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BeneFIX

Last reviewed on RxList: 2/2/2016
Drug Description

BeneFIX, Coagulation Factor IX
(Recombinant) for Injection

DESCRIPTION

BeneFIX, Coagulation Factor IX (Recombinant), is a purified protein produced by recombinant DNA technology. The product is formulated as a sterile, non-pyrogenic, lyophilized powder preparation intended to be reconstituted for intravenous injection. It is available in single-use vials containing the labeled amount of factor IX activity, expressed in International Units (IU). Each vial contains nominally 250, 500, 1000, 2000, or 3000 IU of recombinant coagulation factor IX. The potency (in IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One IU is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. After reconstitution of the lyophilized drug product, the concentrations of excipients are 0.234% sodium chloride, 8 mM L-histidine, 0.8% sucrose, 208 mM glycine, 0.004% polysorbate 80. The specific activity of BeneFIX is greater than or equal to 200 IU per milligram of protein. BeneFIX contains no preservatives and all dosage strengths yield a clear, colorless solution upon reconstitution.

Coagulation factor IX is the active ingredient in BeneFIX. It has a primary amino acid sequence that is identical to the Ala148 allelic form of human factor IX, and has structural and functional characteristics similar to those of endogenous factor IX.

BeneFIX is not derived from human blood. It is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterized. No additives of animal or human origin are used during the cell culture, purification, and formulation processes of BeneFIX. The stored cell banks are free of human blood or plasma products. The CHO cell line secretes recombinant factor IX into a defined cell culture medium, and the recombinant factor IX is purified by a four-step chromatography purification process that does not require a monoclonal antibody step. The process also includes a membrane nanofiltration step that has the ability to retain molecules with apparent molecular weights > 70,000 Da (such as large proteins and viral particles). BeneFIX is a single component by SDS-polyacrylamide gel electrophoresis evaluation.

For Consumers

What are the possible side effects of coagulation factor IX (Alphanine SD, Benefix, Mononine)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • fever or chills;
  • continued bleeding after treatment;
  • feeling like you might pass out;
  • sudden numbness or weakness, especially on one side of the body;
  • sudden headache, confusion, problems with vision, speech, or balance; or
  • swelling in your feet or ankles, weight...
Indications & Dosage

INDICATIONS

BeneFIX®, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease) for:

  • control and prevention of bleeding episodes
  • peri-operative management

Limitations of Use

BeneFIX is NOT indicated for:

  • treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X),
  • treatment of hemophilia A patients with inhibitors to factor VIII,
  • reversal of coumarin-induced anticoagulation,
  • treatment of bleeding due to low levels of liver-dependent coagulation factors.

DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only

  • Each vial of BeneFIX has the recombinant Factor IX (rFIX) potency in the International Units (IU) stated on the vial.
  • Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia B.
  • Dosage and duration of treatment with BeneFIX 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.
  • Dosing of BeneFIX may differ from that of plasma-derived factor IX products [see CLINICAL PHARMACOLOGY]. 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.
  • Monitor patients using a factor IX activity assay to ensure that the desired factor IX activity level has been achieved. Titrate the dose 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.
  • The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see WARNINGS AND PRECAUTIONS].

Dose

Calculating Initial Dose

Use the following formula to calculate the initial dose of BeneFIX:

number of factor IX IU required (IU) = body weight (kg) X desired factor IX increase (% or IU/dL) X reciprocal of observed recovery (IU/kg per IU/dL)

Average Recovery

Adult Patients ( ≥ 15 years)

In adults, 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). Use the following formula to estimate the dose with 0.8 IU/dL average increase of factor IX per IU/kg body weight administered:

number of factor IX IU required (IU) = body weight (kg) X desired factor IX increase (% or IU/dL) X 1.3 (IU/kg per IU/dL)
Pediatric Patients ( < 15 years)

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). Use the following formula to estimate the dose with 0.7 IU/dL average increase of factor IX per IU/kg body weight administered:

number of factor IX IU required (IU) = body weight (kg) X desired factor IX increase (% or IU/dL) X 1.4 (IU/kg per IU/dL)

