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The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII.

The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.

Clinical Trial 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 clinical practice.

ADVATE has been evaluated in five completed studies in previously treated patients (PTPs) and one ongoing study in previously untreated patients (PUPs) with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was 370.5 (range: 1 to 1,256) days and the median number of exposure days to ADVATE per subject was 128.0 (range: 1 to 598).3

The summary of adverse reactions (ADRs) with a frequency ≥ 5% (defined as adverse events occurring within 24 hours of infusion or any event causally related occurring within study period) is shown in Table 3.

No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies.

Table 3: Summary of Adverse Reactions (ADRs)a with a Frequency ≥ 5% in 234 Treated Subjectsb

MedDRAc System Organ Class MedDRA Preferred Term Number of ADRs Number of Subjects Percent of Subjects
General disorders and administration site conditions Pyrexia 78 50 21
Nervous system disorders Headache 104 49 21
Respiratory, thoracic and mediastinal disorders Cough 75 44 19
Infections and infestations Nasopharyngitis 61 40 17
Gastrointestinal disorders Vomiting 35 27 12
Musculoskeletal and connective tissue disorders Arthralgia 44 27 12
Injury, poisoning and procedural complications Limb injury 55 24 10
Infections and infestations Upper respiratory tract infection 24 20 9
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 23 20 9
Respiratory, thoracic and mediastinal disorders Nasal congestion 24 19 8
Gastrointestinal disorders Diarrhea 24 18 8
Gastrointestinal disorders Nausea 21 17 8
General disorders and administration site conditions Pair 19 17 8
Skin and subcutaneous tissue disorders Rash 16 13 6
Infections and infestations Ear infection 16 12 5
Injury, poisoning and procedural complications Procedural pain 16 12 5
Respiratory, thoracic and mediastinal disorders Rhinorrhea 15 12 5
a ADRs are defined as all Adverse Events that occurred (a) within 24 hours after being infused with investigational product or (b) all Adverse Events assessed related or possibly related to investigational product or (c) Adverse Events for which the investigator's or sponsor's opinion of causality was missing or indeterminate.
b The ADVATE clinical program included 234 treated subjects from 5 completed studies in PTPs and 1 ongoing study in PUPs as of 27 March 2006.
c MedDRA version 8.1 was used.

Immunogenicity

The development of Factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with pediatric PTPs ( < 6 years of age with > 50 Factor VIII exposures) and PTPs ( ≥ 10 years of age with > 150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI 0.03 to 2.91% for the risk of any Factor VIII inhibitor development).3,4 No Factor VIII inhibitors were detected in the 53 treated pediatric PTPs.

In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment), 5 (20%) of 25 subjects who received ADVATE developed inhibitors to Factor VIII.3 Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.

Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) cell protein antibodies. Of these patients, 3 showed an upward trend in antibody titer over time and 4 showed repeated but transient elevations of antibodies. 182 treated subjects were assessed for muIgG protein antibodies. Of these, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ADVATE. 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.

Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs). Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

Table 4: Post-Marketing Experience

Organ System [MedDRA Primary SOC] Preferred Term
Immune system disorders Anaphylactic reactiona Hypersensitivitya
Blood and lymphatic system disorders Factor VIII inhibition
General disorders and administration site conditions Injection site reaction Chills Fatigue/Malaise Chest discomfort/pain Less-than-expected therapeutic effect
a These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus.