Summary of the safety profile:
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency were development of neutralising antibodies to factor VIII (inhibitors), headache and fever.
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions may be observed.
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
Tabulated summary of adverse reactions:
The following Table 3 provides the frequency of adverse drug reactions in clinical trials and from spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and Preferred Term Level).
Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 3.)
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Description of selected adverse reactions: ADRs specific to residues from the manufacturing process:
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or transient spikes and one patient had both but no clinical symptoms.
Of the 229 treated patients who were assessed for antibodies to murine IgG, 10 showed a statistically significant upward trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst numerous repeated exposures to the study product.
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and pruritus.
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.