Antihemophilic factor recombinant

Antihemophilic Factor (Recombinant) is a prescription medication used to prevent, treat, and control bleeding episodes in children and adults with hemophilia A. 

Antihemophilic Factor (Recombinant) belongs to a group of drugs called clotting factors. It works by replacing a protein in the blood that is needed to control bleeding that people with hemophilia A are missing.

This medication comes as a dry powder to be mixed into a solution and injected into a vein (IV). 

Common side effects include fever and headache. 

Serious side effects have been reported with this medication including the following:

Hypersensitivity Reactions. Antihemophilic Factor (Recombinant) can cause serious allergic reactions. Tell your healthcare provider immediately about any signs or symptoms of an allergic reaction, which include the following:

• dizziness
• numbness or tingling
• rash
• flushing
• swelling in the face
• hives
• itching
• trouble breathing
• vomiting

Neutralizing antibodies. Your body may form inhibitors to factor VIII, known as antibodies. Antibodies are proteins made by the body as a natural part of the immune system in response to something it recognizes as foreign. If your form these inhibitors, this medication may not work properly. Your healthcare provider will monitor you for development of these inhibitors with blood tests.

Do not receive this medication if you:

• are allergic to antihemophilic factor (recombinant)  or to any of its ingredients
• are allergic to mice or hamsters

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. Always check the strength of the medicine on the label to be sure you are using the correct potency.

Recombinant antihemophilic factor is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Recombinant antihemophilic factor is usually given every 8 to 24 hours for 1 to 4 days, depending on the reason you are using the medicine.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Always wash your hands before preparing and giving your injection.

Recombinant antihemophilic factor must be mixed with a liquid (diluent) before injecting it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

After mixing the medicine and diluent, keep the mixture at room temperature and use it within 3 hours. Do not put mixed medicine into a refrigerator.

Prepare your dose in a syringe only when you are ready to give yourself an injection. A single-use vial is for one use only. After measuring your dose, throw this vial away, even if there is medicine left in it.

Do not use recombinant antihemophilic factor if it has changed colors or has particles in it. Call your pharmacist for new medication.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using recombinant antihemophilic factor, you may need frequent blood tests.

Your body may develop antibodies to antihemophilic factor, making it less effective. Call your doctor if this medicine seems to be less effective in controlling your bleeding.

Carefully follow all instructions about how to store this medicine. Each brand of recombinant antihemophilic factor may have specific storage instructions.

Store the medicine and the diluent in their original container in the refrigerator. Do not freeze. Before preparing your dose, take the medicine and diluent out of the refrigerator and allow them to reach room temperature.

You may also store the medicine and diluent at room temperature until the expiration date on the label. Some brands of this medicine can be stored at room temperature for only a certain number of months, or until the expiration date (whichever comes first). Follow the storage directions on the medicine label.

If you store this medicine at room temperature, do not return it to the refrigerator.

Do not store this medicine in bright light. Throw away any leftover medicine and diluent if the expiration date has passed.

Wear a medical alert tag or carry an ID card stating that you have hemophilia. Any doctor, dentist, or emergency medical care provider who treats you should know that you have a bleeding or blood-clotting disorder.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Other drugs may interact with recombinant antihemophilic factor, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Factor VIII replacement, necessary for clot formation and maintenance of hemostasis. It activates factor X in conjunction with activated factor IX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, and with factor XIII forms a stable clot.

Distribution

Vss: ~0.4 to 0.85 dL/kg

Half-Life Elimination

Advate: Children <12 years: 8.7 to 11.2 hours; Adolescents and Adults: 12 hours

Afstyla: Children <12 years: 10.2 to 10.4 hours; Children ≥12 years and Adolescents: 14.3 hours; Adults: 14.2 hours

Helixate FS, Kogenate FS: Children: 10.7 hours; Adults: 13.7 to 14.6 hours

Kovaltry: Children <12 years: ~12 hours; Children ≥12 years, Adolescents, and Adults: ~14 hours

Novoeight: Children <12 years: 7.7 to 10 hours; Adolescents and Adults: 11 to 12 hours

Nuwiq: Children ≤12 years: 11.9 to 13.1 hours; Adolescents and Adults: 17.1 hours

Recombinate: Adults: 14.6 hours

Xyntha, Xyntha Solofuse: Children and Adolescents: 6.9 to 8.3 hours; Adults: 11 to 17 hours

Hemophilia A:

Control and prevention of bleeding episodes: Prevention and control of bleeding episodes in adults and children with hemophilia A.

Perioperative management: Surgical prophylaxis in adults and children with hemophilia A.

Routine prophylaxis to prevent or reduce the frequency of bleeding: Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A.

Routine prophylaxis to prevent bleeding episodes and joint damage (Helixate FS, Kogenate FS): Routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children without preexisting joint damage.

Limitations of use: Not indicated for the treatment of von Willebrand disease.

Hypersensitivity (eg, anaphylaxis) to antihemophilic factor, mouse or hamster protein (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Recombinate, Xyntha), bovine protein (Recombinate only), or any component of the formulation.

Actual frequency may vary by product.

>10%:

Central nervous system: Headache (7% to 26%)

Dermatologic: Pruritus (≤16%), skin rash (≤16%), urticaria (≤16%)

Gastrointestinal: Nausea (6% to 13%), vomiting (7% to 12%)

Hematologic & oncologic: Increased factor VIII inhibitors (≤20%)

Local: Catheter infection (18% to 19%)

Neuromuscular & skeletal: Arthralgia (8% to 25%)

Respiratory: Cough (11% to 19%), nasopharyngitis (17%)

Miscellaneous: Fever (≤43%; in patients previously exposed to factor VIII products: <1%)

1% to 10%:

Cardiovascular: Chest discomfort (1%), palpitations (1%), sinus tachycardia (1%)

Central nervous system: Pain (8%), procedural pain (5%), insomnia (3%), chills (≤1%), dizziness (≤1%)

Dermatologic: Allergic dermatitis (1%)

Gastrointestinal: Diarrhea (5% to 8%), abdominal distress (2%), abdominal pain (2%), dyspepsia (2%)

Hematologic & oncologic: Lymphadenopathy (1%)

Hepatic: Increased liver enzymes (in patients previously exposed to factor VIII products: 1%)

Hypersensitivity: Hypersensitivity reaction (2%)

Local: injection site reaction (3% to 7%)

Neuromuscular & skeletal: Weakness (5% to 7%), back pain (≤3%; more common in children)

Otic: Otic infection (≤5%)

Respiratory: Pharyngolaryngeal pain (9%), upper respiratory tract infection (9%), nasal congestion (8%), rhinorrhea (5%)

Miscellaneous: Limb injury (10%)

<1% (Limited to important or life-threatening): Anorexia, catheter complication (venous catheter access), cold extremities, cyanosis, epistaxis, facial flushing, feeling hot, hematoma, hypotension, limb pain, loss of consciousness, maculopapular rash, malaise, myalgia, paresthesia, tachycardia, tremor, vasodilatation

Heart rate and blood pressure (before and during IV administration); plasma factor VIII activity prior to and during treatment; development of factor VIII inhibitors; signs of bleeding; hemoglobin, hematocrit; hypersensitivity reactions

When administering as a continuous infusion, monitor frequently for pump failure (WFH [Srivastava 2013]).

Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). The administration of ReFacto Antihemophilic Factor (Recombinant) increases plasma levels of factor VIII activity and can temporarily correct the in vitro coagulation defect in these patients.

Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with hemophilia A and therefore replacement therapy is necessary.

In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto was 14.5 ± 5.3 hours (ranged from 7.6-27.7 hours), which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human) (pdAHF), which had a mean half-life of 13.7 ± 3.4 hours (ranged from 8.8-23.7 hours). Mean incremental recovery (K-value) of ReFacto in plasma was 2.4 ± 0.4 IU/dL per IU/kg (ranged from 1.9-3.3 IU/dL per IU/kg). This was comparable to the mean incremental recovery observed in plasma for pdAHF which was 2.3 ± 0.3 IU/dL per IU/kg (ranged from 1.7-2.9 IU/dL per IU/kg). Results obtained from this controlled pharmacokinetic study, which used a central laboratory for the analysis of all plasma samples, showed that the one-stage factor VIII clotting assay gave results which were approximately 50% of the values obtained with the chromogenic assay (see DOSAGE AND ADMINISTRATION ).

In two additional clinical studies, pharmacokinetic parameters were evaluated for previously treated patients [PTPs] and previously untreated patients [PUPs]. In PTPs (n=87) ReFacto had a mean incremental recovery of 2.4 ± 0.4 IU/dL per IU/kg (ranged from 1.1-3.8 IU/dL per IU/kg) and an elimination half-life (n=67) of 10.7 ± 2.8 hours. In PUPs (n=45) ReFacto had a lower mean incremental recovery of 1.7 ± 0.4 IU/dL per IU/kg (ranged from 0.2-2.8 IU/dL per IU/kg) as compared to PTPs. Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of ReFacto in PUPs of 8.0 ± 2.2 hours. These parameters did not change over time (12 months) for PTPs or PUPs.

