BENEFIX- coagulation factor ix (recombinant)
Wyeth BioPharma Division of Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BeneFIX safely and effectively. See full prescribing information for BeneFIX.
BeneFIX [Coagulation Factor IX (Recombinant)] For Intravenous Use, Lyophilized Powder for Reconstitution
Initial U.S. Approval: 1997
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
For Intravenous Use only
The initial estimated dose may be determined using the following formula: (2)
Average Recovery: Adult and Pediatric (<15 years) Patients
In clinical studies with adult and pediatric (<15 years) patients, one IU of BeneFIX per kilogram of body weight increased the circulating activity of factor IX as follows:
Dosing of BeneFIX may differ from that of plasma-derived factor IX products.
Dosage and duration of treatment with BeneFIX depends 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. (2.1)
DOSAGE FORMS AND STRENGTHS
BeneFIX lyophilized powder is available as 250, 500, 1000, 2000, or 3000 IU in single-use vials. (3)
BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein. (4)
WARNINGS AND PRECAUTIONS
Development of activity-neutralizing antibodies has been detected in patients receiving factor IX-containing products. If expected plasma factor IX activity levels are not attained, or if patient presents with allergic reaction, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. (5.5)
The most common adverse reactions (incidence >5%) from clinical trials were nausea, injection site reaction, injection site pain, headache, dizziness and rash. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
See 17 for FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
BeneFIX®, Coagulation Factor IX (Recombinant), is indicated for the control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease).
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 (5.3)].
The method of calculating the factor IX dose is shown in Table 1.
number of factor IX IU required (IU)
body weight (kg)
desired factor IX increase (% or IU/dL)
reciprocal of observed recovery (IU/kg per IU/dL)
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:
number of factor IX IU required (IU)
body weight (kg)
desired factor IX increase (% or IU/dL)
1.3 (IU/kg per IU/dL)
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:
number of factor IX IU required (IU)
body weight (kg)
desired factor IX increase (% or IU/dL)
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.
Type of Hemorrhage
Circulating Factor IX Activity Required [% or (IU/dL)]
Dosing Interval [hours]
Duration of Therapy [days]
|Adapted from: Roberts and Eberst1|
|Uncomplicated hemarthroses, superficial|
muscle, or soft tissue
|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
retroperitoneum, CNS, surgery
For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling [see Patient Counseling Information (17)].
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 venipuncture 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.
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.
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.
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)].
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 (5.3)].
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)].
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.
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 (6.2)].
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.
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 Adverse Reactions (6.1)]. 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.
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).
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, Coagulation Factor IX (Recombinant), 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 5.
Number of patients (%)
|*Adverse reactions reported within 72 hours of an infusion of BeneFIX.|
2 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.
|Blood and lymphatic system disorders||Factor IX inhibition1||1 (1.5%)|
|Eye disorders||Blurred vision||1 (1.5%)|
|Gastrointestinal disorders||Nausea||4 (6.2%)|
|General disorders and administration site conditions||Injection site reaction||5 (7.7%)|
|Injection site pain||4 (6.2%)|
|Infections and infestations||Cellulitis at IV site||1 (1.5%)|
|Phlebitis at IV site||1 (1.5%)|
|Nervous system disorders||Headache||7 (10.8%)|
|Taste perversion (altered taste)||3 (4.6%)|
|Renal and urinary disorders||Renal infarct2||1 (1.5%)|
|Respiratory, thoracic and mediastinal disorders||Dry cough||1 (1.5%)|
|Chest tightness||1 (1.5%)|
|Skin and subcutaneous disorders||Rash||4 (6.2%)|
|Vascular disorders||Flushing||2 (3.1%)|
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 6.
Number of Patients (%)
|*Adverse reactions reported within 72 hours of an infusion of BeneFIX.|
|Blood and lymphatic system disorders||Factor IX inhibition1||2 (3.2%)|
|General disorders and administration site conditions||Injection site reaction||1 (1.6%)|
|Respiratory, thoracic and mediastinal disorders||Dyspnea (respiratory distress)||2 (3.2%)|
|Skin and subcutaneous disorders||Hives||3 (4.8%)|
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 following post-marketing adverse reactions have been reported for BeneFIX: inadequate factor IX recovery, inadequate therapeutic response, inhibitor development [see Clinical Pharmacology (12)], anaphylaxis [see Warnings and Precautions (5.2)], 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.
