Allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the type/severity of the reaction, if any of these symptoms occur (see PRECAUTIONS).
The diluent vial accompanying this product may contain dry natural rubber that may cause hypersensitivity reactions when handled by or administered to persons with known or possible latex sensitivity.
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 has not been established.
Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC).
Historically, the administration of factor IX complex concentrates derived from human plasma, containing factors II, VII, IX and X, has been associated with the development of thromboembolic complications. 1 Although BeneFIX® contains no coagulation factor other than factor IX, the potential risk of thrombosis and DIC observed with other products containing factor IX should be recognized. Because of the potential risk of thromboembolic complications, caution should be exercised when administering this product to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX® should be weighed against the risk of these complications.
Twelve days after a dose of BeneFIX® for a bleeding episode, one hepatitis C antibody positive patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX® is uncertain but was judged to be unlikely by the investigator. The patient continued to be treated with BeneFIX® .
Activity-neutralizing antibodies (inhibitors) have been detected in patients receiving factor IX-containing products. As with all factor IX products, patients using BeneFIX® should be monitored for the development of factor IX inhibitors (see CLINICAL PHARMACOLOGY and WARNINGS). Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX2. Patients experiencing allergic reactions should be evaluated for the presence of inhibitor. Preliminary information suggests a relationship may exist between the presence of major deletion mutations in a patient's factor IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients known to have major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. In view 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.
Dosing of BeneFIX® may differ from that of plasma-derived factor IX products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Patients should be informed of the early symptoms and signs of hypersensitivity reactions including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the type/severity of the reaction, if any of these symptoms occur. Patients experiencing allergic reactions should be evaluated for the presence of inhibitor.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
BeneFIX® , Coagulation Factor IX (Recombinant), 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.
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 and lactating women only if clearly indicated.
Additional safety and efficacy studies are ongoing in previously treated, minimally treated, and previously untreated pediatric patients (see CLINICAL PHARMACOLOGY, WARNINGS and DOSAGE AND ADMINISTRATION).
Data from BeneFIX® safety, efficacy, and pharmacokinetic studies have been evaluated in previously treated and previously untreated pediatric patients.
Nineteen (19) previously treated pediatric patients (range 4 to =15 years) underwent pharmacokinetic evaluations for up to 24 months. The mean increase in circulating factor IX activity was 0.7 ± 0.2 IU/dL per IU/kg infused (range 0.3 to 1.1 IU/dL per IU/kg; median of 0.6 IU/dL per IU/kg). The mean biological half-life was 20.2 ± 4.0 hours (range 14 to 28 hours).
Fifty-eight previously untreated patients [PUPs] less than 15 years of age at baseline [3 neonates (0-<1 month), 45 infants (>/=1 month-<2 years), 9 children (>/=2 years-<12 years) and 1 adolescent (>12 years)] underwent at least one recovery assessment within 30 minutes post-infusion in the presence or absence of hemorrhage during the study. The mean increase in circulating FIX activity was 0.7 ± 0.3 IU/dL per IU/kg infused (range 0.2 to 2.1 IU/dL per IU/kg; median of 0.6 IU/dL per IU/kg). In addition, there was no difference in the recoveries noted when data were evaluated by age group for infants (0.7 ± 0.4 IU/dL per IU/kg; range 0.2 to 2.1 IU/dL per IU/kg) and children (0.7 ± 0.2 IU/dL per IU/kg; range 0.2 to 1.5 IU/dL per IU/kg). The recoveries in these age groups were consistent with the recovery for the PUP study as a whole. There was insufficient sample size in the neonate and adolescent age groups to perform an analysis in these groups. Data from 57 subjects who
underwent repeat recovery testing for up to 60 months demonstrated that the average incremental FIX recovery was consistent over time.
Clinical studies of BeneFIX® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any patient receiving BeneFIX® , dose selection for an elderly patient should be individualized (see DOSAGE AND ADMINISTRATION).