
4. Remove the transparent protective cover from the short end of the sterile double-ended needle and insert that end into the diluent vial at the center of the stopper.
5. Remove the colored protective cover from the long end of the sterile double-ended needle. Invert the diluent vial and, to minimize leakage, quickly insert the long end of the needle through the center of the stopper of the upright ReFacto vial.
   Note: Point the double-ended needle toward the wall of the ReFacto vial to prevent excessive foaming.
6. The vacuum will draw the diluent into the ReFacto vial.
7. Once the transfer is complete, remove the double-ended needle from the ReFacto vial, and properly discard the needle with the diluent vial.
   Note: If the diluent does not transfer completely into the ReFacto vial, DO NOT USE the contents of the vial. Note that it is acceptable for a small amount of fluid to remain in the solvent vial after transfer.
8. Gently rotate the vial to dissolve the powder.
9. The final solution should be inspected visually for particulate matter before administration. The solution should appear clear and colorless.

ReFacto should be administered within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration.

ADMINISTRATION (INTRAVENOUS INJECTION)

ReFacto^® Antihemophilic Factor (Recombinant) should be administered using a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the sterile filter needle.

1. Using aseptic technique, attach the sterile filter needle to the sterile disposable syringe. Pull back the syringe plunger to the 5 mL mark.
2. Insert the filter needle into the stopper of the ReFacto vial. Push plunger forward to inject air into the vial.
3. Invert the vial and withdraw the reconstituted solution into the syringe.
4. Remove and discard the filter needle.
   Note: If you use more than one vial of ReFacto, the contents of multiple vials may be drawn into the same syringe through a separate, unused filter needle.
5. Attach the syringe to the luer end of the infusion set tubing and perform venipuncture as instructed by your physician.

After reconstitution, ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level.

Dispose of all unused solution, empty vials, and used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly.

STORAGE

Product as packaged for sale: ReFacto^® Antihemophilic Factor (Recombinant) should be stored under refrigeration at a temperature of 2 to 8 °C (36 to 46 °F). ReFacto may also be stored at room temperature not to exceed 25 °C (77 °F) for up to 3 months. Freezing should be avoided to prevent damage to the diluent vial. During storage, avoid prolonged exposure of ReFacto^® vial to light. Do not use ReFacto after the expiry date on the label.

Product after reconstitution: The product does not contain a preservative and should be used within 3 hours.

DOSAGE AND ADMINISTRATION

Treatment with ReFacto^® Antihemophilic Factor (Recombinant) should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.

The labeled potency of ReFacto is based on the European Pharmacopoeial chromogenic substrate assay, whereas other factor VIII products are labeled based on the one-stage clotting assay. With recombinant factor VIII products, the chromogenic assay typically yields results which are higher than the results obtained with the one-stage clotting assay. When switching between products it is important to individually titrate each patient's dose in order to ensure an adequate therapeutic response (see PRECAUTIONS, General). Results obtained from a controlled pharmacokinetic study, which used one central laboratory for the analysis of all plasma samples, showed that the one-stage factor VIII clotting assay gave results that were approximately 50% of those obtained with the chromogenic substrate assay (see CLINICAL PHARMACOLOGY). In addition, in clinical trials of ReFacto use in the surgical setting in which multiple laboratories were used for plasma sample analysis, the ratio of factor VIII activity results obtained by the one-stage clotting and chromogenic substrate assays ranged between 20 and 80%.

When monitoring patients' factor VIII activity levels during treatment, the available clinical data suggest that either assay may be used. Most patients in clinical trials were monitored with the one-stage clotting assay (see CLINICAL PHARMACOLOGY). It is necessary to adhere to the incubation/activation times and other test conditions as specified by the assay manufacturers.

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

Precise monitoring of the replacement therapy by means of coagulation analysis (plasma factor VIII activity) is recommended, particularly for surgical intervention.

One international unit (IU) of factor VIII activity corresponds approximately 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, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity by approximately 2 IU/dL per IU/kg administered. The required dosage is determined using the following formula:

Required units = body weight (kg)
× desired factor VIII rise (IU/dL or % of normal)
× 0.5 (IU/kg per IU/dL)

The following chart can be used to guide dosing in bleeding episodes and surgery:

For short-term routine prophylaxis to prevent or reduce the frequency of spontaneous musculoskeletal hemorrhage in patients with hemophilia A, ReFacto should be given at least twice a week. In some cases, especially pediatric patients, shorter dosage intervals or higher doses may be necessary. Pharmacokinetic/pharmacodynamic modeling, based on pharmacokinetic data from 185 infusions in 102 PTPs, predicts that routine prophylactic dosing 3 times per week may be associated with a lower bleeding risk than with dosing twice weekly. No randomized comparison of different doses or frequency regimens of ReFacto for routine prophylaxis has been performed. In clinical studies in PTPs (ages 8-73 years) and PUPs (ages 9-52 months), the mean dose used for routine prophylaxis was 27 ± 10 IU/kg and 57 ± 20 IU/kg, respectively.

Patients using ReFacto should 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 a factor VIII inhibitor is present. If the inhibitor is present at levels less than 5 Bethesda Units, administration of additional antihemophilic factor may neutralize the inhibitor.

ReFacto is administered by IV infusion after reconstitution of the lyophilized powder with Sodium Chloride Diluent (provided).

HOW SUPPLIED

ReFacto^® Antihemophilic Factor (Recombinant) is supplied in single-use vials which contain nominally 250, 500, 1000 or 2000 IU per vial (NDC 58394-007-01, 58394-006-01, 58394-005-01, 58394-011-01, respectively) with sterile diluent, sterile double-ended needle for reconstitution, sterile filter needle for withdrawal, sterile infusion set, and two (2) alcohol swabs. Actual factor VIII activity in IU is stated on the label of each vial.