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warnings and cautions
5 WARNINGS AND PRECAUTIONS Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with the product should be discontinued, and emergency treatment should be sought. ( 5.2 ) BeneFIX RTS has been associated with the development of thromboembolic complications, including patients receiving continuous infusion through a central venous catheter. ( 5.3 ) 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 ) Patients may develop hypersensitivity to hamster (CHO) protein as BeneFIX RTS contains trace amounts. ( 5.2 ) 5.1 General The clinical response to BeneFIX RTS 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 ) ]. 5.2 Anaphylaxis and Severe Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX RTS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. BeneFIX RTS contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. 5.3 Thromboembolic Complications The safety and efficacy of BeneFIX RTS 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 RTS through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates [ see Adverse Reactions ( 6 ) ]. 5.4 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 RTS for immune tolerance induction have not been established. 5.5 Neutralizing Antibodies (Immunogenicity) Patients using BeneFIX RTS 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 RTS [ see Clinical Pharmacology ( 12 ) ]. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX. 2 Patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10 - 20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided. 5.6 Monitoring Laboratory Tests Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated [ see Dosage and Administration ( 2 ) ]. Patients should be monitored for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of BeneFIX RTS . Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs).
6 ADVERSE REACTIONS 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). 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 6.1 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, 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 . Table 5: Adverse Reactions Reported for PTPs* Body System Adverse Reaction Number of patients (%) *Adverse reactions reported within 72 hours of an infusion of BeneFIX. 1 Low-titer transient inhibitor formation. 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 inhibition 1 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%) Nervous system disorders Headache 7 (10.8%) Dizziness 5 (7.7%) Taste perversion (altered taste) 3 (4.6%) Shaking 1 (1.5%) Drowsiness 1 (1.5%) Renal and urinary disorders Renal infarct 2 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%) 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 . Table 6: Adverse Reactions Reported for PUPs* Body System Adverse Reaction Number of Patients (%) *Adverse reactions reported within 72 hours of an infusion of BeneFIX. 1 Two subjects developed high-titer inhibitor formation during treatment with BeneFIX. Blood and lymphatic system disorders Factor IX inhibition 1 2 (3.2%) General disorders and administration site conditions Injection site reaction 1 (1.6%) 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%) For adverse reactions thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped. 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. 6.2 Post-marketing Experience The following post-marketing adverse reactions have been reported for BeneFIX RTS : 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 RTS 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 RTS through a central venous catheter. Cases of peripheral thrombophlebitis and DVT have also been reported. In some, BeneFIX RTS was administered via continuous infusion, which is not an approved method of administration [ see Dosage and Administration ( 2 ) ].