BeneFIX

Serious side effects have been reported with BeneFIX including:

• Hypersensitivity reactions, including anaphylaxis. Tell your healthcare provider right away if you have some or all of the following symptoms:
  • swelling of the face or lips
  • chest tightness
  • a drop in blood pressure
  • lethargy (sluggishness)
  • nausea
  • vomiting
  • tingling in hands or feet
  • restlessness
  • wheezing
  • difficulty breathing
• Development of proteins that inhibit (stop) the activity of BeneFIX. Your healthcare provider will want to monitor for this development.
• Nephrotic syndrome (kidney damage). Tell your healthcare provider right away if you have some or all of the following symptom:
  • urine with a foamy appearance
  • poor or decreased appetite
  • swelling around the eyes, feet, and ankles, and in the abdomen (stomach area)
  • weight gain from an increase in fluid in the body
• Thromboembolic complications. This is a process of blood clot formation. This can be especially dangerous if a blood clot gets stuck in the leg (deep vein thrombosis), the lungs (pulmonary embolism), or if you have a stroke (clotting of a vessel leading to the brain).

 Do not take BeneFIX if you:

• have a known hypersensitivity (allergic reaction) to BeneFIX or its ingredients
• are allergic to hamsters
• develop disseminated intravascular coagulation (DIC). (DIC is when clotting and bleeding of the blood becomes unbalanced.)
• develop signs of fibrinolysis. (Fibrinolysis is when your blood loses its ability to clot.)

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of BeneFIX, there are no specific foods that you must exclude from your diet when receiving this medication.

Before taking BeneFIX, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• have or have had any medical problems
• have any allergies, including allergies to hamsters
• are breastfeeding. It is not known if BeneFIX passes into your milk and if it can harm your baby.
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

If you take too much BeneFIX call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Other drugs may interact with coagulation factor IX, 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.

Contraindications

• Life-threatening, immediate hypersensitivity (e.g., anaphylaxis) or known hypersensitivity to factor IX (recombinant) or any ingredient in the formulation, including hamster protein.1 25

• Rixubis also contraindicated in patients with disseminated intravascular coagulation (DIC) or signs of fibrinolysis.25

Warnings/Precautions

Warnings

Risk of thromboembolic complications.1 25 Peripheral thrombophlebitis, DVT, and life-threatening superior vena cava syndrome (in critically ill neonates) reported with at least one preparation of factor IX (recombinant); in several cases, patients received the drug by continuous infusion† sometimes via a central venous catheter.1 (See Pediatric Use under Cautions.)

Monitor for early manifestations of thromboembolic and consumptive coagulopathy in patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or DIC.25 (See Contraindications under Cautions.) Also monitor during perioperative or postoperative period for such events.25 Weigh risk of thromboembolism against benefits of therapy in patients with (or at risk of) DIC or thromboembolism.25

Nephrotic syndrome reported following immune tolerance induction with factor IX-containing preparations in patients with hemophilia B who have factor IX inhibitors and a history of hypersensitivity to factor IX.1 5 15 16 17 25

Safety and efficacy of factor IX (recombinant) for immune tolerance induction not established.1 25

Sensitivity Reactions

Hypersensitivity reactions, including bronchospastic reactions and anaphylaxis, reported.1 5 25 Manifestations have included pruritus, rash, urticaria, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, generalized discomfort, and fatigue.1

Increased risk in patients with certain genetic mutations of factor IX and/or those with inhibitors to factor IX.1 5 9 15 16 17 18 19 25 171 Up to 50% of hemophilia B patients with inhibitors to factor IX may experience a severe hypersensitivity reaction, including anaphylaxis, to factor IX concentrates.171

Closely observe for hypersensitivity reactions, especially during initial exposure to the drug.1 25 Administer initial (e.g., approximately 10–20) infusions in a hospital or clinic setting where severe allergic reactions can be managed.1 16 171 If manifestations of hypersensitivity or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.1 25

Evaluate any patient who experiences a hypersensitivity reaction to factor IX (recombinant) for presence of inhibitors.1 (See Development of Inhibitors to Factor IX under Cautions.)

Commercially available preparations of factor IX (recombinant) (BeneFIX, Rixubis) contain trace amounts of hamster proteins; possibility of hypersensitivity reactions to these nonhuman mammalian proteins.1 25 (See Contraindications.)