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

Table 1

Type of Hemorrhage Circulating Factor IX Activity Required [% or (IU/dL)] Dosing Interval [hours] Duration of Therapy [days]
Minor
Uncomplicated hemarthroses, superficial muscle, or soft tissue 20-30 12-24 1-2
Moderate
Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria 25-50 12-24 Treat until bleeding stops and healing begins, about 2 to 7 days
Major
Pharynx, retropharynx, retroperitoneum, CNS, surgery 50-100 12-24 7-10
Adapted from: Roberts and Eberst1

Preparation And Reconstitution

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

Preparation

1. Always wash hands before performing the following procedures.

2. Use aseptic technique (meaning clean and germ-free) 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.

4. Pooling: If needing more than one vial of BeneFIX per infusion, reconstitute each vial according to the following instructions. Remove the diluent syringe leaving the vial adapter in place, and use a separate large luer lock syringe 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.

Reconstitution

1. If refrigerated, 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.

Remove the plastic flip-top cap - Illustration

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.

Place the vial adapter over the vial and press down firmly - Illustration

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.

Attach the threaded end of the plunger rod to the diluent syringe - Illustration

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.

Break off the tamper-resistant plastic-tip cap - Illustration

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

Lift the package away - Illustration

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.

Connect the diluent syringe to the vial adapter - Illustration

10. Slowly depress the plunger rod to inject all the diluent into the BeneFIX vial.

depress the plunger rod to inject all the diluent into the BeneFIX vial - Illustration

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

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

Slowly draw the solution into the syringe - Illustration

13. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached.

14. The reconstituted solution should be clear and colorless. If it is not, discard and use a new kit. If the solution is not to be used immediately, recap the syringe. Do not touch the syringe tip or the inside of the cap.

15. Store the reconstituted solution at room temperature and use it within 3 hours.

Note: 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 Dose and Administration sections].

Note: The tubing of the infusion set included with this kit does not contain DEHP.

Administration

For intravenous use after reconstitution only.

The safety and efficacy of administration by continuous infusion have not been established [see WARNINGS AND PRECAUTIONS].

  • Inspect BeneFIX solution for particulate matter and discoloration prior to administration, whenever solution and container permit.
  • Administer BeneFIX using the tubing provided in this kit, and the pre-filled diluent syringe provided, or a single sterile disposable plastic syringe.
  • Do not mix or administer BeneFIX in the same tubing or container with other medicinal products.
Administration

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.

prepare the injections site - Illustration

3. Perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Inject the reconstituted BeneFIX intravenously over several minutes. Adjust the rate of administration based on the patient's comfort level.

Perform venipuncture - Illustration

Note: 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.

4. Following completion of BeneFIX treatment, remove and discard the infusion set. Dispose of all unused solution, empty vial(s), and used needles and syringes in an appropriate container.

HOW SUPPLIED

Dosage Forms And Strengths

BeneFIX is supplied as a white lyophilized powder in the following dosages:

  • 250 IU
  • 500 IU
  • 1000 IU
  • 2000 IU
  • 3000 IU

BeneFIX, Coagulation Factor IX (Recombinant), is supplied in kits that include single-use vials which contain nominally 250, 500, 1000, 2000, or 3000 IU per vial (NDC 58394-633-03, 58394-634-03, 58394-635-03, 58394-636-03 and 58394-637-03, respectively) with sterile pre-filled diluent syringe, vial adapter reconstitution device, sterile infusion set, and two (2) alcohol swabs, one bandage, and one gauze pad. Actual factor IX activity in IU is stated on the label of each vial.

Storage And Handling

Product Kit as Packaged for Sale
  • Store BeneFIX at room temperature or under refrigeration, at a temperature of 2 to 30°C (36 to 86°F).
  • Do not freeze to prevent damage to the diluent syringe.
  • Do not use BeneFIX after the expiration date on the label.
Product After Reconstitution

The product does not contain a preservative and should be used within 3 hours.

Manufactured by: Wyeth Pharmaceuticals Inc., A subsidiary of Pfizer Inc., Philadelphia, PA 19101. Revised: Sep 2015

Side Effects & Drug Interactions

SIDE EFFECTS

The most serious adverse reactions are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy.

