Xyntha Adverse Reactions

Adverse reactions to XYNTHA are listed in the table as follows. The information in this section is supported by the following studies: 300, 301, 306, 307, 310, 311, 313, 4432, 4433 and 4434. (See Table 7.)

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Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently for XYNTHA, and may in some cases progress to severe anaphylaxis (including shock).
Inhibitor development: Patients with hemophilia A may develop neutralizing antibodies (inhibitors) to factor VIII. See also Dosage & Administration and Precautions. As with all coagulation factor VIII products, patients are to be monitored for the development of inhibitors that are quantified in BUs using the Nijmegen modification of the Bethesda assay. 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.
The risk of developing inhibitors is correlated to the exposure to anti-hemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in PTPs with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.
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.
Factor VIII inhibition: Previously treated patients (PTPs): Within a pooled dataset of 641 PTPs treated with ReFacto (1 clinical study) or moroctocog alfa (AF-CC) (XYNTHA and ReFacto AF) (7 clinical studies), there were 11 (1.7%) confirmed factor VIII inhibitor cases (1 high-titre (≥5 BU/mL), 10 low-titre (<5 BU/mL)).
In a pivotal phase 3 study (study 310), in which 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 factor VIII inhibitors was the primary safety endpoint. Two patients with low titre, transient inhibitors were observed in these 94 patients (2.1%). In a supporting study (study 306), 1 de novo and 2 recurrent inhibitors (all low-titre, central laboratory determination) were observed in 110 patients; median exposure of 58 exposure days (ED) (range 5-140) and 98 patients had at least 50 ED. 98 of the original 110 patients continued treatment in a second supportive study (307) and had subsequent extended exposure with a median of 169 additional ED (range 9-425). 1 additional low-titre de novo inhibitor was observed. The frequency of inhibitors observed in these studies is within the expected range.
In a Bayesian statistical analysis, results from study 310 (2 out of 94 subjects developed an inhibitor, 89 had 50 or more exposure days) were used to update PTP results from prior supporting studies, where one de novo and two recurrent inhibitors were observed in 110 subjects, and 1 inhibitor was observed in 113 subjects. This Bayesian analysis indicates that the population (true) inhibitor rate 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.
In a clinical study (study 4433) in pediatric (n=37, <12 years of age) PTPs (FVIII:C <1%) receiving moroctocog alfa (AF-CC) (ReFacto AF), the percentage of patients with clinically significant inhibitor development was the primary safety outcome. No patient met the protocol-defined criteria of clinically significant FVIII inhibition. Transient, low-titre FVIII inhibitor development was observed in 2 patients (<6 years of age). Both patients showed a dip in recovery at the same visit (ED 10-15), the inhibitor test was positive, with subsequent return to expected recovery. Neither patient experienced any clinical manifestation of FVIII inhibition and did not receive specific treatment for the event.
Enrolled PTP patients (N=37) were treated with ReFacto AF at a dose and frequency prescribed by the patient's treating physicians as per local standard of care. Median annualized bleeding rate (ABR) was 38.50 (min to max = 0.0, 50.6) for on-demand regimen (N=14) and 3.67 (min to max = 0.0, 13.0) for prophylaxis regimen (N=22) patients. The majority of the first infusions were rated as "Excellent" (88.7%). The incidence rate of less-than-expected therapeutic effect (LETE) following on-demand treatment was 0.00% (no LETE bleeds from 804 bleeding episodes). The incidence rate of LETE following 2457 prophylaxis infusions was 0.08% (2 LETE bleeds with no confounding factors).
In a clinical study (study 313) in pediatric (6 months to <16 years) PTPs (≥20 ED) with hemophilia A (factor VIII:C ≤2%), 1 low-titre, clinically silent inhibitor was observed in 49 patients at risk in the study for developing an inhibitor.
In a clinical trial with the predecessor product ReFacto (study 300), 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, the inhibitor level rose to nearly 13 BU/mL and a bleeding episode failed to respond to treatment.
Laboratory increases in anti-factor VIII antibody titres, in the absence of inhibitor development, have been observed in clinical trials. In a study of PTPs 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-factor VIII 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 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 for surgical prophylaxis (study 311), 1 of 30 (3%) patients developed a lab increase for antibody to CHO. Twenty (20) of 113 (18%) PTPs receiving the predecessor product ReFacto (study 300) had an increase in anti-CHO antibody titre, without any apparent clinical effect.
Previously untreated patients (PUPs): In a clinical trial (study 301), 32 out of 101 (32%) PUPs treated with ReFacto developed inhibitors: 16 out of 101 (16%) with a titre >5 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 titre <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. There have been spontaneous post-marketing reports of high-titre inhibitors developing in PTPs.
In a clinical study (study 4434) PUPs (<6 years of age, n=23) treated with moroctocog alfa (AF-CC) (ReFacto AF), there were 8 patients (34.8%) with FVIII inhibitors (4 patients with high titres >5 BU/mL and 4 patients with low titres ≤5 BU/mL). Five (21.7%) of these patients met the protocol-defined criteria of clinically significant FVIII inhibitors with positive inhibitor at 2 consecutive blood draws and the need to administer alternative hemostatic products and/or low FVIII recovery levels and lack of efficacy.
Enrolled PUP patients (N=23) were treated with ReFacto AF at a dose and frequency prescribed by the patient's treating physicians as per local standard of care. During the study, 21 (91.3%), 22 (95.7%), and 7 (30.4%) patients had at least 1 on-demand, prophylaxis, or preventive infusion, respectively. Median ABR during the study, regardless of regimen, was 3.17 (min to max = 0.0 to 39.5). The majority (99/149, 66.4%) of the first infusions to treat a bleed were rated as "Excellent" (34.2%) or "Good" (32.2%). The incidence rate of LETE following on-demand treatment was 0.00% (no LETE bleeds from 150 bleeding episodes). The incidence rate of LETE following 1752 prophylaxis infusions was 0.11% (2 LETE bleeds with no confounding factors).