General Precautions

Risk for development of neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations.1 6 9 15 16 17 18 19 21 25 171 Inhibitors reported in about 1–5% of patients with hemophilia B, usually within the first 10–20 days of treatment.6 9 15 17 19 21 171 Patients with certain genetic mutations of the factor IX gene may be at higher risk of inhibitor development and of experiencing a hypersensitivity reaction.1 5 9 14 15 16 17 18 19 21 171 (See Hypersensitivity Reactions under Cautions.)

High-titer inhibitors observed in a few previously untreated pediatric patients receiving BeneFIX; may require use of an alternative treatment to factor IX replacement therapy.1

Neutralizing antibodies to factor IX not reported to date with Rixubis;25 however, inhibitor formation is a concern with any clotting factor therapy.27 171

Monitor regularly for development of inhibitors with appropriate clinical observation and laboratory tests.1 Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding is not controlled with a recommended dose.1 25 171

Patients who develop inhibitors may be at increased risk of anaphylaxis following re-exposure to factor IX (recombinant).25 (See Hypersensitivity Reactions under Cautions.)

Consultation with a hemophilia treatment center strongly recommended for patients with inhibitors.25

Monitor factor IX levels to guide dosing and assess therapeutic response.1 21 25 171 Use of one-stage clotting assay recommended.1 25

Monitor for development of inhibitors (with clinical observation and appropriate laboratory tests).1 25 171 (See Development of Inhibitors to Factor IX under Cautions.) If expected plasma factor IX levels are not attained or bleeding is not controlled with the recommended dose, perform appropriate laboratory test (Bethesda assay) to detect presence of factor IX inhibitors.1 25

Specific Populations

Category C.1 25

Not known whether distributed into human milk; use with caution.1 25

Safety, efficacy, and pharmacokinetics of BeneFIX evaluated in previously treated and previously untreated pediatric patients <15 years of age;1 on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.1 19

Safety, efficacy, and pharmacokinetics of Rixubis evaluated in previously treated pediatric patients <12 years of age; on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.25

High-titer inhibitors detected in several pediatric patients receiving BeneFIX who had no prior exposure to factor IX preparations; these patients were withdrawn from study.1

Rare postmarketing reports of critically ill neonates who experienced thrombotic events, including life-threatening superior vena cava syndrome, while receiving continuous infusions of BeneFIX through a central venous catheter.1 (See Thromboembolic Events under Cautions.)

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 25 Individualize dosage.1 25

Common Adverse Effects

BeneFIX: Headache,1 dizziness,1 nausea,1 9 injection site reactions/pain,1 skin-related hypersensitivity reactions (e.g., rash, hives).1

Rixubis: Dysgeusia, pain in extremity, positive furin antibody test.25

Absorption

Plasma Concentrations

In vivo recovery of factor IX following IV administration of 50 units/kg factor IX (recombinant) as the BeneFIX preparation was approximately 28% lower than that achieved following administration of equivalent dose of plasma-derived factor IX; difference presumably due to structural modifications of factor IX (recombinant).1 5 7 9 18 19 21

Decreased in vivo recovery in pediatric patients ≤15 years of age compared with patients >15 years of age.1 19 25 Incremental recovery of Rixubis in pediatric patients <12 years of age approximately 22% lower than in older individuals; mean incremental recovery lower in younger (<6 years of age) versus older (6–12 years of age) pediatric patients.25

Pharmacokinetic profiles of the 2 currently available preparations of factor IX (recombinant) (BeneFIX and Rixubis) appear to be comparable.27

Distribution

Extent

Readily diffuses through interstitial fluid; distributes through both intravascular and extravascular compartments.6 14 17

Circulates in plasma as unbound drug.6

Binds rapidly and reversibly to vascular endothelium.6

Not known whether factor IX (recombinant) crosses the placenta or is distributed into milk.1 20

Elimination

Elimination Route

Clearance correlates with body weight; generally increases through adolescence, then stabilizes during adulthood.6 Clearance of Rixubis is higher in younger (<6 years of age) versus older (6–12 years of age) pediatric patients.25

Half-life

Half-life of BeneFIX is approximately 18–24 hours in adults and approximately 20–21 hours in pediatric patients.1

Half-life of Rixubis is approximately 26.7 hours in adults and adolescents ≥12 years of age; in pediatric patients, half-life is approximately 23 hours for those 6–11 years of age and approximately 28 hours for those < 6 years of age.25

Factor IX is a protein produced naturally in the body. It helps the blood form clots to stop bleeding. Injections of factor IX are used to treat hemophilia B, which is sometimes called Christmas disease. This is a condition in which the body does not make enough factor IX. If you do not have enough factor IX and you become injured, your blood will not form clots as it should, and you may bleed into and damage your muscles and joints.

