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 previously treated patients (PTPs) or previously untreated patients (PUPs)] were fever, cough, headaches, dizziness, nausea, injections site reaction, injection site pain and skin-related hypersensitivity reactions (e.g., rash, hives).
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 trials with BeneFIX conducted in 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.
|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%)|
|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 infarct‡||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 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.
|Body System||Adverse Reaction||Number of Patients (%)|
|Blood and lymphatic system disorders||Factor IX inhibition†||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 a multi-center, prospective, open-label clinical trial with BeneFIX administered at 100 IU/kg once weekly, 25 PTPs (exposed to a factor IX containing product for ≥100 exposure days) were evaluated, with 25 subjects treated for approximately 52 weeks. Common (≥5%) adverse reactions were headache (36%), fever (20%), and cough (8%). No subject was withdrawn from the trial due to an adverse reaction. In the trial, no inhibitors were detected and no thrombotic events or anaphylactic reactions were reported.
In clinical trials 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 the trial and had normal factor IX recovery at the trial completion (approximately 15 months after inhibitor detection).
In clinical trials 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 trial.
In a clinical trial of 25 PTPs, with BeneFIX administered at 100 IU/kg once weekly, no inhibitors were detected.
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.
All subjects participating in the PTP, PUP and surgery trials 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 thrombogenicity (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.
6.2 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 (12)], anaphylaxis [see Warnings and Precautions (5.1)], 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 (2)]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Warnings and Precautions (5.2)].