The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Warnings and Precautions (5.3)]. 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 (2)].
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.
Safety, efficacy, and pharmacokinetics of BeneFIX have been evaluated in previously treated (PTP) and previously untreated pediatric patients (PUP) [see Dosage and Administration (2), Clinical Pharmacology (12.3), Clinical Studies (14) and Adverse Reactions (6)]. On average, lower recovery has been observed in pediatric patients (<15 years). A dose adjustment may be needed [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
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 (2)].
BeneFIX, Coagulation Factor IX (Recombinant), is a purified protein produced by recombinant DNA. It has a primary amino acid sequence that is identical to the Ala148 allelic form of plasma-derived factor IX, and has structural and functional characteristics similar to those of endogenous factor IX. BeneFIX is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterized. No human or animal proteins are added during the purification and formulation processes of BeneFIX.
BeneFIX is not derived from human blood and contains no preservatives, and the manufacture of BeneFIX includes no added animal or human components. 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 that does not contain any proteins derived from animal or human sources, and the recombinant factor IX is purified by a 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. The potency (in International Units, IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One International Unit is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. The specific activity of BeneFIX is greater than or equal to 200 IU per milligram of protein.
BeneFIX is formulated as a sterile, nonpyrogenic, lyophilized powder preparation. BeneFIX is intended for intravenous (IV) injection. It is available in single-use vials containing the labeled amount of factor IX activity, expressed in IU. Each vial contains nominally 250, 500, 1000, 2000, or 3000 IU of Coagulation Factor IX (Recombinant). 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. All dosage strengths yield a clear, colorless solution upon reconstitution.
The activated partial thromboplastin time (aPTT) is prolonged in people with hemophilia B. Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX. The administration of BeneFIX, 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 previously marketed BeneFIX, Coagulation Factor IX (Recombinant) [reconstituted with Sterile Water for Injection], 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 half-life was 18.8 ® 5.4 hours (range 11 to 36 hours). In the original randomized, cross-over pharmacokinetic study in previously treated patients (PTPs), the in vivo recovery using previously marketed BeneFIX was statistically significantly less (28% lower, p<0.05) than the recovery using a highly purified plasma-derived factor IX product (pdFIX). A summary of pharmacokinetic data for BeneFIX and pdFIX are presented in Table 7.
BeneFIX, n = 11
pdFIX, n = 11
Mean ± SD
Mean ± SD
|Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; K-value = incremental recovery; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.|
|AUC∞ (IU∙hr/dL)||548 ± 92||928 ± 191|
|t1/2 (hr)||18.1 ± 5.1||17.7 ± 5.3|
|CL (mL/hr/kg)||8.62 ± 1.7||6.00 ± 1.4|
|K-value (IU/dL per IU/kg)||0.84 ± 0.30||1.17 ± 0.26|
In vivo Recovery (%)
|37.8 ± 14.0||52.6 ± 12.4|
There was no significant difference in biological half-life. Structural differences of the BeneFIX 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.
In a subsequent randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX (reconstituted with Sterile Water for Injection) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 previously treated patients after repeated administration of BeneFIX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data are presented in Table 8:
Parameters at Initial Visit (Cross-over phase), n = 24
Mean ± SD
Parameters at Month 6 (Follow-up phase), n = 23
Mean ± SD
|Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; AUCt = area under the plasma concentration-time curve from zero to the last measurable concentration; Cmax = peak concentration; K-value = incremental recovery; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.|
|Cmax (IU/dL)||54.5 ± 15.0||57.3 ± 13.2|
|AUC∞ (IU∙hr/dL)||940 ± 237||923 ± 205|
|t1/2 (hr)||22.4 ± 5.3||23.8 ± 6.5|
|CL (mL/hr/kg)||8.47 ± 2.12||8.54 ± 2.04|
(IU/dL per IU/kg)
|0.73 ± 0.20||0.76 ± 0.18|
In vivo Recovery (%)
|34.5 ± 9.3||36.8 ± 8.7|
Nineteen (19) previously treated pediatric patients (range 4 to ≤15 years) underwent pharmacokinetic evaluations for up to 24 months. Fifty-eight previously untreated patients [PUPs] less than 15 years of age at baseline underwent at least one recovery assessment within 30 minutes post-infusion in the presence or absence of hemorrhage during the study. A total of 202 recovery assessments collected during the 60-month period from these 58 PUPs are combined with 19 recovery assessments from PTPs and were summarized by age group in Table 9. There was one recovery assessment in a neonate, which had a value of 0.46 IU/dL per IU/kg. The overall mean recovery and FIX elimination half-life values were 0.7 ® 0.3 IU/dL per IU/kg and 20.2 ® 4.0 hours, respectively.
K-value (IU/dL per IU/kg)
|a n = 13|
|Infants (≥1 month to <2 years)||33||0.7 ± 0.4 (0.2, 2.1)||ND|
|Children (≥2 years to <12 years)||61||0.7 ± 0.2 (0.2, 1.5)||19.8 ± 4.0 (14, 27)a|
|Adolescents (≥12 years to ≤15 years)||9||0.8± 0.3 (0.4, 1.4)||21.1 ± 4.5 (15, 28)b|
Data from 57 PUP subjects who underwent repeat recovery testing for up to 60 months demonstrated that the average incremental FIX recovery was consistent over time, as shown in Figure 1.
Figure 1. Average Incremental rFIX Recovery over Time
Efficacy of BeneFIX has been evaluated in clinical studies in which a total of 128 subjects received BeneFIX either for the treatment of bleeding episodes on an on-demand basis, for the prevention of bleeds (prophylaxis) or for management of hemostasis in the surgical setting (surgical prophylaxis).
Fifty-six PTPs and sixty-three PUPs were treated for bleeding episodes on an on-demand basis or for the prevention of bleeds (see Tables 9 and 10). The PTPs were followed over a median interval of 24 months (mean 23.4 ® 5.3 months) and for a median of 83.5. The PUPs were followed over a median interval of 37 months (mean 38.1 ® 16.4 months) and for a median of 89 exposure days.
Fifty-five PTPs and fifty-four PUPs received BeneFIX for the treatment of bleeding episodes (see Table 10). Bleeding episodes that were managed successfully included hemarthrosis and bleeding in soft tissue and muscle. Data concerning the severity of bleeding episodes were not reported. In the PTPs, 88% of total infusions administrated for on-demand treatment were rated as an "excellent" or "good" response.
Median dose: IU/kg (range)
Rate of bleeds resolved with 1 infusion
Response to 1st
|a 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.|
(6.5 - 224.6)
(8.2 - 292)
A total of 20 PTPs were treated with BeneFIX 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 (see Table 11). Thirty-two PUPs were administered BeneFIX for routine (primary and secondary) prophylaxis (see Table 11). Twenty-four PUPs were administered BeneFIX at least twice weekly, and eight PUPs were administered BeneFIX once weekly. Seven PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion. Six spontaneous bleeds within 48 hours after an infusion were reported in 5 PUPs. Prophylaxis therapy was rated as "excellent" or "effective" in 93% of PTPs receiving prophylaxis one to two times per week.
Total exposure (infusions)
Duration of prophylaxis (months) (mean ± SD)
Dose IU/kg (mean ± SD)
Spontaneous bleeds within 48 hrs of infusion
|a Response ratings provided at approximately 3-month intervals. In total, 116 and 172 assessments reported for PTPs and PUPs, respectively. Response ratings not provided for 2.6% and 0.6% of intervals for PTPs and PUPs, respectively.|
|20||2985||18.2 ® 8.4b||40.3 ® 15.2b||28||56.0%||37.1%||4.3%|
|32||3158||14.4 ® 8.1||73.3 ® 33.1||6||91.3%||6.4%||1.7%|
Management of hemostasis was evaluated in the surgical setting in both PTPs and PUPs (see Table 12). Thirty-six surgical procedures have been performed in 28 PTPs with 23 major surgical procedures performed (including 6 complicated dental extractions). Thirty surgical procedures have been performed in 23 PUPs. Twenty-eight of these procedures were considered minor. Hemostasis was maintained throughout the surgical period; however, one PTP subject required evacuation of a surgical wound-site hematoma, and another PTP subject who received BeneFIX 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.
Among the PTP 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 PTP surgery subjects was 19.4 hours (range 10 – 37 hours; mean 21.3 ® 8.1 hours).