The most common adverse reactions observed in clinical trials (frequency > 5% of PTPs or PUPs) were headaches, dizziness, nausea, injections site reaction, injection site pain and skin-related hypersensitivity reactions (e.g., rash, hives).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During uncontrolled, open-label clinical studies with BeneFIX conducted in previously treated patients (PTPs), 113 adverse reactions with known or unknown relation to BeneFIX therapy were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than one event) who received a total of 7,573 infusions. These adverse reactions are summarized in Table 2.

Table 2: Adverse Reactions Reported for PTPs*

Body System Adverse Reaction Number of patients (%)
Blood and lymphatic system disorders Factor IX inhibition† 1 (1.5%)
Eye disorders Blurred vision 1 (1.5%)
Gastrointestinal disorders Nausea 4 (6.2%)
Vomiting 1 (1.5%)
General disorders and administration
site conditions
Injection site reaction 5 (7.7%)
Injection site pain 4 (6.2%)
Fever 2 (3.1%)
Infections and infestations Cellulitis at IV site 1 (1.5%)
Phlebitis at IV site 1 (1.5%)
Headache 7 (10.8%)
Dizziness 5 (7.7%)
Nervous system disorders Taste perversion (altered taste) 3 (4.6%)
Shaking 1 (1.5%)
Drowsiness 1 (1.5%)
Renal and urinary disorders Renal infarct‡ 1 (1.5%)
Respiratory, thoracic and mediastinal
disorders
Dry cough 1 (1.5%)
Hypoxia 1 (1.5%)
Chest tightness 1 (1.5%)
Skin and subcutaneous disorders Rash 4 (6.2%)
Hives 2 (3.1%)
Vascular disorders Flushing 2 (3.1%)
*Adverse reactions reported within 72 hours of an infusion of BeneFIX.
†Low-titer transient inhibitor formation.
‡The renal infarct developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode. The relationship of the infarct to the prior administration of BeneFIX is uncertain.

In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions, 10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or unknown relationship to BeneFIX. These events are summarized in Table 3.

Table 3: Adverse Reactions Reported for PUPs*

Body System Adverse Reaction Number of Patients (%)
Blood and lymphatic system disorders Factor IX inhibition† 2 (3.2%)
General disorders and administration site Injection site reaction 1 (1.6%)
conditions Chills 1 (1.6%)
Respiratory, thoracic and mediastinal disorders Dyspnea (respiratory distress) 2 (3.2%)
Skin and subcutaneous disorders Hives 3 (4.8%)
Rash 1 (1.6%)
*Adverse reactions reported within 72 hours of an infusion of BeneFIX.
†Two subjects developed high-titer inhibitor formation during treatment with BeneFIX.

Immunogenicity

In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer inhibitor was observed in one patient. The inhibitor was transient, the patient continued on study and had normal factor IX recovery pharmacokinetics at study completion (approximately 15 months after inhibitor detection).

In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63 patients (3.2%), both were high-titer ( > 5 BU) inhibitors detected after 7 and 15 exposure days, respectively. Both patients were withdrawn from the study.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BeneFIX with the incidence of antibodies to other products may be misleading.

Thromboembolic Complications

All subjects participating in the PTP, PUP and surgery studies were monitored for clinical evidence of thrombosis. No thrombotic complications were reported in PUPs or surgery subjects. One PTP subject experienced a renal infarct (see Table 2). Laboratory studies of thrombogenecity (fibrinopeptide A and prothrombin fragment 1 + 2) were obtained in 41 PTPs and 7 surgery subjects prior to infusion and up to 24 hours following infusion. The results of these studies were inconclusive. Out of 29 PTP subjects noted to have elevated fibrinopeptide A levels post-infusion of BeneFIX, 22 also had elevated levels at baseline. Surgery subjects showed no evidence of significant increase in coagulation activation.

Postmarketing Experience

The following post-marketing adverse reactions have been reported for BeneFIX: inadequate factor IX recovery, inadequate therapeutic response, inhibitor development [see CLINICAL PHARMACOLOGY], anaphylaxis [see WARNINGS AND PRECAUTIONS], angioedema, dyspnea, hypotension, and thrombosis.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been post-marketing reports of thrombotic events, including life-threatening SVC syndrome in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter. Cases of peripheral thrombophlebitis and DVT have also been reported. In some, BeneFIX was administered via continuous infusion, which is not an approved method of administration [see DOSAGE AND ADMINISTRATION]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see WARNINGS AND PRECAUTIONS].

DRUG INTERACTIONS

No information provided.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

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.

Closely monitor patients 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, perform the initial (approximately 10 – 20) administrations of factor IX under medical supervision where proper medical care for allergic reactions could be provided. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. Immediately discontinue the administration and initiate appropriate treatment if symptoms occur.

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

Thromboembolic Complications

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]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see DOSAGE AND ADMINISTRATION].

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 (Inhibitors)

Neutralizing antibodies (inhibitors) have been reported following administration of BeneFIX [see ADVERSE REACTIONS]. Evaluate patients using BeneFIX for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor IX inhibitor concentration.

Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis upon subsequent challenge with factor IX. Evaluate patients experiencing allergic reactions for the presence of an inhibitor and closely monitor patients with inhibitors for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product [see Hypersensitivity Reactions].

Monitoring Laboratory Tests

  • Monitor patients 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].
  • Monitor patients 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. Determine factor IX inhibitor levels in Bethesda Units (BUs).

Patient Counseling Information

  • Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use)
  • Allergic-type hypersensitivity reactions are possible. Inform patients of the early signs of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product and contact their physicians if these symptoms occur.
  • Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

BeneFIX has been shown to be nonmutagenic in the Ames assay and non-clastogenic in a chromosomal aberrations assay. No investigations on carcinogenesis or impairment of fertility have been conducted.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction and lactation studies have not been conducted with BeneFIX, Coagulation Factor IX (Recombinant). It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX should be administered to pregnant women only if needed.

Labor And Delivery

There is no information available on the effect of factor IX replacement therapy on labor and delivery. Use only if 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 BeneFIX is administered to nursing mothers.

Use only if needed.

Pediatric Use

Safety, efficacy, and pharmacokinetics of BeneFIX have been evaluated in previously treated (PTP) and previously untreated pediatric patients (PUP) [see Clinical Studies and ADVERSE REACTIONS]. On average, lower recovery has been observed in pediatric patients younger than 15 years old [see CLINICAL PHARMACOLOGY]. Dose adjustment may be needed [see DOSAGE AND ADMINISTRATION].

Geriatric Use

Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized [see DOSAGE AND ADMINISTRATION].

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

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

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Factor IX is activated by factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed.

Factor IX is the specific clotting factor deficient in patients with hemophilia B. The administration of BeneFIX (coagulation factor ix recombinant) ®, Coagulation Factor IX (Recombinant), increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients.

After single intravenous (IV) doses of 50 IU/kg of BeneFIX®, Coagulation Factor IX (Recombinant), in 37 previously treated adult patients (>15 years), each given as a 10-minute infusion, the mean increase from pre-infusion level in circulating factor IX activity was 0.8 ± 0.2 IU/dL per IU/kg infused (range 0.4 to 1.4 IU/dL per IU/kg) and the mean biologic halflife was 18.8 ± 5.4 hours (range 11 to 36 hours). In the randomized, cross-over pharmacokinetic study in previously treated patients (PTPs), the in vivo recovery using BeneFIX® (coagulation factor ix recombinant) was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. There was no significant difference in biological half-life. Structural differences of the BeneFIX® (coagulation factor ix recombinant) molecule compared with pdFIX were shown to contribute to the lower recovery. In subsequent evaluations for up to 24 months, the pharmacokinetic parameters were similar to the initial results.

For specific information regarding pediatric pharmacology, see PRECAUTIONS, Pediatric Use.

Clinical Studies

There are ongoing safety and efficacy studies of BeneFIX® (coagulation factor ix recombinant) in previously treated, previously untreated, and minimally treated patients.