Injections of one form of factor IX, called factor IX complex, also are used to treat certain people with hemophilia A. In hemophilia A, sometimes called classical hemophilia, the body does not make enough factor VIII, and, just as in hemophilia B, the blood cannot form clots as it should. Injections of factor IX complex may be used in patients in whom the medicine used to treat hemophilia A is no longer effective. Injections of factor IX complex also may be used for other conditions as determined by your doctor.

The factor IX product that your doctor will give you is obtained naturally from human blood or artificially by a man-made process. Factor IX obtained from human blood has been treated and is not likely to contain harmful viruses such as hepatitis B virus, hepatitis C (non-A, non-B) virus, or human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). The man-made factor IX product does not contain these viruses.

Factor IX is available only with your doctor's prescription.

This section provides information on the proper use of a number of products that contain factor ix. It may not be specific to Benefix. Please read with care.

Some medicines given by injection may sometimes be given at home to patients who do not need to be in the hospital. If you are using this medicine at home, your health care professional will teach you how to prepare and inject the medicine. You will have a chance to practice preparing and injecting it. Be sure that you understand exactly how the medicine is to be prepared and injected.

To prepare this medicine:

• Take the dry medicine and the liquid (diluent) out of the refrigerator and bring them to room temperature, as directed by your doctor.
• When injecting the liquid (diluent) into the dry medicine, aim the stream of liquid (diluent) against the wall of the container of dry medicine to prevent foaming.
• Swirl the container gently to dissolve the medicine. Do not shake the container.

Use this medicine right away. It should not be kept longer than 3 hours after it has been prepared.

A plastic disposable syringe and filter needle must be used with this medicine. The medicine may stick to the inside of a glass syringe, and you may not receive a full dose.

Do not reuse syringes and needles. Put used syringes and needles in a puncture-resistant disposable container, or dispose of them as directed by your health care professional.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• The condition for which you are using this medicine.
• Your body weight.
• The amount of factor IX your body is able to make.
• How much, how often, and where in your body you are bleeding.
• Whether or not your body has built up a defense (antibody) against this medicine.

Missed Dose

Call your doctor or pharmacist for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Some factor IX products must be stored in the refrigerator, and some may be kept at room temperature for short periods of time. Store this medicine as directed by your doctor or the manufacturer.

If you were recently diagnosed with hemophilia B, you should receive hepatitis A and hepatitis B vaccines to reduce even further your risk of getting hepatitis A or hepatitis B from factor IX products.

After a while, your body may build up a defense (antibody) against this medicine. Tell your doctor if this medicine seems to be less effective than usual.

It is recommended that you carry identification stating that you have hemophilia A or hemophilia B. If you have any questions about what kind of identification to carry, check with your health care professional.

General Considerations for Administration

For Intravenous Use after Reconstitution

• Treatment with BeneFIX, Coagulation Factor IX (Recombinant), should be initiated under the supervision of a physician experienced in the treatment of hemophilia B.
• Each vial of BeneFIX has the rFIX potency in the International Units (IU) stated on the vial.
• Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX.

To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised. Doses should be titrated using the factor IX activity, pharmacokinetic parameters, such as half-life and recovery, as well as taking the clinical situation into consideration in order to adjust the dose as appropriate.

Dosing of BeneFIX may differ from that of plasma-derived factor IX products [see Clinical Pharmacology (12)]. Subjects at the low end of the observed factor IX recovery may require upward dosage adjustment of BeneFIX to as much as two times (2X) the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity.

The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Warnings and Precautions (5)].

Method of Calculating Initial Estimated Dose

The method of calculating the factor IX dose is shown in Table 1.

