Xyntha Adverse Reactions

The most frequently reported treatment-emergent adverse reaction, on a per infusion basis, was vomiting. Most adverse reactions reported were considered mild or moderate in severity.
In addition, as with any intravenous protein product, allergic type hypersensitivity reactions are possible. Manifestations of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
Patients with hemophilia A may develop neutralizing antibodies (inhibitors) to factor VIII. As with all coagulation factor VIII products, patients are to be monitored for the development of inhibitors that are quantified in Bethesda Units (BUs) using either the Bethesda assay or Bethesda assay with the Nijmegen modification. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response or an unexpectedly low yield of plasma factor VIII activity. In such cases, it is recommended that a specialized hemophilia center be contacted.
Reports of lack of effect, mainly in prophylaxis patients, have been received during the clinical trials and post-marketing setting. The lack of effect and/or low factor VIII recovery has been reported in patients with inhibitors but also in patients who had no evidence of inhibitors. The lack of effect has been described as bleeding into target joints, bleeding into new joints, other bleeding, or a subjective feeling by the patient of a new onset bleeding. In order to ensure an adequate therapeutic response, it is important to individually titrate and monitor each patient's dose of Xyntha, particularly when initiating treatment with Xyntha (see Precautions and Dosage & Administration).
If any reaction takes place that is thought to be related to the administration of Xyntha, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient.
Clinical Trial Adverse Reactions: Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. (See Table 7.)

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In a clinical trial (Study 301), 32 out of 101 (32%) previously untreated patients treated with Xyntha manufactured by the previous process developed inhibitors: 16 out of 101 (16%) with a titre >5 Bethesda Units (BU/mL) and 16 out of 101 (16%) with a titre ≤5 BU/mL. The median number of exposure days prior to inhibitor development in these patients was 12 days (range 3 - 49 days). Of the 16 high responder patients, 15 received immune tolerance (IT) treatment. Eleven (11) of the high responders had a titre of <0.6 BU/mL at their latest available test after IT. In addition, IT treatment was started in 10 of the 16 low titre (≤5 BU/mL) patients, 9 of whom had titres <0.6 BU/mL for their latest value. Therefore, IT had an overall efficacy of 80% (20/25), 73% for high responders and 90% for low responders. Five (5) of the 6 remaining low responder patients who did not receive IT also had a titre <0.6 BU/mL for their latest value.
In a clinical trial of Xyntha manufactured by the previous process, one (1) of 113 (0.9%) previously heavily treated patients who were evaluated for efficacy in bleeding episodes developed a high titre inhibitor. Inhibitor development in this patient occurred in the same time frame as the development of monoclonal gammopathy of uncertain significance. The patient was noted initially at a local laboratory to have a treatment-emergent low titre inhibitor at 98 exposure days, which was confirmed at 2 BU/mL at the central laboratory at 113 exposure days. After 18 months on continued treatment with Xyntha, the inhibitor level rose to nearly 13 BU/mL and a bleeding episode failed to respond to Xyntha treatment.
In a pivotal phase 3 study, in which previously treated patients (PTPs) with hemophilia A received Xyntha for routine prophylaxis and on-demand treatment, 94 subjects received at least one dose of Xyntha resulting in a total of 6775 infusions. In this study, the incidence of FVIII inhibitors to Xyntha was the primary safety endpoint. Two patients with low titre, transient inhibitors were observed in these 94 patients (2.1%). In a Bayesian statistical analysis, results from this study (two out of 94 subjects developed an inhibitor, 89 had 50 or more exposure days to XYNTHA) were used to update PTP results from prior supporting studies of Xyntha. This Bayesian analysis indicates that the population (true) inhibitor rate for Xyntha was below a predefined acceptable value of 4.4%; the estimate of the 95% upper limit of the true inhibitor rate was 4.07%.
In a pivotal phase 3 study for surgical prophylaxis in patients with hemophilia A (study 311), one low titre persistent inhibitor and one transient, false-positive inhibitor were reported.
Laboratory increases in anti-FVIII antibody titres, in the absence of inhibitor development, have been observed in clinical trials. In a study of PTPs receiving XYNTHA for routine treatment and prevention of bleeding episodes (study 310) and in a study of PTPs for surgical prophylaxis (study 311), 1 of 94 (1%) patients, and 1 of 30 (3%) patients, respectively, developed anti-FVIII antibodies; these patients did not develop an inhibitor. The clinical significance of these antibodies, in the absence of an inhibitor, is unclear.
In clinical trials of PTPs receiving Xyntha for routine treatment and prevention of bleeding episodes, 0 of 94 (0%) patients in study 310, and 3 of 110 (3%) patients in study 306/307, developed a lab increase in anti-CHO (Chinese hamster ovary, the cell line which is the source of factor VIII for Xyntha) antibody titre, without any apparent clinical effect. In a study of Xyntha for surgical prophylaxis (study 311) 1 of 30 (3%) patients developed a lab increase for antibody to CHO. Twenty of 113 (18%) previously treated patients (PTPs) receiving Xyntha manufactured by the previous process (study 300) had an increase in anti-CHO (Chinese hamster ovary, the cell line which is the source of factor VIII for Xyntha) antibody titre, without any apparent clinical effect.
Trace amounts of hamster protein may be present in Xyntha. Development of antibodies to hamster protein has been observed in clinical studies, but there were no associated clinical sequelae.
Clinical Trial Adverse Reactions - Pediatrics: In a clinical study (study 313) in pediatric (6 months to <16 years) PTPs (≥20 ED) with hemophilia A (FVIII:C ≤2%), 2 low-titre, clinically silent inhibitor were observed in 49 patients at risk in the study for developing an inhibitor.
Post-Market Adverse Reactions: There have been spontaneous post-marketing reports of high titre inhibitors developing in previously treated patients.