In 4 clinical studies of BeneFIX® (coagulation factor ix recombinant) , a total of 128 subjects 56 previously treated patients [PTPs], 9 subjects participating only in the surgical study, and 63 previously untreated patients (PUPs) received more than 28 million IU administered over a period of up to 64 months. The studies included 121 HIV-negative and 7 HIV-positive subjects.

Fifty-six PTPs received approximately 20.9 million IU of BeneFIX® (coagulation factor ix recombinant) in two clinical studies. The median number of exposure days was 83.5. These PTPs who were treated for bleeding episodes on an on-demand basis or for the prevention of bleeds were followed over a median interval of 24 months (range 1 to 29 months; mean 23.4 ± 5.34 months). Fifty-five of these PTPs received a median of 42.8 IU/kg (range 6.5 to 224.6 IU/kg; mean 46.6 ± 23.5 IU/kg) per infusion for bleeding episodes. All subjects were evaluable for efficacy. One subject discontinued the study after one month of treatment due to bleeding episodes that were difficult to control; he did not have a detectable inhibitor. The subject's dose had not been adequately titrated. The remaining 55 subjects were treated successfully. Bleeding episodes that were managed successfully included hemarthroses and bleeding in soft tissue and muscle. Data concerning the severity of bleeding episodes were not reported. Eighty-eight percent of the total infusions administered for bleeding episodes were rated as providing an "excellent" or "good" response. Eighty-one percent of all bleeding episodes were managed with a single infusion of BeneFIX® (coagulation factor ix recombinant) . One subject developed a low titer, transient inhibitor (maximum titer 1.5 BU). This subject had previously received plasma-derived products without a history of inhibitor development. He was able to continue treatment with BeneFIX® (coagulation factor ix recombinant) with no anamnestic rise in inhibitor or anaphylaxis, however, increased frequency of BeneFIX® (coagulation factor ix recombinant) administration was required; subsequently the subject's factor IX inhibitor and its effect on the half-life of BeneFIX® (coagulation factor ix recombinant) resolved.

Forty-one of the subjects had measurements of fibrinopeptide A and prothrombin fragment 1 + 2 prior to infusion, 4 to 8 hours and then 24 hours following the infusion. Twenty-nine of the subjects had elevations in fibrinopeptide A with a maximum value of 35.3 nmol/L (22 of the 29 subjects had elevated baseline values). Ten of the subjects had elevated prothrombin fragment 1 + 2 with a maximum value of 1.82 nmol/L (3 of the 10 subjects had elevated baseline values).

A total of 20 PTPs were treated with BeneFIX® (coagulation factor ix recombinant) for secondary prophylaxis (the regular administration of FIX replacement therapy to prevent bleeding in patients who may have already demonstrated clinical evidence of hemophilic arthropathy or joint disease) at some regular interval during the study with a mean of 2.0 infusions per week. Nineteen subjects were administered BeneFIX® (coagulation factor ix recombinant) for routine secondary prophylaxis (at least twice weekly) for a total of 345 patient-months with a median follow-up period of 24 months per subject. The average dose used by these 19 subjects was 40.3 IU/kg, ranging from 13 to 78 IU/kg. One additional subject was treated weekly, using an average dose of 33.3 IU/kg, over a period of 21 months. Ninetythree percent of the responses were rated as "excellent" or "effective". These 20 PTPs received a total of 2985 infusions of BeneFIX® (coagulation factor ix recombinant) for routine prophylaxis. Seven of these PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion.

Management of hemostasis was evaluated in the surgical setting. Thirty-six surgical procedures have been performed in 28 subjects. Thirteen (13) minor surgical procedures were performed in 12 subjects, including 7 dental procedures, 1 punch biopsy of the skin, 1 cyst removal, 1 male sterilization, 1 nevus ablation, and 2 ingrown toenail removals. Twenty-three (23) major surgical procedures were performed in 19 subjects including a liver transplant, splenectomy, 3 inguinal hernia repairs, 11 orthopedic procedures, a calf-debridement and 6 complicated dental extractions.