In adult PTPs, on average, one International Unit (IU) of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.8 ± 0.2 IU/dL (range 0.4 to 1.2 IU/dL). The method of dose estimation is illustrated in Table 2. If you use 0.8 IU/dL average increase of factor IX per IU/kg body weight administered, then:

In pediatric patients, on average, one international unit of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.7 ± 0.3 IU/dL (range 0.2 to 2.1 IU/dL; median of 0.6 IU/dL per IU/kg). The method of dose estimation is illustrated in Table 3. If you use 0.7 IU/dL average increase of factor IX per IU/kg body weight administered, then:

Doses administered should be titrated to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to BeneFIX. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests, including serial factor IX activity assays, be performed.

Dosing Guide for Control and Prevention of Bleeding Episodes and Peri-operative Management

Instructions for Use

BeneFIX is administered by intravenous (IV) infusion after reconstitution of the lyophilized powder with the supplied pre-filled diluent (0.234% sodium chloride solution) syringe.

Patients should follow the specific reconstitution and administration procedures provided by their physicians.

For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling [see Patient Counseling Information (17.3)].

Reconstitution, product administration, and handling of the administration set must be done with caution. Discard all equipment, including any reconstituted BeneFIX product, in an appropriate container. Place needles used for venopuncture in a sharps container after single use. Percutaneous puncture with a needle contaminated with blood from an infected patient can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.

Preparation and Reconstitution

The procedures below are provided as general guidelines for the reconstitution and administration of BeneFIX.

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

   Note: If you use more than one vial of BeneFIX per infusion, each vial should be reconstituted according to the following instructions. The diluent syringe should be removed leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the reconstituted contents of each vial. 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.

1. Allow the vial of lyophilized BeneFIX and the pre-filled diluent syringe to reach room temperature.
2. Remove the plastic flip-top cap from the BeneFIX 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. Place the vial on a flat surface. While holding the adapter in the package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper.
6. Grasp the plunger rod as shown in 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. 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. The diluent syringe may need to be recapped (if not administering reconstituted BeneFIX immediately), so place the cap on its top 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 the package.
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.
10. Slowly depress the plunger rod to inject all the diluent into the BeneFIX vial.
11. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved.

    Note: The final solution should be inspected visually for particulate matter before administration. The solution should appear clear and colorless. If it is not, the solution should be discarded and a new kit should be used.

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

BeneFIX, 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 BeneFIX, including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations for dosage and administration be followed closely [see Dosage and Administration (2)].

Administration (Intravenous Injection)

For Intravenous Use only after Reconstitution

BeneFIX is administered by intravenous (IV) infusion after reconstitution with the pre-filled diluent (0.234% sodium chloride solution) syringe.

• BeneFIX should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.
• The reconstituted solution may be stored at room temperature prior to administration, but BeneFIX should be administered within 3 hours. BeneFIX 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.
• A dose of BeneFIX may be administered over a period of several minutes. The rate of administration, however, should be adapted to the comfort level of each individual patient.

1. Attach the syringe to the luer end of the infusion set tubing provided.
2. Apply a tourniquet and prepare the injections site by wiping the skin well with an alcohol swab provided in the kit.
3. Perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. The reconstituted BeneFIX product should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level.

Reconstituted BeneFIX should not be administered in the same tubing or container with other medicinal products.

Agglutination of red blood cells in the tubing/syringe has been reported with the administration of BeneFIX. No adverse events have been reported in association with this observation. To minimize the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If red blood cell agglutination is observed in the tubing or syringe, discard all material (tubing, syringe and BeneFIX solution) and resume administration with a new package.

Following completion of BeneFIX treatment, remove the infusion set and discard. Dispose of all unused solution, empty vial(s), and used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly.

The safety and efficacy of administration by continuous infusion have not been established [see Warnings and Precautions (5)].

BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein.

General

The clinical response to BeneFIX may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor IX should be determined, and a sufficient dose of BeneFIX should be administered to achieve a satisfactory clinical response. If the patient's plasma factor IX 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 Warnings and Precautions (5.6)].

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care.

BeneFIX contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Thromboembolic Complications

The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Dosage and Administration (2)]. There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates [see Adverse Reactions (6)].

Nephrotic Syndrome

Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not been established.

Neutralizing Antibodies (Immunogenicity)

Patients using BeneFIX should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of BeneFIX [see Clinical Pharmacology (12)]. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed.

Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX.2 Patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10 - 20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided.

Monitoring Laboratory Tests

• Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated [see Dosage and Administration (2)].
• Patients should be monitored for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of BeneFIX. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs).