ADAKVEO SIDE EFFECTS

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion-related reactions

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.

Sickle Cell Disease

The safety of ADAKVEO was evaluated in the SUSTAIN trial. Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta⁰-thalassemia, HbSbeta⁺-thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 66) or 2.5 mg/kg (N = 64) or placebo (N = 62) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg.

Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 6 months or longer and 61% were exposed for approximately one year; forty-two (64%) patients were treated with ADAKVEO in combination with hydroxyurea.

Serious adverse reactions were reported in 2 patients (3%) treated with ADAKVEO 5 mg/kg; both reactions were pyrexia.

Two deaths (3%) occurred in the ADAKVEO 5 mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO.

The most common adverse reactions (≥ 10%) were nausea, arthralgia, back pain, abdominal pain, and pyrexia. These adverse reactions, along with myalgia, musculoskeletal chest pain, and diarrhea may be signs and symptoms of an infusion-related reaction when observed during/within 24 hours of an infusion.

Table 1 summarizes the adverse reactions in the SUSTAIN trial.

Table 1: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in SUSTAIN

Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

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 in the studies described below with the incidence of antibodies in other studies or to other crizanlizumab products may be misleading.

The immunogenicity of ADAKVEO was evaluated using a validated bridging immunoassay for the detection of binding anti-crizanlizumab-tmca antibodies. In a single arm, open label multiple dose study, 0 of the 45 patients with sickle cell disease treated with ADAKVEO 5 mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In a single-dose study of healthy subjects, 1 of the 61 (1.6%) evaluable subjects tested positive for a treatment-induced anticrizanlizumab-tmca antibodies.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ADAKVEO. 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.

General Disorders and Administration-site Conditions: Pain (in various locations) occurring during/within 24 hours of the infusion (e.g., potential infusion-related reaction)