Refacto Indications, Dosage, Storage, Stability - Antihemophilic Factor

Refacto Indications, Dosage, Storage, Stability - Antihemophilic Factor

INDICATIONS

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 VIII ⁶ . In clinical studies of ReFacto, patients who developed inhibitors on study continued to manifest a clinical response when inhibitor titers were < 10 BU/mL. 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.

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

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.

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:

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

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

Product is labeled on the basis of the chromogenic assay. The available clinical trial data suggest either the one-stage clotting assay or the chromogenic assay may be used to help follow patients clinically. Most clinical trial subjects were monitored with the one-stage clotting assay. It must be noted that the one-stage clotting assay yields results which are lower than the values obtained with the chromogenic assay (see CLINICAL PHARMACOLOGY).

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 and57 ± 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 10 Bethesda Units per mL, 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).

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 theReFacto vial, DO NOT USE the contents of the vial. Note that it is acceptable for a small amount of fluid to remian 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® AntihemophilicFactor (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.

ReFacto® Antihemophilic Factor (Recombinant) is supplied in single-use vials which contain nominally 250, 500, or 1000 IU per vial (NDC 58394-007-01, 58394-006-01, 58394-005-01, 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.

REFERENCES

1. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598.
2. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435.
3. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, Group TKPUPS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459.
4. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet 1990; 335:1403.
5. Scharrer I, Bray G. Incidence of inhibitors in haemophilia A patients a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Hemophilia 1999; 5:145.
6. Kessler CM. An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. American Journal of Medicine 91 1991, (Supplement 5A): 1S-5S.

KEY CODE      Genetics Institute, Inc.

Cambridge MA 02140-2387, USA