Label: RECOMBINATE- antihemophilic factor recombinant kit

General

The clinical response to RECOMBINATE may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of RECOMBINATE should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. (see PRECAUTIONS: Monitoring Laboratory Tests ).

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with RECOMBINATE and have been manifested as dizziness pruritus, rash, urticaria, flushing, angioedema/face swelling, laryngeal edema, dyspnea, pallor, pyrexia, nausea, paresthesia, hypotension, and loss of consciousness. Discontinue RECOMBINATE if symptoms occur and seek immediate emergency treatment. RECOMBINATE contains trace amounts of bovine proteins, mouse immunoglobulin G (MuIgG), and hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Neutralizing Antibodies

Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of RECOMBINATE predominantly in previously untreated and minimally treated patients. The risk of developing inhibitors is highest during the first 20 exposure days. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed (see PRECAUTIONS: Monitoring Laboratory Tests).

General

 Certain components used in the packaging of this product contain natural rubber latex.

Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE [Antihemophilic Factor (Recombinant)] is initiated. No benefit may be expected from this product in treating other deficiencies.

Formation of Antibodies to Mouse, Hamster or Bovine Protein

As RECOMBINATE contains trace amounts of mouse protein (maximum of 0.1 ng/IU RECOMBINATE), hamster protein (maximum of 1.5 ng CHO protein/IU RECOMBINATE), and bovine protein (maximum of 1 ng BSA/IU RECOMBINATE), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Information for Patients

The patient and physician should discuss the risks and benefits of this product.

Allergic type hypersensitivity reactions have been observed with RECOMBINATE. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, symptoms of laryngeal edema, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur. Additionally, patients should be informed that local tissue irritation may occur when infusing RECOMBINATE reconstituted with 5 mL sWFI.

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. (see DOSAGE AND ADMINISTRATION).
• Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present if expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of RECOMBINATE. Use Bethesda Units (BU) to titer inhibitors.
• If the inhibitor is less than 10 BU per mL, the administration of additional RECOMBINATE concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response.
• Adequate hemostasis may not be achieved if Inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following RECOMBINATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations of Factor VIII in vitro and at doses up to ten times the expected maximum clinical dose in vivo, and did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes. Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Pediatric Use

RECOMBINATE is appropriate for use in children of all ages, including the newborn. Safety and efficacy studies have been performed in both previously treated (n=23) and previously untreated (n=75) children. (See Clinical Pharmacology and Precautions).

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with RECOMBINATE. The safety of RECOMBINATE for use in pregnant women has not been established. It is not known whether RECOMBINATE can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing RECOMBINATE. RECOMBINATE should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if RECOMBINATE is administered to nursing mothers. RECOMBINATE should be given to nursing mothers only if clinically needed.

Adverse Reactions from Clinical Trials

During controlled clinical studies with RECOMBINATE enrolling 210 subjects, the most commonly reported adverse drug reactions were chills, flushing, rash and epistaxis.

During the Previously Treated Patients (PTP) study, none of the 71 subjects developed de novo evidence of Factor VIII inhibitor. However, during the phase II/III portion of the study, 1 subject with a history of inhibitors exhibited inhibitor activity at 6 months (0.8 Bethesda Units [BU]), which resolved by 9 months. One other subject in this study had detectable Factor VIII inhibitor at baseline (1.26 BU) and exhibited an anamnestic response at 6 months (10.3 BU). During a prospective pharmaco-surveillance study of subjects who received batches of RECOMBINATE containing modestly increased Chinese Hamster Ovary (CHO) cell protein levels, none of the 34 treated subjects developed a Factor VIII inhibitor.

During the Previously Untreated Patients (PUP) study, 22 of the 73 evaluable subjects developed inhibitors to Factor VIII. Of these, 13 subjects displayed no detectable Factor VIII inhibitors at study exit.

Post-Marketing Adverse Reactions

In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience. These adverse reactions are listed by MedDRA (version 12.1) System Organ Class (SOC), then by MedDRA coding system Preferred Term in order of severity.

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Factor VIII inhibition

CARDIAC DISORDERS: Tachycardia, Cyanosis
GASTROINTESTINAL DISORDERS: Vomiting, Abdominal pain
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malaise, Injection site reactions, Chest pain, Chest discomfort
IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity
NERVOUS SYSTEM DISORDERS: Loss of consciousness, Headache, Paresthesia
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea, Cough, Laryngeal edema
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Urticaria, Erythema

Recommended Dosage Schedule

Physician supervision of the dosage is required. The following dosage schedule may be used as a guide.

If bleeding is not controlled with the recommended dose, the plasma level of Factor VIII should be determined and a sufficient dose of RECOMBINATE should be administered to achieve a satisfactory clinical response.

The careful control of the substitution therapy is especially important in cases of major surgery or life threatening hemorrhages. In presence of a low titer inhibitor, doses larger than those recommended may be necessary as per standard care.

Although dosage can be estimated by the calculations above, it is strongly recommended that whenever possible, appropriate laboratory tests including serial Factor VIII assays be performed on the patient’s plasma at suitable intervals to assure that adequate Factor VIII levels have been reached and are maintained. Patients should be evaluated for the development of Factor VIII inhibitors, if the expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose.

Reconstitution: Use Aseptic Technique

1. Bring RECOMBINATE, (dry factor concentrate) and Sterile Water for Injection, USP, (diluent) to room temperature.
2. Remove caps from concentrate and diluent vials.
3. Cleanse stoppers with germicidal solution and allow to dry prior to use. Place vials on a flat surface
4. Remove protective covering from one end of double-ended needle and insert exposed needle through the center of the stopper.
5. Remove protective covering from other end of double-ended needle. Invert diluent vial over the upright RECOMBINATE vial, then rapidly insert free end of the needle through the RECOMBINATE vial stopper at its center. The vacuum in the vial will draw in the diluent.
6. Disconnect the two vials by removing needle from diluent vial stopper, then remove needle from RECOMBINATE vial. Swirl gently until RECOMBINATE is completely dissolved, otherwise active material will be removed by the filter needle. After reconstitution, the solution should be colorless to faint yellow, and substantially free from foreign particles.

NOTE: Do not refrigerate after reconstitution. (See Administration)

Administration: Use Aseptic Technique

RECOMBINATE is administered by intravenous (IV) injection after reconstitution.

Administer at room temperature.

RECOMBINATE should be administered not more than 3 hours after reconstitution.

Intravenous Syringe Injection

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be colorless to faint yellow in appearance. If not, do not use the solution and notify Baxter immediately.

Plastic syringes are recommended for use with this product since proteins such as RECOMBINATE tend to stick to the surface of glass syringes.

1. Attach filter needle to a disposable syringe and draw back plunger to admit air into the syringe.
2. Insert the needle into reconstituted RECOMBINATE .
3. Inject air into vial and then withdraw the reconstituted material into the syringe.
4. Remove and discard the filter needle from the syringe; attach a suitable needle and inject intravenously as instructed under Rate of Administration.
5. If a patient is to receive more than one vial of RECOMBINATE, the contents of multiple vials may be drawn into the same syringe by drawing up each vial through a separate unused filter needle. Filter needles are intended to filter the contents of a single vial of RECOMBINATE only.

Rate of Administration

The rate of administration should be a rate that ensures the comfort of the patient. Preparations of RECOMBINATE can be administered at a rate of up to 5 mL per minute when reconstituted with 5 mL of sWFI.

The pulse rate should be determined before and during administration of RECOMBINATE. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.

What is the most important information I need to know about RECOMBINATE [Antihemophilic Factor (Recombinant)]?

Do not attempt to do an infusion to yourself unless you have been taught how by your doctor or hemophilia center.

You must carefully follow your doctor's or other healthcare provider's instructions regarding the dose and schedule for infusing RECOMBINATE so that your treatment will work best for you.

What is RECOMBINATE [Antihemophilic Factor (Recombinant)]?

RECOMBINATE is a medicine used to replace a clotting factor (Factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally.

RECOMBINATE is used to prevent and control bleeding in people with hemophilia A.

RECOMBINATE is not used to treat von Willebrand’s Disease.

Who should not use RECOMBINATE [Antihemophilic Factor (Recombinant)]?

You should not use RECOMBINATE if you

• are allergic to mouse, hamster or bovine proteins.
• are allergic to any ingredients in RECOMBINATE.

Tell your healthcare provider if you are pregnant or breast-feeding because RECOMBINATE may not be right for you.

How should I use RECOMBINATE [Antihemophilic Factor (Recombinant)] ?

RECOMBINATE is given directly into the blood stream.

You may infuse RECOMBINATE at a hemophilia treatment center, at your healthcare provider’s office or in your home. You should be trained on how to do infusions by your hemophilia treatment center or healthcare provider. Many people with hemophilia A learn to infuse their RECOMBINATE by themselves or with the help of a family member.

Your healthcare provider will tell you how much RECOMBINATE to use based on your weight, the severity of your hemophilia A, and where you are bleeding.

You may have to have blood tests done after getting RECOMBINATE to be sure that your blood level of Factor VIII is high enough to clot your blood.

Call your healthcare provider right away if your bleeding does not stop after taking RECOMBINATE.
 

What should I tell my healthcare provider before I use RECOMBINATE [Antihemophilic Factor (Recombinant)]?

You should tell your healthcare provider if you

• have or have had any medical problems.
• take any medicines, including non-prescription medicines and dietary supplements.
• have any allergies, including allergies to mouse, hamster or bovine proteins.
• are nursing.
• are pregnant.
• have been told that you have inhibitors to Factor VIII (because Factor VIII may not work for you).

What are the possible side effects of RECOMBINATE [Antihemophilic Factor (Recombinant)]?

You could have an allergic reaction to RECOMBINATE.

Call your healthcare provider right away and stop treatment if you get:

• Rash or hives
• itching
• tightness of the throat
• chest pain or tightness
• difficulty breathing
• light-headed, dizziness
• fainting

The most common side effects are chills, flushing, rash and nose bleeds. These are not all possible side effects with RECOMBINATE. You can ask your healthcare provider for information that is written for healthcare professionals. Tell your doctor about any side effect that bothers you or that does not go away.

What are the RECOMBINATE [Antihemophilic Factor (Recombinant)] dosage strengths?

RECOMBINATE comes in three different dosage strengths. The actual strength will be imprinted on the label and on the box. The three different strengths are coded, as follows:

Always check the potency printed on the label to make sure you are using the strength prescribed by your doctor. Always check the expiration date printed on the box. You should not use the product after the expiration date printed on the box.

How do I store RECOMBINATE [Antihemophilic Factor (Recombinant)]?

RECOMBINATE vials containing powdered product (without sterile diluent added) should be stored in a refrigerator (2° to 8°C [36° to 46°F]) or at room temperature (up to 30°C [86°F]).

If you choose to store RECOMBINATE at room temperature:

• it should remain at room temperature until infused.
• do not put room temperature product back in the refrigerator.

Store vials in their original box and protect them from extreme exposure to light.

Do not freeze.

Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Any RECOMBINATE left in the vial at the end of your infusion should be discarded.

What else should I know about RECOMBINATE [Antihemophilic Factor (Recombinant)] and hemophilia A?

Your body may form inhibitors to Factor VIII. An inhibitor is part of the body’s normal defense system. If you form inhibitors, it may stop RECOMBINATE from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to Factor VIII. Call your healthcare provider right away if your bleeding does not stop after taking RECOMBINATE.

Resources at Baxter available to the patients:

Contact Baxter to receive more product information:

Baxter Customer Service 1-800-423-2090

Baxter, RECOMBINATE, and HEMOFIL are trademarks of Baxter International Inc.

Manufactured by:
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140

Printed in USA

Issued Jan 2010