Twenty-three (23) subjects underwent 27 surgical procedures with a pulse-replacement regimen. The mean perioperative (preoperative and intraoperative) dose for these procedures was 85 ± 32.8 IU/kg (range 25-154.9 IU/kg). The mean total post-operative (inpatient and outpatient) dose was 63.1 ± 22.0 IU/kg (range 28.6-129.0).

Total BeneFIX® (coagulation factor ix recombinant) coverage during the surgical period for the major procedures ranged from 4230 to 385,800 IU. The pre-operative dose for the major procedures ranged from 75 to 155 IU/kg. Nine of the major surgical procedures were performed in 8 subjects using a continuous infusion regimen. Following pre-operative bolus doses (94.1 -144.5 IU/kg), continuous infusion of BeneFIX® (coagulation factor ix recombinant) was administered at a median rate of 6.7 IU/kg/hr (range of average rates: 4.3-8.6 IU/kg/hr; mean 6.4 ± 1.5 IU/kg/hr) for a median duration of 5 days (range 1-11 days; mean 4.9 ± 3.1). Six of the 8 subjects who had received continuous infusion of BeneFIX® (coagulation factor ix recombinant) in conjunction with major surgeries were switched over to intermittent pulse regimens at a median dose of 56.3 IU/kg (range 33.6-89.1 IU/kg; mean 57.8 ± 18.1 IU/kg SD) for a median of 3.5 exposure days (range 1-5 days, mean 3.3 ± 1.4 SD) during the post-operative period. Although circulating factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens, clinical trial experience with continuous infusion of BeneFIX® (coagulation factor ix recombinant) for surgical prophylaxis in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion. Subjects administered BeneFIX® (coagulation factor ix recombinant) by continuous infusion for surgical prophylaxis also received intermittent bolus infusions of the product.

Among the surgery subjects, the median increase in circulating factor IX activity was 0.7 IU/dL per IU/kg infused (range 0.3-1.2 IU/dL; mean 0.8 ± 0.2 IU/dL per IU/kg). The median elimination half-life for the surgery subjects was 19.4 hours (range 10-37 hours; mean 21.3 ± 8.1 hours).

Hemostasis was maintained throughout the surgical period, however, one subject required evacuation of a surgical wound site hematoma and another subject who received BeneFIX® (coagulation factor ix recombinant) after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of the subjects. In seven subjects for whom fibrinopeptide A and prothrombin fragment 1 + 2 were measured pre-infusion, at 4 to 8 hours, and then daily up to 96 hours, there was no evidence of significant increase in coagulation activation. Data from two other subjects were judged to be not evaluable.

Sixty-three PUPs received approximately 6.2 million IU of BeneFIX® (coagulation factor ix recombinant) in an open-label safety and efficacy study over 89 median exposure days. These PUPs were followed over a median interval of 37 months (range 4 to 64 months; mean 38.1 ± 16.4 months). Fifty-four of these PUPs received a median dose of 62.7 IU/kg (range 8.2 to 292.0 IU/kg; mean 75.6 ± 42.5 IU/kg) per infusion for bleeding episodes. Data concerning the severity of bleeding episodes were not reported. Seventy-five percent of all bleeding episodes were managed with a single infusion of BeneFIX® (coagulation factor ix recombinant) . Three of these 54 subjects were not successfully treated; including one episode in a subject due to delayed time to infusion and insufficient dosing and in 2 subjects due to inhibitor formation. One subject developed a high titer inhibitor (maximum titer 42 BU) on exposure day 7. A second subject developed a high titer inhibitor (maximum titer 18 BU) after 15 exposure days. Both subjects experienced allergic manifestations in temporal association with their inhibitor development.

Thirty-two PUPs administered BeneFIX® (coagulation factor ix recombinant) for routine prophylaxis. Twenty-four PUPs administered BeneFIX® (coagulation factor ix recombinant) at least twice weekly for a total of 2587 infusions. The mean dose per infusion was 72.5 ± 37.1 IU/kg, and the mean duration of prophylaxis was 13.4 ± 8.2 months. Eight PUPs administered BeneFIX® (coagulation factor ix recombinant) once weekly for a total of 571 infusions. The mean dose per infusion was 75.9 ± 17.9 IU/kg, and the mean duration of prophylaxis was 17.6 ± 7.4 months. Five PUPs experienced a total of 6 spontaneous bleeding episodes within 48 hours after an infusion.

