Nucala

1 INDICATIONS AND USAGE NUCALA is an interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa) indicated for: • Add-on maintenance treatment of adult and pediatric patients aged 6 years and older with severe asthma and with an eosinophilic phenotype. ( 1.1 ) • Add-on maintenance treatment of adult patients aged 18 years and older with chronic rhinosinusitis with nasal polyps (CRSwNP). ( 1.2 ) • Add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. ( 1.3 ) • The treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). ( 1.4 ) • The treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for greater than or equal to 6 months without an identifiable non-hematologic secondary cause. ( 1.5 ) Limitations of use: Not for relief of acute bronchospasm or status asthmaticus. ( 1.1 , 1.3 ) 1.1 Maintenance Treatment of Severe Asthma NUCALA is indicated for the add-on maintenance treatment of adult and pediatric patients aged 6 years and older with severe asthma and with an eosinophilic phenotype [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.1 )] . Limitations of Use NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions ( 5.2 )] . 1.2 Maintenance Treatment of Chronic Rhinosinusitis with Nasal Polyps NUCALA is indicated for the add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients aged 18 years and older with inadequate response to nasal corticosteroids. 1.3 Maintenance Treatment of Chronic Obstructive Pulmonary Disease NUCALA is indicated for the add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. Limitations of Use NUCALA is not indicated for the relief of acute bronchospasm [see Warnings and Precautions ( 5.2 )]. 1.4 Eosinophilic Granulomatosis with Polyangiitis NUCALA is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). 1.5 Hypereosinophilic Syndrome NUCALA is indicated for the treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for greater than or equal to 6 months without an identifiable non-hematologic secondary cause.

2 DOSAGE AND ADMINISTRATION • Severe asthma in patients aged 12 years and older: 100 mg administered subcutaneously once every 4 weeks. ( 2.1 ) • Severe asthma in patients aged 6 to 11 years: 40 mg administered subcutaneously once every 4 weeks. ( 2.1 ) • CRSwNP: 100 mg administered subcutaneously once every 4 weeks. ( 2.1 ) • COPD: 100 mg administered subcutaneously once every 4 weeks. ( 2.1 ) • EGPA: 300 mg administered subcutaneously once every 4 weeks. ( 2.1 ) • HES: 300 mg administered subcutaneously once every 4 weeks. ( 2.1 ) 2.1 Recommended Dosage NUCALA is for subcutaneous use only, and should be injected into the upper arm, thigh, or abdomen [see Dosage and Administration ( 2.2 , 2.3 )]. Table 1. Recommended Dosage of NUCALA a 300 mg dose is administered as 3 separate 100 mg dose injections administered at least 5 cm (approximately 2 inches) apart. Indication Adults Pediatric Patients Severe asthma 100 mg every 4 weeks • 12 to 17 years of age: 100 mg every 4 weeks • 6 to 11 years of age: 40 mg every 4 weeks Chronic rhinosinusitis with nasal polyps 100 mg every 4 weeks Not applicable Chronic obstructive pulmonary disease 100 mg every 4 weeks Not applicable Eosinophilic granulomatosis with polyangiitis 300 mg a every 4 weeks Not applicable Hypereosinophilic syndrome 300 mg a every 4 weeks 12 to 17 years of age: 300 mg a every 4 weeks 2.2 Preparation and Administration of NUCALA for Injection Vial NUCALA for injection 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 for injection 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 powder, which may have a cake-like appearance. 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 for injection, 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 of 100 mg Dose 1. For subcutaneous 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 for injection. 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. Administration of 40 mg Dose 1. For subcutaneous 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 0…

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after administration of NUCALA. Discontinue NUCALA in the event of a hypersensitivity reaction. ( 5.1 ) • Herpes zoster infections have occurred in patients receiving NUCALA. Consider vaccination if medically appropriate. ( 5.3 ) • Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decrease corticosteroids gradually, if appropriate. ( 5.4 ) • Treat patients with pre-existing helminth infections before therapy with NUCALA. If patients become infected while receiving treatment with NUCALA and do not respond to anti-helminth treatment, discontinue NUCALA until parasitic infection resolves. ( 5.5 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred following administration of NUCALA. These reactions generally occur within hours of administration, but in some instances can have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, NUCALA should be discontinued [see Contraindications ( 4 )] . 5.2 Acute Symptoms of Asthma or Chronic Obstructive Pulmonary Disease or Acute Deteriorating Disease NUCALA should not be used to treat acute symptoms or acute exacerbations of asthma or COPD. Do not use NUCALA to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma or COPD remains uncontrolled or worsens after initiation of treatment with NUCALA. 5.3 Opportunistic Infections: Herpes Zoster Herpes zoster has occurred in subjects receiving NUCALA 100 mg in controlled clinical trials [see Adverse Reactions ( 6.1 )] . Consider vaccination if medically appropriate. 5.4 Reduction of Corticosteroid Dosage Do not discontinue systemic or inhaled corticosteroids (ICS) abruptly upon initiation of therapy with NUCALA. Reductions in corticosteroid dosage, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dosage may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. 5.5 Parasitic (Helminth) Infection Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical trials. It is unknown if NUCALA will influence a patient’s response against parasitic infections. Treat patients with pre-existing helminth infections before initiating therapy with NUCALA. If patients become infected while receiving treatment with NUCALA and do not respond to anti-helminth treatment, discontinue treatment with NUCALA until infection resolves.

4 CONTRAINDICATIONS NUCALA is contraindicated in patients with a history of hypersensitivity to mepolizumab or excipients in the formulation [see Warnings and Precautions ( 5.1 ), Description ( 11 )] . History of hypersensitivity to mepolizumab or excipients in the formulation. ( 4 )

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

8.1 Pregnancy 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 intravenous 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 subcutaneous (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 intravenous 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 intravenous 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.

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 ≥5%): • Asthma: Headache, injection site reaction, back pain, and fatigue. ( 6.1 ) • CRSwNP: Oropharyngeal pain and arthralgia. ( 6.1 ) • COPD: Back pain, diarrhea, and cough. ( 6.1 ) • EGPA and HES: Most common adverse reactions are similar to asthma. ( 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. Adverse Reactions in Adult and Adolescent Patients Aged 12 Years and Older with Severe Asthma A total of 1,327 patients with severe asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Severe Asthma Trials DREAM, MENSA, and SIRIUS). 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) (Severe Asthma Trials DREAM and MENSA), 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 (Severe Asthma Trial SIRIUS). All patients had markers of eosinophilic airway inflammation [see Clinical Studies ( 14.1 )] . 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 subcutaneously) 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). The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials MENSA and SIRIUS with NUCALA 100 mg is shown in Table 2 . Table 2. Adverse Reactions with NUCALA with ≥3% Incidence and More Common than Placebo in Patients with Severe Asthma (MENSA and SIRIUS) 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 the Severe Asthma Trial DREAM with 52 weeks of treatment with mepolizumab 75 mg intravenously (n = 153) or placebo (n = 155) and with ≥3% incidence and more common than placebo and not shown in Table 2 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 intravenously compared with 2 patients in the placebo group. Systemic Reactions, including Hypersensitivity Reactions: In the Severe Asthma Trials DREAM, MENSA, and SIRIUS 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 m…