The following serious adverse reactions are described elsewhere in the labeling:
- Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.1)]
- Thromboembolism Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.2)]
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 the clinical trials of another drug and may not reflect the rates observed in practice.
The following adverse reactions are based on pooled data from two randomized trials in adult and adolescent patients (HAVEN 1 and HAVEN 3), one single-arm trial in adult and adolescent patients (HAVEN 4), one single-arm trial in pediatric patients (HAVEN 2), and one dose-finding trial, in which a total of 391 male patients with hemophilia A received at least one dose of HEMLIBRA as routine prophylaxis. Two hundred eighty-one patients (72%) were adults (18 years and older), 50 (13%) were adolescents (12 years up to less than 18 years), 55 (14%) were children (2 years up to less than 12 years), and five (1%) were infants (1 month up to less than 2 years). The median duration of exposure across the studies was 34.1 weeks (0.1 to 224.4 weeks).
The most frequently reported adverse reactions observed in ≥ 10% of patients treated with HEMLIBRA were injection site reactions, headache, and arthralgia.
Four patients (1%) in the clinical trials receiving HEMLIBRA prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, headache, and injection site reaction.
One patient withdrew from treatment after developing an anti-emicizumab-kxwh neutralizing antibody associated with loss of efficacy [see Adverse Reactions (6.2)].
Adverse reactions observed in patients who received HEMLIBRA are shown in Table 2.
|Body System||Adverse Reaction||Number of Patientsn (%)(N = 391)|
|General Disorders and Administration Site Conditions||Injection site reaction *||85 (22%)|
|Nervous System Disorders||Headache||57 (15%)|
|Gastrointestinal Disorders||Diarrhea||22 (6%)|
|Musculoskeletal and Connective Tissue Disorders||Arthralgia||59 (15%)|
Characterization of aPCC treatment in pooled clinical trials
There were 130 instances of aPCC treatment in 37 patients, of which 13 instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with TMA (Table 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment.
|Duration of aPCC treatment||Average cumulative amount of aPCC over 24 hours (U/kg/24 hours)|
|< 50||50 – 100||> 100|
|< 24 hours||11||76||18|
|24 – 48 hours||0||6||3†|
|> 48 hours||1||5||10†, ‡, ‡, ‡|
Injection Site Reactions
In total, 85 patients (22%) reported injection site reactions (ISRs). All ISRs observed in HEMLIBRA clinical trials were reported as mild to moderate intensity and 93% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%), and injection site pruritus (4%).
Other Less Common (<1%) Reactions
Rhabdomyolysis was reported in two adult patients with asymptomatic elevations in serum creatine kinase without associated renal or musculoskeletal symptoms. In both instances, the event occurred following an increase in physical activity.
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to emicizumab-kxwh in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
The immunogenicity of HEMLIBRA was evaluated using an enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence (ECL) assay. In the dose-finding trial (n = 18), four patients tested positive for anti-emicizumab-kxwh antibodies. In the pooled HAVEN clinical trials, 3.5% of patients (14/398) tested positive for anti-emicizumab-kxwh antibodies and <1% of patients (3/398) developed anti-emicizumab-kxwh antibodies with neutralizing potential (based on declining pharmacokinetics). One patient from HAVEN 2, who developed an anti-emicizumab-kxwh neutralizing antibody, experienced loss of efficacy after 5 weeks of treatment.
There was no clinically apparent impact of the presence of anti-emicizumab-kxwh antibodies on safety.
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