Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 11 July 2018

Indication(s)

1 INDICATIONS AND USAGE NUCALA is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) indicated for: •Add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. (1.1) •The treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). (1.2) Limitation of use: Not for relief of acute bronchospasm or status asthmaticus. (1.1) 1.1 Maintenance Treatment of Severe Asthma NUCALA is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype [see Clinical Studies (14.1)]. Limitation of Use NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus. 1.2 Eosinophilic Granulomatosis with Polyangiitis NUCALA is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA) .

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Advisory information

contraindications
4 CONTRAINDICATIONS NUCALA should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation. History of hypersensitivity to mepolizumab or excipients in the formulation. (4)
Adverse reactions
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)] 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. Most common adverse reactions (incidence ≥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 in Severe Asthma 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 ICS plus additional controller(s) (Trials 1 and 2), and 135 subjects 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 subjects had markers of eosinophilic airway inflammation [see Clinical Studies (14.1)]. Of the subjects 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 subjects received NUCALA (mepolizumab 100 mg SC) for at least 24 weeks. Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects receiving NUCALA 100 mg (n = 263) than placebo (n = 257) included 1 event, herpes zoster (2 subjects vs. 0 subjects, respectively). Approximately 2% of subjects receiving NUCALA 100 mg 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 100 mg is shown in Table 1. Table 1. Adverse Reactions with NUCALA with ≥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 ≥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 receiving 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 100 mg. Systemic allergic/hypersensitivity reactions were reported by 2% of subjects in the placebo group and 1% of subjects in the group receiving NUCALA 100 mg. 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 subjects in the group receiving NUCALA 100 mg and 3% of subjects 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 subjects 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 subjects receiving NUCALA 100 mg compared with 3% in subjects receiving placebo. Long-term Safety Nine hundred ninety-eight subjects 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 asthma trials described above. 6.2 Clinical Trials Experience in Eosinophilic Granulomatosis with Polyangiitis A total of 136 subjects with EGPA were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. Subjects received 300 mg of NUCALA or placebo subcutaneously once every 4 weeks. Subjects 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 [see Clinical Studies (14.2)]. Of the subjects 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 subjects who experienced systemic (allergic and non‑allergic) reactions was 1% in the placebo group and 6% in the group receiving 300 mg of NUCALA. Systemic allergic/hypersensitivity reactions were reported by 1% of subjects in the placebo group and 4% of subjects in the group receiving 300 mg of NUCALA. 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%) subject in the group receiving 300 mg of NUCALA and no subjects 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 subjects 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 subjects receiving NUCALA compared with 13% in subjects receiving placebo. 6.3 Immunogenicity In subjects with asthma receiving NUCALA 100 mg, 15/260 (6%) developed anti-mepolizumab antibodies. Neutralizing antibodies were detected in 1 subject 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 subjects with EGPA receiving 300 mg of NUCALA, 1/68 (<2%) had detectable anti-mepolizumab antibodies. No neutralizing antibodies were detected in any subjects with EGPA. 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. 6.4 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION NUCALA is for subcutaneous (SC) use only. •Asthma: 100 mg administered subcutaneously once every 4 weeks. (2.1) •EGPA: 300 mg as 3 separate 100-mg injections administered subcutaneously once every 4 weeks. (2.2) See Full Prescribing Information for instructions on reconstitution of lyophilized powder and preparation and administration of the injection. (2.3) 2.1 Severe Asthma The recommended dosage of NUCALA is 100 mg administered once every 4 weeks by SC injection into the upper arm, thigh, or abdomen. 2.2 Eosinophilic Granulomatosis with Polyangiitis The recommended dosage of NUCALA is 300 mg administered once every 4 weeks by SC injection as 3 separate 100-mg injections into the upper arm, thigh, or abdomen. It is recommended that the individual 100-mg injections be administered at least 5 cm (approximately 2 inches) apart if more than 1 injection is administered at the same site. Preparation of the 300-mg dose for treatment of EGPA requires the reconstitution of 3 separate 100-mg vials as described below [see Dosage and Administration (2.3)]. 2.3 Preparation and Administration NUCALA should be reconstituted and administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions (5.1)]. Reconstitution Instructions 1.Reconstitute NUCALA in the vial with 1.2 mL of Sterile Water for Injection, USP, preferably using a 2- or 3-mL syringe and a 21-gauge needle. The reconstituted solution will contain a concentration of 100 mg/mL mepolizumab. Do not mix with other medications. 