ADVERSE REACTIONS
Adverse reactions were examined among a total of 96 subjects > 16 years of age and 54 subjects </= 16 years of age who received at least one infusion of ADVATE rAHF-PFM. For subjects > 16 years of age, the mean ± SD and median (range) values for time on study per subject were 319 ± 213 days and 403 days (1 to 654); the mean ± SD and median (range) exposure days to ADVATE rAHF-PFM per subject were 130 ± 84 days and 140 days (1 to 289); and the mean ± SD and median (interquartile range) IU/kg per infusion were 32.0 ± 8.27 IU/kg and 30.7 IU/kg (27.8 to 33.8).
For subjects </= 16 years of age, the mean ± SD and median (range) values for time on study per subject were 321 ± 210 days and 428 days (1 to 651); the mean ± SD and median (range) exposure days to ADVATE rAHF-PFM per subject were 138 ± 93 days and 181 days (1 to 284); and the mean ± SD and median (interquartile range) IU/kg per infusion were 36.5 ± 11.7 IU/kg and 33.4 IU/kg (29.7 to 40.4).
Across all clinical studies, a total of 1304 adverse events were reported among 128 of the 150 subjects who received at least 1 infusion of ADVATE rAHF-PFM. Of the 1304 adverse events, 696 were reported among 85 subjects > 16 years of age and 608 were reported among 43 subjects </= 16 years of age. All adverse events (product-related and unrelated) reported by at least 10% of subjects are shown in Table 6.
Table 6.
Summary of All Adverse Experiences (Product-Related and Unrelated) that Occurred in Greater than or Equal to 10% of Study Subjects
| MedDRA System Organ Class |
MedDRA Preferred Term |
Number of Events |
Number of Subjects |
Percent of Evaluable Subjects a |
|
Gastrointestinal disorders
|
Pharyngolaryngeal pain
|
22
|
17
|
11.3
|
|
General disorders and administration site conditions
|
Fall
|
25
|
19
|
12.7
|
|
|
Pyrexia
|
37
|
25
|
16.7
|
|
Infections and infestations
|
Nasopharyngitis
|
32
|
22
|
14.7
|
|
Injury, poisoning and procedural complications
|
Accident nos
|
62
|
26
|
17.3
|
|
|
Limb injury nos
|
195
|
52
|
34.7
|
|
Musculoskeletal and connective tissue disorders
|
Arthralgia
|
74
|
35
|
23.3
|
|
Nervous system disorders
|
Headache nos
|
138
|
44
|
29.3
|
|
Respiratory, thoracic and mediastinal disorders
|
Cough
|
37
|
23
|
15.3
|
| a Percent relative to 150, the total number of subjects across all studies who received at least one infusion of ADVATE rAHF-PFM
|
|
Eighteen of the 1304 adverse events were deemed serious; none were related to the study medication. There were no deaths. Among the 1286 non-serious adverse events, only 28 in 12 subjects were judged by the investigator to be related to the study drug. Severity ratings among the 28 events were mild in 8 cases, moderate in 16 cases, and severe in 4 cases (Table 7).
Table 7.
Summary of Non-Serious, Study-Drug Related
Adverse Events
| Severity |
MedDRA Preferred Term |
Number of Events |
|
Mild
|
Dysgeusia
|
3
|
|
Pruritis
|
1
|
|
Dizziness
|
1
|
|
Catheter-related infection
|
1
|
|
Rigors
|
1
|
|
Headache nos
|
1
|
|
Total
|
8
|
|
Moderate
|
Dysgeusia
|
1
|
|
Dizziness
|
2
|
|
Headache nos
|
1
|
|
Hot flushes
|
2
|
|
Diarrhoea nos
|
1
|
|
Oedema lower limb
|
1
|
|
Sweating increased
|
1
|
|
Nausea
|
1
|
|
Dyspnoea nos
|
1
|
|
Abdominal pain upper
|
1
|
|
Chest pain
|
1
|
|
Bleeding tendency a |
1
|
|
Haematocrit decreased
|
1
|
|
Joint Swelling
|
1
|
|
Total
|
16
|
|
Severe
|
Headache nos
|
1
|
|
Pyrexia
|
1
|
|
Haematoma nos
|
1
|
|
Coagulation factor VIII decreased
|
1
|
|
Total
|
4
|
| a Recorded as prolonged bleeding after postoperative drain removal on the case report form
|
|
The unexpected decreased coagulation factor VIII levels occurred in one subject during continuous infusion of ADVATE rAHF-PFM following surgery (postoperative Days 10-14). Hemostasis was maintained at all times during this period and both plasma Factor VIII levels and clearance rates returned to appropriate levels by postoperative Day 15. Factor VIII inhibitor assays performed after completion of continuous infusion and at study termination were negative.
Factor VIII inhibitor testing was performed throughout all studies in the rAHF-PFM clinical program. Among 136 treated subjects >/=10 years of age, all of whom had >/=150 exposure days to Factor VIII products at study entry, 102 had at least 75 exposure days to ADVATE rAHF-PFM. None of these subjects developed an inhibitor. One subject who had < 50 exposure days to ADVATE rAHF-PFM while on study developed an inhibitor. This subject manifested a low titer inhibitor (2.0 BU by the Bethesda assay) after 26 ADVATE rAHF-PFM 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 RECOMBINATE rAHF. For the group comprising all subjects with at least 75 exposure days to ADVATE rAHF-PFM and the single subject who developed an inhibitor, the 95% confidence interval (Poisson distribution) for the risk of developing an inhibitor to Factor VIII was 0.02 to 5.4%.
|
