HEMLIBRA SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Thrombotic Microangiopathy Associated with HEMLIBRA and PCC
• Thromboembolism Associated with HEMLIBRA and PCC
• Immunogenicity

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 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 (1/668) withdrew from treatment after developing neutralizing anti-emicizumabkxwh antibodies associated with loss of efficacy.

Adverse reactions observed in patients who received HEMLIBRA are shown in Table 1.

Table 1 Adverse Reactions Reported in ≥ 5% of Patients from Pooled Clinical Trials with HEMLIBRA

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 2). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment.

Table 2 Characterization of aPCC Treatment* in Pooled Clinical Trials

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

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.

Immunogenicity

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 for anti-emicizumab-kxwh antibodies. In the 7 phase III clinical trials, antibody positive samples were further evaluated for neutralizing anti-emicizumab-kxwh antibodies using a modified FVIII chromogenic assay. A total of 668 patients were tested for anti-emicizumab-kxwh antibodies. In the pooled phase III clinical trials, 5.1% of patients (34/668) tested positive for anti-emicizumab-kxwh antibodies and 2.7% of patients (18/668) developed anti-emicizumab-kxwh antibodies that were neutralizing in vitro. The anti-emicizumab antibody positive rate may be under-reported due to the limitation of the assay. Of these 18 patients, the neutralizing anti-emicizumab-kxwh antibodies did not have a clinically meaningful impact on the pharmacokinetics or efficacy of HEMLIBRA in 14 patients, while decreased emicizumab-kxwh plasma concentrations were observed in four patients (0.6%). One patient (0.2%) from HAVEN 2, who developed neutralizing anti-emicizumab-kxwh antibodies and decreased emicizumab-kxwh plasma concentrations, experienced loss of efficacy (manifest as breakthrough bleeding) after 5 weeks of treatment and discontinued HEMLIBRA treatment. Overall, the safety profile of HEMLIBRA was similar between those patients with anti-emicizumab-kxwh antibodies (including neutralizing antibodies) and those without.