6 ADVERSE REACTIONS
The most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache, arthralgia, pyrexia, and cough.
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.
XYNTHA was evaluated in five clinical studies (N=155), four completed studies with adult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age.
The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in previously treated patients (PTPs) with hemophilia A (factor VIII activity in plasma ≤ 2%)who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in previously treated patients with severe or moderately severe hemophilia A (FVIII:C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1161 infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery. [see Clinical Studies (14)]
Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to <16 years of age). A total of 7,150 infusions of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg).
Across all studies, the most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea (8%), vomiting (7%), asthenia (7%), and nausea (6%).
There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).
The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who had previously been treated with factor VIII (PTPs). In the safety and efficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and the experience with predecessor product (with one inhibitor observed in 113 subjects). The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.
None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.
In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.
Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents, 12 to <16 years of age). Of these, one pediatric subject developed an inhibitor.
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, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading.
6.3 Postmarketing Experience
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 following postmarketing adverse reactions have been reported for XYNTHA:
Inadequate therapeutic response