In clinical studies of ReFacto involving a total of 218 patients (117 PTPs including 4 who participated in the surgery study only, and 101 PUPs), more than 84 million IU were administered over a period of up to 54 months. The 117 PTPs were given a median of 230 injections (range of 4-1530 injections) over a median of 1200 days (range of 31-1640 days). The 101 PUPs were given a median of 26 injections (range of 1-490 injections) over a median of 830 days (range of 1-1298 days). One hundred thirteen PTPs and 99 PUPs were evaluated for efficacy in bleeding episodes. The 113 PTPs experienced a median of 54 bleeding episodes and the 99 PUPs experienced a median of 12 bleeding episodes. All were treated successfully on an on-demand basis or for the reduction of bleeding episodes except for one PTP and two PUPs who discontinued ReFacto treatment and switched to another product after the development of inhibitors. Bleeding episodes included hemarthroses, and bleeding in soft tissue, muscle, and other anatomical sites.

One of 113 previously treated patients (PTPs) who were evaluated for efficacy in bleeding episodes developed a high titer inhibitor. The patient was noted initially to have low titer inhibitor (1.2 BU) at a local laboratory at 98 exposure days and 2 BU at the central laboratory at 113 exposure days. After 18 months on continued treatment with ReFacto, the inhibitor level rose to nearly 13 BU and a bleeding episode failed to respond to ReFacto treatment. In this study the incidence of inhibitor development to factor VIII using ReFacto is similar to that reported for other factor VIII products 1-4 .

ReFacto has been studied in short-term routine prophylaxis. In uncontrolled clinical trials, an average dose of 27 ± 10 IU/kg in PTPs (n=77) and an average dose of 57 ± 20 IU/kg in PUPs (n=17) was given repeatedly at variable intervals longer than 2 weeks. In 64 patients who had both on-demand and prophylactic periods during their time on study, the mean rate of spontaneous musculoskeletal bleeding episodes was less during periods of routine prophylaxis. There were an average of 10 bleeding episodes per year during the prophylactic periods compared to an average of 37 bleeding episodes per year during the on-demand periods. The clinical trial experience with routine prophylaxis in PUPs is limited (n=17). These non-randomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated.

Management of hemostasis was evaluated in the surgical setting where 28 surgical procedures have been performed in 25 patients. The average preoperative dose in PTPs was 59 IU/kg. Procedures included orthopedic procedures, inguinal hernia repair, epidural hematoma evacuation, transposition ulnar nerve, and other minor procedures (e.g., venous access catheter placement and explantation, toenail removal). Circulatory factor VIII levels targeted to restore and maintain hemostasis were achieved. While the one-stage clotting assay was used most frequently in the surgical setting (24 versus 4 surgeries), hemostasis was maintained throughout the surgical period regardless of which assay was used. Hemostatic efficacy was rated as excellent or good in all procedures.

The occurrence of neutralizing antibody (inhibitors) is well known in the treatment of patients with hemophilia A 5,6,7 . Thirty-two out of 101 PUPs (32%) developed an inhibitor: 16 out of 101 (16%) with a high titer (> 5 BU) (12 of the 16 patients had peak values >/= 10 BU) and 16 out of 101 (16%) with a low titer (</= 5 BU). In this study the incidence of inhibitor development to factor VIII using ReFacto is similar to that reported for other factor VIII products 5-10 .

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:

 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).

ReFacto, 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, 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.

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 and the pre-filled diluent syringe to reach room temperature.
2. Remove the plastic flip-top cap from the ReFacto vial to expose the central portions of the rubber stopper.
   
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. Leave the adapter package in place.
   
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.
   
7. Remove the tamper-resistant plastic tip cap from the diluent syringe by bending down and up to break the perforation. Do not touch the inside of the cap or the syringe tip. Place the cap on its side on a clean surface in a spot where it would be least likely to become environmentally contaminated.
   
8. Lift the package away from the adapter and discard.
   
9. 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.
   
10. Inject all the diluent into the ReFacto vial.
    
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 per infusion, reconstitute each vial as per the previous instructions.
13. Invert the vial and draw the solution into the syringe.
    Note:  If you prepared more than one vial of ReFacto, 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 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.

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

Following completion of ReFacto 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 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 vial to light. Do not useReFacto after the expiry date on the label.

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