The most common adverse reactions observed in > 1% of subjects in clinical studies were dysgeusia, pain in extremity, and positive furin antibody test.
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 clinical development, in a combined study, 91 male previously treated patients (PTPs; exposed to a factor IX-containing product for ≥ 150 days) received at least one infusion of RIXUBIS as part of either on-demand treatment of bleeding episodes, perioperative management of major and minor surgical, dental, or other invasive procedures, routine prophylaxis, or pharmacokinetic evaluation of RIXUBIS. Six subjects (6.6%) were < 6 years of age, 10 (11%) were 6 to < 12 years of age, 3 (3.3%) were adolescents (12 to < 16 years of age), and 72 (79%) were adults (16 years of age and older). The subjects received a total of 7,353 infusions with a median of 85 infusions of RIXUBIS (range 3 to 212 infusions), for a median of 83 exposure days (range 83 to 209 days).
A total of 161 adverse events were reported in 48 (52.7%) of the 91 subjects. Adverse reactions that occurred in > 1% of subjects are shown in Table 3.
Table 3 : Summary of Adverse Reactions
|System Organ Class||Adverse Reactions (AR)||Number of ARs
|Number of Subjects
|Percent per Infusion
|Nervous System Disorders||Dysgeusia||2||1 (1.1%)||0.03%|
|Musculoskeletal and Connective Tissue Disorders||Pain in extremity||1||1 (1.1%)||0.01%|
|Investigations||Positive furin antibody testa||1||1 (1.1%)||0.01%|
|Factor IX or furin antibodies of indeterminate specificitya||9||7 (7.7%)||0.12%|
|a See Immunogenicity.|
All 91 subjects were monitored for inhibitory and binding antibodies to factor IX, and binding antibodies to CHO protein and furin, at the following time points: at screening, at 72 hours following the first infusion of RIXUBIS and the commercial recombinant factor IX product in the cross-over portion of the pharmacokinetic study, after 5 and 13 weeks following first exposure to RIXUBIS, and thereafter every 3 months. Antibodies against furin were tested by an in-house enzyme-linked immunosorbent assay (ELISA). A titer of 1:20 or 1:40 was considered to be indeterminate for the above validated assay, as these titers were too low to be verified by the confirmatory assay.
No subjects developed neutralizing antibodies to factor IX. Thirteen subjects (14.3%) developed low-titer, non-neutralizing antibodies against factor IX at one or more time points. Two of these 13 subjects were found to have these antibodies at screening, prior to receiving RIXUBIS. No clinical adverse findings were observed in any of these 13 subjects.
Thirteen subjects (14.3%) had signals for antibodies against furin (indeterminate specificity). Four of these 13 subjects expressed signals for antibodies at screening, prior to RIXUBIS treatment. An additional subject had an antibody signal after treatment with the comparator product and prior to RIXUBIS treatment. Another additional subject had a positive titer of 1:80 that was not present when checked at a later time point and therefore considered transient. A second subject had a positive antibody signal after the data cutoff date that was also transient. No clinical adverse findings were observed in any of these 15 subjects.
In a study of 500 normal volunteers, using the same assay as in the clinical trial, 7% had titers of 1:20 or 1:40 and 1.2% had higher titers ranging from 1:80 to 1:320. These antibodies are thought to be part of a natural immune system response. To date, these antibodies have not been associated with any clinical adverse findings.
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.
There was no clinical evidence of thromboembolic complications in any of the subjects. Out-of-range values for thrombogenicity markers (thrombin-antithrombin III, prothrombin fragment 1.2, and D-dimer), determined during the pharmacokinetic portion of the combined study, did not reveal any pattern indicative of clinically relevant thrombogenicity with either RIXUBIS or a comparator factor IX-containing product.
Because the following 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.
Immune System Disorders: Hypersensitivity (including symptoms such as dyspnea, pruritus)
The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis.