Adynovate Adverse Reactions

The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache, diarrhea, rash, nausea, dizziness and urticaria.
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 clinical trials of another drug and may not reflect the rates observed in practice.
The safety of ADYNOVATE was evaluated in 365 previously treated patients (PTPs) and previously untreated patients (PUPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 6 completed multi-center, prospective, open label clinical studies and 1 ongoing clinical studies. The total number of infusions within the safety database is 74487. Table 7 lists the adverse reactions reported during clinical studies. (See Table 7.)

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Two cases of acute pancreatitis, with no precipitating cause identified in one case, were reported in adults during an extension study of the clinical trial which evaluated 216 subjects. Administration of ADYNOVATE continued and both cases resolved.
Immunogenicity: Clinical trial subjects were monitored for neutralizing (inhibitory) antibodies to FVIII. Of the 6 completed clinical trials in previously treated patients (PTPs), in the randomized controlled trial comparing different dosing regimens of Adynovate, one previously treated patient developed a transient low titer FVIII inhibitor at 0.6 BU while receiving more frequent dosing with Adynovate. In a continuation study with Adynovate, one patient developed a transient low titer (0.6BU) FVIII inhibitor. Repeat testing did not confirm the presence of inhibitor. Both of these subjects continued treatment without change in the dose of Adynovate.
Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. Persistent treatment-emergent binding antibodies against FVIII, PEG-FVIII or PEG were not detected. Out of 365 subjects, thirty six subjects in total showed pre-existing antibodies to factor VIII (n=5), PEG-factor VIII (n=31) and/or PEG (n=6) prior to the first exposure to ADYNOVATE. Twenty four subjects who tested negative at screening developed transient antibodies against factor VIII (n= 10), PEG-FVIII (n= 16) and/or PEG (n=3) at one or two consecutive study visits. Antibodies were transient and not detectable at subsequent visits. Two subjects showed positive results for binding antibodies at study completion or at the time of data cutoff. Binding antibodies that were detected prior to exposure to ADYNOVATE, that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters. There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data. No subject had pre-existing or treatment-emergent antibodies to CHO protein.
From an ongoing study in previously untreated patients < 6 years with severe hemophilia A, 9 cases of FVIII inhibitor development associated with treatment with Adynovate were reported.
The detection of antibodies that are reactive to factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading.