NUCALA SIDE EFFECTS

Last updated on MDtodate: 10/9/2022

SIDE EFFECTS

The following adverse reactions are described in greater detail in other sections:

• Hypersensitivity reactions
• Opportunistic infections: herpes zoster

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.

Clinical Trials Experience In Severe Asthma

Adult And Adolescent Patients Aged 12 Years And Older

A total of 1,327 patients with severe asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Trial 1, NCT01000506; Trial 2, NCT01691521; and Trial 3, NCT01691508). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose ICS plus additional controller(s) (Trials 1 and 2), and 135 patients required daily oral corticosteroids (OCS) in addition to regular use of high-dose ICS plus additional controller(s) to maintain asthma control (Trial 3). All patients had markers of eosinophilic airway inflammation. Of the patients enrolled, 59% were female, 85% were White, and ages ranged from 12 to 82 years. Mepolizumab was administered subcutaneously or intravenously once every 4 weeks; 263 patients received NUCALA (mepolizumab 100 mg subcutaneous) for at least 24 weeks. Serious adverse events that occurred in more than 1 patient and in a greater percentage of patients receiving NUCALA 100 mg (n = 263) than placebo (n = 257) included 1 event, herpes zoster (2 patients vs. 0 patients, respectively). Approximately 2% of patients receiving NUCALA 100 mg withdrew from clinical trials due to adverse events compared with 3% of patients 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 100 mg is shown in Table 1.

Table 1: Adverse Reactions with NUCALA with ≥3% Incidence and More Common than Placebo in Patients with Severe 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 ≥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 patients receiving mepolizumab 75 mg IV compared with 2 patients in the placebo group.

Systemic Reactions, Including Hypersensitivity Reactions

In Trials 1, 2, and 3 described above, the percentage of patients who experienced systemic (allergic and non-allergic) reactions was 3% in the group receiving NUCALA 100 mg and 5% in the placebo group. Systemic allergic/hypersensitivity reactions were reported by 1% of patients in the group receiving NUCALA 100 mg and 2% of patients in the placebo group. The most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving NUCALA 100 mg included rash, pruritus, headache, and myalgia. Systemic non-allergic reactions were reported by 2% of patients in the group receiving NUCALA 100 mg and 3% of patients in the placebo group. The most commonly reported manifestations of systemic non-allergic reactions reported in the group receiving NUCALA 100 mg included rash, flushing, and myalgia. A majority of the systemic reactions in patients receiving NUCALA 100 mg (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 patients receiving NUCALA 100 mg compared with 3% in patients receiving placebo.

Long-term Safety

Nine hundred ninety-eight patients received NUCALA 100 mg in ongoing open-label extension studies, during which additional cases of herpes zoster were reported. The overall adverse event profile has been similar to the severe asthma trials described above.

Pediatric Patients Aged 6 To 11 Years

The safety data for NUCALA is based upon 1 open-label clinical trial that enrolled 36 patients with severe asthma aged 6 to 11 years. Patients received 40 mg (for those weighing <40 kg) or 100 mg (for those weighing ≥40 kg) of NUCALA administered subcutaneously once every 4 weeks. Patients received NUCALA for 12 weeks (initial short phase). After a treatment interruption of 8 weeks, 30 patients received NUCALA for a further 52 weeks (long phase). The adverse reaction profile for patients aged 6 to 11 years was similar to that observed in patients aged 12 years and older.

Clinical Trials Experience In Chronic Rhinosinusitis With Nasal Polyps

A total of 407 patients with CRSwNP were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. Patients received NUCALA 100 mg or placebo subcutaneously once every 4 weeks. Patients had recurrent CRSwNP with a history of prior surgery and were on nasal corticosteroids for at least 8 weeks prior to screening. Of the patients enrolled, 35% were female, 93% were White, and ages ranged from 18 to 82 years. Approximately 2% of patients receiving NUCALA 100 mg withdrew from study treatment due to adverse events compared with 2% of patients receiving placebo.

Table 2 summarizes adverse reactions that occurred in ≥ 3% of NUCALA-treated patients and more frequently than in patients treated with placebo in the CRSwNP trial.

Table 2: Adverse Reactions with NUCALA with ≥3% Incidence and More Common than Placebo in Patients with CRSwNP

Adverse Reaction	NUCALA (Mepolizumab 100 mg Subcutaneous) (n = 206) %	Placebo (n = 201) %
Oropharyngeal pain	8	5
Arthralgia	6	2
Abdominal Pain Upper	3	2
Diarrhea	3	2
Pyrexia	3	2
Nasal dryness	3	<1
Rash	3	<1
CRSwNP = Chronic Rhinosinusitis with Nasal Polyps.

 

Systemic Reactions, Including Hypersensitivity Reactions

In the 52-week trial, the percentage of patients who experienced systemic (allergic [type I hypersensitivity] and other) reactions was <1% in the group receiving NUCALA 100 mg and <1% in the placebo group. Systemic allergic (type I hypersensitivity) reactions were reported by <1% of patients in the group receiving NUCALA 100 mg and no patients in the placebo group. The manifestations of systemic allergic (type I hypersensitivity) reactions included urticaria, erythema, and rash and 1 of the 3 reactions occurred on the day of dosing. Other systemic reactions were reported by no patients in the group receiving NUCALA 100 mg and <1% of patients in the placebo group.

Injection Site Reactions

Injection site reactions (e.g., erythema, pruritus) occurred at a rate of 2% in patients receiving NUCALA 100 mg compared with <1% in patients receiving placebo.

Clinical Trials Experience In Eosinophilic Granulomatosis With Polyangiitis

A total of 136 patients with EGPA were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. Patients received 300 mg of NUCALA or placebo subcutaneously once every 4 weeks. Patients enrolled had a diagnosis of EGPA for at least 6 months prior to enrollment with a history of relapsing or refractory disease and were on a stable dosage of oral prednisolone or prednisone of greater than or equal to 7.5 mg/day (but not greater than 50 mg/day) for at least 4 weeks prior to enrollment. Of the patients enrolled, 59% were female, 92% were White, and ages ranged from 20 to 71 years. No additional adverse reactions were identified to those reported in the severe asthma trials.

Systemic Reactions, Including Hypersensitivity Reactions

In the 52-week trial, the percentage of patients who experienced systemic (allergic and non-allergic) reactions was 6% in the group receiving 300 mg of NUCALA and 1% in the placebo group. Systemic allergic/hypersensitivity reactions were reported by 4% of patients in the group receiving 300 mg of NUCALA and 1% of patients in the placebo group. The manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving 300 mg of NUCALA included rash, pruritus, flushing, fatigue, hypertension, warm sensation in trunk and neck, cold extremities, dyspnea, and stridor. Systemic non-allergic reactions were reported by 1 (1%) patient in the group receiving 300 mg of NUCALA and no patients in the placebo group. The reported manifestation of systemic non-allergic reactions reported in the group receiving 300 mg of NUCALA was angioedema. Half of the systemic reactions in patients receiving 300 mg of NUCALA (2/4) were experienced on the day of dosing.

Injection Site Reactions

Injection site reactions (e.g., pain, erythema, swelling) occurred at a rate of 15% in patients receiving 300 mg of NUCALA compared with 13% in patients receiving placebo.

Clinical Trials Experience In Hypereosinophilic Syndrome

A total of 108 adult and adolescent patients aged 12 years and older with HES were evaluated in a randomized, placebo-controlled, multicenter, 32-week treatment trial. Patients with non-hematologic secondary HES or FIP1L1-PDGFRα kinase-positive HES were excluded from the trial. Patients received 300 mg of NUCALA or placebo subcutaneously once every 4 weeks. Patients must have been on a stable dose of background HES therapy for the 4 weeks prior to randomization. Of the patients enrolled, 53% were female, 93% were White, and ages ranged from 12 to 82 years. No additional adverse reactions were identified to those reported in the severe asthma trials.

Systemic Reactions, Including Hypersensitivity Reactions

In the trial, no systemic allergic (type I hypersensitivity) reactions were reported. Other systemic reactions were reported by 1 (2%) patient in the group receiving 300 mg of NUCALA and no patients in the placebo group. The reported manifestation of other systemic reaction was multifocal skin reaction experienced on the day of dosing.

Injection Site Reactions

Injection site reactions (e.g., burning, itching) occurred at a rate of 7% in patients receiving 300 mg of NUCALA compared with 4% in patients receiving placebo.

Immunogenicity

In adult and adolescent patients with severe asthma receiving NUCALA 100 mg, 15/260 (6%) had detectable anti-mepolizumab antibodies. Neutralizing antibodies were detected in 1 patient with asthma receiving NUCALA 100 mg. 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. In the clinical trial of children aged 6 to 11 years with severe asthma receiving NUCALA 40 or 100 mg, 2/35 (6%) had detectable anti-mepolizumab antibodies during the initial short phase of the trial. No children had detectable anti-mepolizumab antibodies during the long phase of the trial.

In patients with CRSwNP receiving NUCALA 100 mg, 6/196 (3%) had detectable anti-mepolizumab antibodies. No neutralizing antibodies were detected in any patients with CRSwNP.

In patients with EGPA receiving 300 mg of NUCALA, 1/68 (<2%) had detectable anti-mepolizumab antibodies. No neutralizing antibodies were detected in any patients with EGPA.

In adult and adolescent patients with HES receiving 300 mg of NUCALA, 1/53 (2%) had detectable anti-mepolizumab antibodies. No neutralizing antibodies were detected in any patients with HES.

The reported frequency of anti-mepolizumab antibodies may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. 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.

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.