CABLIVI SIDE EFFECTS

SIDE EFFECTS

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Bleeding

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 safety of CABLIVI was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received CABLIVI; and TITAN, in which 35 patients received CABLIVI). The data described below and in the Warnings and Precautions reflect exposure to CABLIVI during the blinded periods of both studies, which include 106 patients with aTTP who received at least one dose, age 18 to 79 years, of whom 69% were female and 73% were White. The median treatment duration with CABLIVI was 35 days (range 1-77 days).

The most frequently reported adverse reactions (>15%) were epistaxis, headache and gingival bleeding. Seven patients (7%) in the CABLIVI group experienced an adverse reaction leading to study drug discontinuation. None of the adverse reactions leading to discontinuation were observed in more than 1% of patients.

Among 106 patients treated with CABLIVI during the TITAN and HERCULES studies, serious bleeding adverse reactions reported in ≥2% patients included epistaxis (4%) and subarachnoid hemorrhage (2%).

Adverse reactions that occurred in ≥2% of patients treated with CABLIVI and more frequently than in those treated with placebo across the pooled data from the two trials are summarized in Table 1. Urticaria was seen during plasma exchange.

Table 1: Adverse Reactions in ≥2% of Patients Treated with CABLIVI and More Frequent than Placebo during the Blinded Periods of aTTP Studies (HERCULES and TITAN)

Immunogenicity

As with all therapeutic proteins, there is 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 (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to caplacizumab-yhdp in the studies described below, with the incidence of antibodies in other studies, or to other products, may be misleading.

The prevalence of pre-existing antibodies binding to caplacizumab-yhdp observed during clinical studies and during evaluation of commercially available human samples varied between 4% and 63%. In aTTP patients, pre-existing antibodies can be produced by the patient or can originate from donor plasma during plasma exchange. No clinically apparent impact of these pre-existing antibodies on clinical efficacy or safety was found. Treatment-emergent antidrug antibodies (TE ADA) against caplacizumab-yhdp were detected in 3% of patients treated with CABLIVI in the HERCULES study. In the HERCULES study, TE ADA were further characterized as having neutralizing potential. There was no clinically apparent impact on clinical efficacy or safety.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CABLIVI. 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 caplacizumab-yhdp exposure.

General disorders and administration site conditions:

• injection site erythema