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Refacto

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Refacto

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 (antihemophilic factor) 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 (antihemophilic factor) can be of a significant therapeutic value for treatment of hemophilia A in certain patients with inhibitors to factor VIII11. In clinical studies of ReFacto (antihemophilic factor) , study subjects 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 (antihemophilic factor) does not contain von Willebrand factor and therefore is not indicated in von Willebrand's disease.

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 (antihemophilic factor) 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 of a comparative study that evaluated the effect of phospholipids on the one-stage clotting and chromogenic assays showed that the one-stage clotting assay gave results that were approximately 50% of the values obtained with the chromogenic assay (see CLINICAL PHARMACOLOGY). In addition, in clinical trials of ReFacto (antihemophilic factor) use in the surgical setting in which multiple laboratories were used for plasma sample analysis, the ratio of factor VIII activity results as measured by a local laboratory one-stage clotting assay and the central laboratory chromogenic substrate assay was 0.8 (0.2-3.0).

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)
x desired factor VIII rise (IU/dL or % of normal)

x 0.5 (IU/kg per IU/dL)

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

Type of Hemorrhage Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (h)/ Duration of Therapy (d)
Minor
  Early hemarthrosis, minor muscle or oral bleeds. 20–40 Repeat every 12 to 24 hours as necessary until resolved. At least 1 day, depending upon the severity of the hemorrhage.
Moderate
  Hemorrhages into muscles. Mild trauma capitis. Minor operations including tooth extraction. Hemorrhages into the oral cavity. 30–60 Repeat infusion every 12–24 hours for 3–4 days or until adequate local hemostasis is achieved. For tooth extraction a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.
Major
  Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic hemorrhages. Fractures. Major operations. 60–100 Repeat infusion every 8–24 hours until threat is resolved or in the case of surgery, until adequate local hemostasis is achieved.

For short-term routine prophylaxis to prevent or reduce the frequency of spontaneous musculoskeletal hemorrhage in patients with hemophilia A, ReFacto (antihemophilic factor) 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 (antihemophilic factor) for routine prophylaxis has been performed. In clinical studies in PTPs (ages 8-73 years) and PUPs (ages < 1-52 months), the mean dose used per infusion for routine prophylaxis was 29 ± 11 IU/kg and 53 ± 22 IU/kg, respectively.

Patients using ReFacto (antihemophilic factor) 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, administration of additional antihemophilic factor may neutralize the inhibitor.

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

ReFacto (antihemophilic factor) , when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of ReFacto (antihemophilic factor) , including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations in DOSAGE AND ADMINISTRATION be followed closely.

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 (antihemophilic factor) .

Reconstitution

Always wash your hands before performing the following procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure. All components used in the reconstitution and administration of this product should be used as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere.

ReFacto® Antihemophilic Factor (Recombinant) is administered by intravenous (IV) infusion after reconstitution with the supplied diluent (0.9% Sodium Chloride Diluent, 4 mL disposable syringe for drug diluent use with ReFacto Antihemophilic Factor [Recombinant]) syringe.

1. Allow the vials of lyophilized ReFacto (antihemophilic factor) and the pre-filled diluent syringe to reach room temperature.

2. Remove the plastic flip-top cap from the ReFacto (antihemophilic factor) vial to expose the central portions of the rubber stopper.

Instructions for Use - Illustration 1

3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface.

4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package.

5. While holding the adapter package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper.

Instructions for Use - Illustration 2

6. Grasp the plunger rod per the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly.

Instructions for Use - Illustration 3

7. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. Place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. The cap may need to be replaced (if not administering reconstituted ReFacto (antihemophilic factor) immediately).

Instructions for Use - Illustration 4

8. Lift the package away from the adapter and discard the package.

Instructions for Use - Illustration 5

9. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured.

Instructions for Use - Illustration 6

10. Slowly depress the plunger rod to inject all the diluent into the ReFacto (antihemophilic factor) vial.

Instructions for Use - Illustration 7

11. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved.

12. Inspect the final solution for specks before administration. The solution should appear clear and colorless.

Note: If you use more than one vial of ReFacto (antihemophilic factor) per infusion, reconstitute each vial as per the previous instructions.

13. Invert the vial and slowly draw the solution into the syringe.

Instructions for Use - Illustration 8

Note: If you prepared more than one vial of ReFacto (antihemophilic factor) , remove the diluent syringe from the vial adapter, leaving the vial adapter attached to the vial. Quickly attach a separate large luer lock syringe and draw back the reconstituted contents as instructed above. Repeat this procedure with each vial in turn. Do not detach the diluent syringes or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter.

14. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached. Note: If the solution is not to be used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inside of the cap.

ReFacto (antihemophilic factor) 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 the tubing provided in this kit, and the pre-filled diluent syringe provided or a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the vial adapter.

1. Attach the syringe to the luer end of the infusion set tubing provided and perform venipuncture as instructed by your physician. In the absence of incompatibility studies, reconstituted ReFacto (antihemophilic factor) should not be administered in the same tubing or container with other medicinal products. In vitro studies suggest that factor VIII may adsorb to the internal surfaces of some infusion equipment.

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

Following completion of ReFacto (antihemophilic factor) treatment, remove the infusion set and discard. The amount of drug product remaining in the infusion set is not clinically significant.

Dispose of all unused solution, the empty vial(s), and the 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 (antihemophilic factor) may also be stored at room temperature not to exceed 25°C (77°F) for up to 3 months, until the expiration date. The patient should write in the space provided on the outer carton the date the product was placed at room temperature. At the end of the 3-month period, the product should not be put back into the refrigerator, but should be used immediately or discarded. Freezing should be avoided to prevent damage to the pre-filled diluent syringe. During storage, avoid prolonged exposure of ReFacto® (antihemophilic factor) vial to light. Do not use ReFacto (antihemophilic factor) after the expiry date on the label.

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

HOW SUPPLIED

ReFacto® Antihemophilic Factor (Recombinant) is supplied in kits that include single-use (4 mL size, dried) vials which contain nominally 250, 500, 1000 or 2000 IU per vial:

250 IU Kit: NDC 58394–007–04
500 IU Kit
: NDC 58394–006–04
1000 IU Kit
: NDC 58394–005–04
2000 IU Kit
: NDC 58394–011–04

Actual factor VIII activity in IU is stated on the label of each ReFacto® Antihemophilic Factor (Recombinant) vial.

In addition, each ReFacto® Antihemophilic Factor (Recombinant) kit contains: one pre-filled diluent syringe containing 4 mL 0.9% Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusion set, two alcohol swabs, one bandage, one gauze, and one package insert.

REFERENCES

11. Kessler CM. An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. American Journal of Medicine. 1991;91(Supplement 5A):1S-5S.

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Manufactured and Distributed by: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. Rev 12/07.

Last reviewed on RxList: 2/19/2009
This monograph has been modified to include the generic and brand name in many instances.

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