2.Direct the stream of Sterile Water for Injection vertically onto the center of the lyophilized cake. Gently swirl the vial for 10 seconds with a circular motion at 15-second intervals until the powder is dissolved. Note: Do not shake the reconstituted solution during the procedure as this may lead to product foaming or precipitation. Reconstitution is typically complete within 5 minutes after the Sterile Water for Injection has been added, but it may take additional time. 3.If a mechanical reconstitution device (swirler) is used to reconstitute NUCALA, swirl at 450 rpm for no longer than 10 minutes. Alternatively, swirling at 1,000 rpm for no longer than 5 minutes is acceptable. 4.Visually inspect the reconstituted solution for particulate matter and clarity before use. The solution should be clear to opalescent and colorless to pale yellow or pale brown, essentially particle free. Small air bubbles, however, are expected and acceptable. If particulate matter remains in the solution or if the solution appears cloudy or milky, the solution must not be administered. 5.If the reconstituted solution is not used immediately: •store below 30°C (86°F), •do not freeze, and •discard if not used within 8 hours of reconstitution. Administration 1.For SC administration, preferably using a 1-mL polypropylene syringe fitted with a disposable 21- to 27-gauge x 0.5-inch (13-mm) needle. 2.Just before administration, remove 1 mL of reconstituted NUCALA. Do not shake the reconstituted solution during the procedure as this could lead to product foaming or precipitation. 3.Administer the 1-mL injection (equivalent to 100 mg of mepolizumab) subcutaneously into the upper arm, thigh, or abdomen.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women with asthma exposed to NUCALA during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting www.mothertobaby.org/asthma. Risk Summary The data on pregnancy exposure are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of mepolizumab throughout pregnancy at doses that produced exposures up to approximately 9 times the exposure at the maximum recommended human dose (MRHD) of 300 mg SC (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. Data Animal Data: In a prenatal and postnatal development study, pregnant cynomolgus monkeys received mepolizumab from gestation Days 20 to 140 at doses that produced exposures up to approximately 9 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 100 mg/kg once every 4 weeks). Mepolizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 9 months after birth. Examinations for internal or skeletal malformations were not performed. Mepolizumab crossed the placenta in cynomolgus monkeys. Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers up to Day 178 postpartum. Levels of mepolizumab in milk were ≤0.5% of maternal serum concentration. In a fertility, early embryonic, and embryofetal development study, pregnant CD-1 mice received an analogous antibody, which inhibits the activity of murine interleukin-5 (IL-5), at an IV dose of 50 mg/kg once per week throughout gestation. The analogous antibody was not teratogenic in mice. Embryofetal development of IL-5–deficient mice has been reported to be generally unaffected relative to wild-type mice. 8.2 Lactation Risk Summary There is no information regarding the presence of mepolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. However, mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. Mepolizumab was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy [see Use in Specific Populations (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NUCALA and any potential adverse effects on the breastfed infant from mepolizumab or from the underlying maternal condition. 8.4 Pediatric Use The safety and efficacy in pediatric patients younger than 12 years with asthma have not been established. A total of 28 adolescents aged 12 to 17 years with asthma were enrolled in the Phase 3 asthma studies. Of these, 25 were enrolled in the 32-week exacerbation trial (Trial 2) and had a mean age of 14.8 years. Subjects had a history of 2 or more exacerbations in the previous year despite regular use of high-dose ICS plus additional controller(s) with or without OCS and had blood eosinophils of ≥150 cells/mcL at screening or ≥300 cells/mcL within 12 months prior to enrollment. [See Clinical Studies (14.1).] Subjects had a reduction in the rate of exacerbations that trended in favor of mepolizumab. Of the 19 adolescents who received mepolizumab, 9 received NUCALA 100 mg and the mean apparent clearance in these subjects was 35% less than that of adults. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies [see Adverse Reactions (6.1)]. The safety and efficacy in pediatric patients other than those with asthma have not been established. 8.5 Geriatric Use Clinical trials of NUCALA did not include sufficient numbers of subjects aged 65 years and older that received NUCALA (n = 46) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Based on available data, no adjustment of the dosage of NUCALA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Interactions

7 DRUG INTERACTIONS Formal drug interaction trials have not been performed with NUCALA.

More information

Category Value
Authorisation number BLA125526
Agency product number 90Z2UF0E52
Orphan designation No
Product NDC 0173-0881
Date Last Revised 12-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1720606
Marketing authorisation holder GlaxoSmithKline LLC