Twenty-three PUPs received BeneFIX® (coagulation factor ix recombinant) for surgical prophylaxis in 30 surgical procedures. All surgical procedures were minor except 2 hernia repairs. The preoperative bolus dose ranged from 32.3 IU/kg to 247.2 IU/kg. The perioperative total dose ranged from 385 to 23280 IU. Five of the surgical procedures were performed using a continuous infusion regimen over 3 to 5 days. Clinical trial experience with continuous infusion of BeneFIX® (coagulation factor ix recombinant) for surgical prophylaxis in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion.

Medication Guide

PATIENT INFORMATION

BeneFIX®/ BEN-uh-fiks/
[Coagulation Factor IX (Recombinant)] for Injection

Please read this Patient Leaflet carefully before using BeneFIX and each time you get a refill. There may be new information. This Patient Leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is BeneFIX?

BeneFIX is an injectable medicine that is used to help control and prevent bleeding in people with hemophilia B. Hemophilia B is also called congenital factor IX deficiency or Christmas disease.

BeneFIX is NOT used to treat hemophilia A.

What should I tell my doctor before using BeneFIX?

Tell your doctor and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines, such as overthe- counter medicines, supplements, or herbal medicines.

Tell your doctor about all of your medical conditions, including if you:

  • are pregnant or planning to become pregnant. It is not known if BeneFIX may harm your unborn baby.
  • are breastfeeding. It is not known if BeneFIX passes into the milk and if it can harm your baby.

How should I infuse BeneFIX?

The initial administrations of BeneFIX should be administered under proper medical supervision, where proper medical care for severe allergic reactions could be provided.

See the step-by-step instructions for infusing BeneFIX at the end of this leaflet. You should always follow the specific instructions given by your doctor. The steps listed below are general guidelines for using BeneFIX. If you are unsure of the procedures, please call your doctor or pharmacist before using.

Call your doctor right away if bleeding is not controlled after using BeneFIX.

Your doctor will prescribe the dose that you should take.

Your doctor may need to test your blood from time to time.

BeneFIX should not be administered by continuous infusion.

What if I take too much BeneFIX?

Call your doctor if you take too much BeneFIX.

What are the possible side effects of BeneFIX?

Allergic reactions may occur with BeneFIX. Call your doctor or get emergency treatment right away if you have any of the following symptoms:

wheezing
difficulty breathing
chest tightness
turning blue (look at lips and gums)
fast heartbeat
swelling of the face
faintness
rash
hives

Your body can also make antibodies, called “inhibitors,” against BeneFIX, which may stop BeneFIX from working properly.

Some common side effects of BeneFIX are nausea, injection site reaction, injection site pain, headache, dizziness and rash.

BeneFIX may increase the risk of thromboembolism (abnormal blood clots) in your body if you have risk factors for developing blood clots, including an indwelling venous catheter through which BeneFIX is given by continuous infusion. There have been reports of severe blood clotting events, including life-threatening blood clots in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter. The safety and efficacy of BeneFIX administration by continuous infusion have not been established.

These are not all the possible side effects of BeneFIX.

Tell your doctor about any side effect that bothers you or that does not go away.

How should I store BeneFIX?

DO NOT FREEZE BeneFIX kit.

BeneFIX kit can be stored at room temperature (below 86°F) or under refrigeration.

Throw away any unused BeneFIX and diluent after the expiration date indicated on the label.

Freezing should be avoided to prevent damage to the pre-filled diluent syringe.

BeneFIX does not contain a preservative. After reconstituting BeneFIX, you can store it at room temperature for up to 3 hours. If you have not used it in 3 hours, throw it away.

Do not use BeneFIX if the reconstituted solution is not clear and colorless.

What else should I know about BeneFIX?

Medicines are sometimes prescribed for purposes other than those listed here. Do not use BeneFIX for a condition for which it was not prescribed. Do not share BeneFIX with other people, even if they have the same symptoms that you have.

This Patient Leaflet summarizes the most important information about BeneFIX. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BeneFIX that was written for healthcare professionals.

Instructions for Use

BeneFIX®/ BEN-uh-fiks/
[Coagulation Factor IX (Recombinant)]

BeneFIX is supplied as a powder. Before it can be infused in your vein (intravenous injection), you must reconstitute the powder by mixing it with the liquid diluent supplied. The liquid diluent is 0.234% sodium chloride. BeneFIX should be reconstituted and infused using the infusion set, diluent, syringe, and adapter provided in this kit, and by following the directions below.

RECONSTITUTION

Always wash your hands before performing the following steps. Try to keep everything clean and germ-free while you are reconstituting

BeneFIX. Once you open the vials, you should finish reconstituting BeneFIX as soon as possible. This will help keep the infusion set materials germ-free.

Note: If you use more than one vial of BeneFIX per infusion, reconstitute each vial according to steps 1 through 13.

1. If refrigerated, let the vial of BeneFIX and the pre-filled diluent syringe reach room temperature.

2. Remove the plastic flip-top cap from the BeneFIX vial to show the center part of the rubber stopper.

Remove the plastic flip-top cap - Illustration

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. Press down firmly on the package until the adapter snaps into place on top of the vial, with the adapter spike penetrating the vial stopper.

Place the vial adapter over the vial and press down firmly - Illustration

6. Grasp the plunger rod as shown in the picture below. Do not touch the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly.

Attach the threaded end of the plunger rod to the diluent syringe - Illustration

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 reconstituted BeneFIX is not used immediately), so place the cap on its tip on a clean surface in a spot where it will stay clean.

Break off the tamper-resistant plastic-tip cap - Illustration

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

Lift the package away - Illustration

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

Connect the diluent syringe to the vial adapter - Illustration

10. Slowly push the plunger rod to inject all the diluent into the BeneFIX vial.

depress the plunger rod to inject all the diluent into the BeneFIX vial - Illustration

11. With the syringe still connected to the adapter, gently swirl the contents of the vial until the powder is dissolved. Look at the final solution before infusing it. The solution should be clear to colorless. If it is not, throw away the solution and use a new kit.

12. Make sure the syringe plunger rod is still fully pressed down, then turn over the vial. Slowly pull the solution into the syringe. Turn the syringe upward again and remove any air bubbles by gently tapping the syringe with your finger and slowly pushing air out of the syringe.

If you reconstituted more than one vial of BeneFIX, remove the diluent syringe from the vial adapter and leave the vial adapter attached to the vial. Quickly attach a separate large luer lock syringe and pull the reconstituted solution 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.

Slowly draw the solution into the syringe - Illustration

13. Remove the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Throw away the vial with the adapter attached.

If you are not using the solution right away, you should carefully replace the syringe cap. Do not touch the syringe tip or the inside of the cap.

BeneFIX should be infused within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to infusion.

INFUSION
(Intravenous Injection)

Continuous infusion is not an approved way to administer BeneFIX.

Your doctor or healthcare professional should teach you how to infuse BeneFIX. Once you learn how to self-infuse, you can follow the instructions in this insert.

1. Attach the syringe to the luer end of the provided infusion set tubing.

2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.

prepare the injections site - Illustration

3. Insert the butterfly needle of the infusion set tubing into your vein as instructed by your doctor or healthcare provider. Remove the tourniquet. Infuse the reconstituted BeneFIX product over several minutes. Your comfort level should determine the rate of infusion.

Perform venipuncture - Illustration

Clumping 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 clumping it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe.
Note: If red blood cell clumping is observed in the tubing or syringe, discard all material (tubing, syringe and BeneFIX solution) and continue administration with a new package.

4. After infusing BeneFIX, remove the infusion set and discard. The amount of drug product left in the infusion set will not affect your treatment. Dispose of all unused solution, the empty vial(s), and the used needles and syringes in an appropriate container used for throwing away waste that might hurt others if not handled properly.

It is a good idea to record the lot number from the BeneFIX vial label every time you use BeneFIX. You can use the peel-off label found on the vial to record the lot number.

If you have any questions or concerns about BeneFIX, ask your doctor or healthcare provider.

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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