6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: •Hypersensitivity reactions [see Warnings and Precautions (5.1)] •Opportunistic infections: herpes zoster [see Warnings and Precautions (5.3)] Most common adverse reactions (incidence greater than or equal to 5%) include headache, injection site reaction, back pain, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1,327 subjects with asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Trials 1, 2, and 3). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) (Trials 1 and 2), and 135 subjects required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control (Trial 3). All subjects had markers of eosinophilic airway inflammation [see Clinical Studies (14)]. Of the subjects enrolled, 59% were female, 85% were white, and subjects ranged in age from 12 to 82 years. Mepolizumab was administered subcutaneously or intravenously once every 4 weeks; 263 subjects received NUCALA (mepolizumab 100 mg subcutaneous [SC]) for at least 24 weeks. Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects treated with NUCALA (n = 263) than placebo (n = 257) included 1 event, herpes zoster (2 subjects vs. 0 subjects, respectively). Approximately 2% of subjects receiving NUCALA withdrew from clinical trials due to adverse events compared with 3% of subjects receiving placebo. The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials (Trials 2 and 3) with NUCALA is shown in Table 1. Table 1. Adverse Reactions with NUCALA with Greater than or Equal to 3% Incidence and More Common than Placebo in Subjects with Asthma (Trials 2 and 3) Adverse Reaction NUCALA (Mepolizumab 100 mg Subcutaneous) (n = 263) % Placebo (n = 257) % Headache 19 18 Injection site reaction 8 3 Back pain 5 4 Fatigue 5 4 Influenza 3 2 Urinary tract infection 3 2 Abdominal pain upper 3 2 Pruritus 3 2 Eczema 3 <1 Muscle spasms 3 <1 52-Week Trial Adverse reactions from Trial 1 with 52 weeks of treatment with mepolizumab 75 mg intravenous (IV) (n = 153) or placebo (n = 155) and with greater than or equal to 3% incidence and more common than placebo and not shown in Table 1 were: abdominal pain, allergic rhinitis, asthenia, bronchitis, cystitis, dizziness, dyspnea, ear infection, gastroenteritis, lower respiratory tract infection, musculoskeletal pain, nasal congestion, nasopharyngitis, nausea, pharyngitis, pyrexia, rash, toothache, viral infection, viral respiratory tract infection, and vomiting. In addition, 3 cases of herpes zoster occurred in subjects treated with mepolizumab 75 mg IV, compared with 2 subjects in the placebo group. Systemic Reactions, including Hypersensitivity Reactions In Trials 1, 2, and 3 described above, the percentage of subjects who experienced systemic (allergic and non-allergic) reactions was 5% in the placebo group and 3% in the group receiving NUCALA. Systemic allergic/hypersensitivity reactions were reported by 2% of subjects in the placebo group and 1% of subjects in the group receiving NUCALA. The most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving NUCALA included rash, pruritus, headache, and myalgia. Systemic non-allergic reactions were reported by 2% of subjects in the group receiving NUCALA and 3% of subjects in the placebo group. The most commonly reported manifestations of systemic non-allergic reactions reported in the group receiving NUCALA included rash, flushing, and myalgia. A majority of the systemic reactions in subjects receiving NUCALA (5/7) were experienced on the day of dosing. Injection Site Reactions Injection site reactions (e.g., pain, erythema, swelling, itching, burning sensation) occurred at a rate of 8% in subjects treated with NUCALA compared with 3% in subjects treated with placebo. Long-term Safety Nine hundred ninety-eight (998) subjects have received NUCALA in ongoing open-label extension studies, during which additional cases of herpes zoster have been reported. The overall adverse event profile was similar to the asthma trials described above. 6.2 Immunogenicity Overall, 15/260 (6%) of subjects treated with NUCALA developed anti-mepolizumab antibodies. The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 1 subject receiving mepolizumab. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known. The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of NUCALA. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to NUCALA or a combination of these factors. Immune System Disorders Hypersensitivity reactions, including anaphylaxis.