Number of Procedures (Number of Subjects)
|a Response assessment not provided for 1 procedure.|
Previously Treated Patients
|Ankle surgery||2 (2)||2 (100%)||-||-|
|Hip prosthesis implant (right)||1 (1)||1 (100%)||-||-|
|Knee arthroplasty (2 bilateral, 1 right)||3 (3)||3 (100%)||-||-|
|Knee arthroscopic synovectomy||2 (2)a||1 (50%)||-||-|
|Liver transplantation (orthotopic)||1 (1)||1 (100%)||-||-|
|Splenectomy||1 (1)||1 (100%)||-||-|
|External fixation device removal (wrist)||1 (1)||1 (100%)||-||-|
|Hernia repair||3 (2)||3 (100%)||-||-|
|Subacromial decompression (left)||1 (1)||1 (100%)||-||-|
|Calf debridement, dental extractionb||1 (1)||1 (100%)||-||-|
|Lymph node removal, dental extractionb||1 (1)||1 (100%)||-||-|
|Left heel cord lengthening||1 (1)||1 (100%)||-||-|
|Dental proceduresc||12 (11)||11 (92%)||1 (8%)||-|
|Minor procedures||6 (6)||6 (100%)||-||-|
Previously Untreated Patients
|Hernia repair||2 (2)||2 (100%)||-||-|
|Minor procedures||28 (21)a||27 (96%)||-||-|
Nine of the major surgical procedures were performed in 8 PUPs using a continuous-infusion regimen. Five of the surgical procedures were performed in PUPs using a continuous-infusion regimen over 3 to 5 days. 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 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.
All subjects participating in the PTP, PUP and surgery studies were monitored for clinical evidence of thrombosis [see Warnings and Precautions (5.3)]. No thrombotic complications were reported in PUPs or surgery subjects. One PTP subject experienced a renal infarct 12 days after a dose of BeneFIX for a bleeding episode; the relationship of the infarct to the prior administration of BeneFIX is uncertain. 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.
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 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.
Product kit as packaged for sale: BeneFIX, Coagulation Factor IX (Recombinant), can be stored at room temperature or under refrigeration, at a temperature of 2 to 30°C (36 to 86°F). Do not use BeneFIX after the expiration date on the label.
|Store at 2 to 30°C (36 to 86°F).||If the product kit is labeled for room temperature storage, it can be stored at room temperature (not to exceed 30°C or 86°F) or under refrigeration (2 to 8°C or 36 to 46°F).|
[2 to 8°C (36 to 46°F)]
|If the product kit labeled for refrigerated storage has been continuously refrigerated at 2 to 8°C (36 to 46°F), the labeled expiration date on the package is still applicable and the product kit should be stored as labeled on the carton. |
Prior to the expiration date, the product kit may be stored at room temperature, not to exceed 30°C (86°F), for up to 6 months.
If the product kit labeled for refrigerated storage has been removed from refrigeration and stored at room temperature (not to exceed 30°C or 86°F)*, the expiration period should be up to 6 months from the date of removal from refrigeration. Do not use the product once this six month period has elapsed even if the expiration date on the carton has not been exceeded.
*If you have removed the product kit labeled for refrigerated storage from refrigeration as a result of our April 2011 communication on the "Daily Med", and have not recorded the date of removal from refrigeration, the assigned expiration date (printed on the end flap of the product carton) must be reduced by 12 months.
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.
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.
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.
|Store at 2 to 30°C (36 to 86°F).||If you have the product kit labeled for room temperature storage, it can be stored at room temperature (below 30°C or 86°F) or in the refrigerator (2 to 8°C or 36 to 46°F).|
[2 to 8°C (36 to 46°F)]
|If you have the product kit labeled for storage in the refrigerator (2 to 8°C or 36 to 46°F) and you have not taken the kit out of the refrigerator, then the expiration date printed on the package still applies. You can store the product at room temperature (below 30°C or 86°F) for up to 6 months or until it has reached its expiration date, whichever comes first. |
If you have taken the product kit labeled for storage in the refrigerator out of the refrigerator and stored it at room temperature (below 30°C or 86°F), then use the product within 6 months from the time you took the product out of the refrigerator or until it has reached its expiration date, whichever comes first.
If you cannot remember when you took the product out of the refrigerator, then subtract one year (12 months) from the date that is printed on the end flap of the carton package. The date you get is your new expiration date. Throw away any product that has gone over the new expiration date.
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.
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.
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.
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.
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.
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.
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.