Nucala

Mechanism of Action

Humanized IgG1 kappa monoclonal antibody specific for IL-5; binds IL-5, and therefore stops IL-5 from binding to its receptor on the surface of eosinophils

Inhibiting IL-5 binding to eosinophils reduces blood, tissue, and sputum eosinophil levels

Absorption

Bioavailability: 80%

Distribution

Vd: 3.6 L

Metabolism

Degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue

Elimination

Half-life: 16-22 days

Systemic clearance: 0.28 L/day

Nucala is a prescription medicine used with other asthma medicines for the maintenance treatment of asthma in people aged 12 years and older whose asthma is not controlled with their current asthma medicines. Nucala helps prevent severe asthma attacks (exacerbations). Nucala reduces blood eosinophils. Eosinophils are a type of white blood cells that may contribute to your asthma.

Nucala is not used to treat other problems caused by eosinophils. Nucala is not used to treat sudden breathing problems.

It is not known if Nucala is safe and effective in children under 12 years of age.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Before receiving Nucala, tell your healthcare provider about all of your medical conditions, including if you:

• have a parasitic (helminth) infection
• have not had chickenpox (varicella) or the chickenpox vaccine
• are taking oral or inhaled corticosteroid medicines. Do not stop taking your corticosteroid medicines unless instructed by your healthcare provider. This may cause other symptoms that were controlled by the corticosteroid medicine to come back.
• are pregnant or plan to become pregnant. It is not known if Nucala may harm your unborn baby. There is a pregnancy registry for women who receive Nucala while pregnant. The purpose of the registry is to collect information about the health of you and your baby. You can talk to your healthcare provider about how to take part in this registry or you can get more information and register by calling 1-877-311-8972 or go to www.mothertobaby.org/asthma.
• are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will use Nucala and breastfeed. You should not do both without talking with your healthcare provider first.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not stop taking your other asthma medicines unless instructed to do so by your healthcare provider.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Asthma

Adjunctive maintenance therapy in patients with severe eosinophilic asthma.1 2 3 4

Reduces asthma exacerbation rate and decreases oral corticosteroid dosage requirements.1 2 3 4 No effect on lung function as measured by change in baseline FEV1.1

Eosinophilic phenotype (i.e., eosinophilic asthma) is generally characterized by blood and sputum eosinophilia, eosinophilic inflammation, recurrent asthma exacerbations, and frequently, responsiveness to corticosteroids.6 8 9 11

Not indicated for treatment of other eosinophilic conditions.1

Not indicated for relief of acute bronchospasm or status asthmaticus.1

Contraindications

• History of hypersensitivity to the drug or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) reported, generally occurring within hours or possibly days following administration.1 If hypersensitivity reaction occurs, discontinue mepolizumab.1 (See Contraindications under Cautions.)

Deterioration of Disease and Acute Episodes

Not indicated for treatment of acute asthma symptoms or exacerbations, acute bronchospasm, or status asthmaticus.1 (See Advice to Patients.)

Infectious Complications

Herpes zoster infection (sometimes serious) reported.1 Consider varicella (zoster) vaccination before starting therapy, if medically appropriate.1 13

Immune response against some parasitic (helminth) infections may be altered.1 Not studied in patients with known parasitic infections.1 Treat patients with preexisting parasitic (helminth) infections before initiating mepolizumab.1 If parasitic infection occurs and does not respond to anthelmintic treatment, interrupt mepolizumab therapy until infection resolves.1

Do not abruptly discontinue systemic or inhaled corticosteroid therapy upon initiation of mepolizumab therapy.1 If appropriate, reduce corticosteroid dosage gradually and supervise such reduction carefully.1

Antibodies to mepolizumab detected in 6% of patients and associated with approximately 20% increased drug clearance.1 No apparent correlation between anti-mepolizumab antibody titers and change in eosinophil concentrations.1 Clinical importance of such antibodies not known.1

Specific Populations

No evidence of fetal harm in monkeys following IV mepolizumab during pregnancy.1 Potential effects of monoclonal antibodies (e.g., mepolizumab) more likely to occur in second and third trimesters.1

Encourage patients to enroll in pregnancy registry at 877-311-8972 or .1

Distributed into milk in monkeys.1 Not known whether distributed into human milk.1 Since IgG distributes into milk in humans, mepolizumab is expected to distribute into human milk.1

Weigh potential risks to infants against clinical need and known benefits of breast-feeding.1

Safety and efficacy not established in children <12 years of age.1

Evaluated in 19 adolescent patients 12–17 years of age with asthma; adverse effect profile generally similar to that observed in adults.1 Mean apparent clearance was 35% less than that of adults.1

Insufficient experience in patients ≥65 years of age.1 No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Pharmacokinetics not studied in patients with hepatic impairment.1

Pharmacokinetics not studied in patients with renal impairment.1

Common Adverse Effects

Headache,1 injection site reaction,1 back pain,1 fatigue,1 influenza,1 urinary tract infection,1 upper abdominal pain,1 pruritus,1 eczema,1 muscle spasm.1

Storage

Parenteral

<25°C.1 Keep in original package and protect from light.1 Do notfreeze.1

Reconstituted solution: Use immediately or store at <30°C for up to 8 hours.1 Do notfreeze.1

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

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)

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.

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.

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.

Formal drug interaction trials have not been performed with Nucala.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of mepolizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as mepolizumab is unknown.

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with mepolizumab for 6 months at IV doses up to 100 mg/kg once every 4 weeks (approximately 70 times the MRHD on an AUC basis). Mating and reproductive performance were unaffected in male and female CD-1 mice treated with an analogous antibody, which inhibits the activity of murine IL-5, at an IV dose of 50 mg/kg once per week.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after administration of Nucala. Instruct patients to contact their physicians if such reactions occur.

Not for Acute Symptoms or Deteriorating Disease

Inform patients that Nucala does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Nucala.

Opportunistic Infections: Herpes Zoster

Inform patients that herpes zoster infections have occurred in patients receiving Nucala and where medically appropriate, inform patients varicella vaccination should be considered before starting treatment with Nucala.

Reduction of Corticosteroid Dosage

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Pregnancy Exposure Registry

Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Nucala during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting www.mothertobaby.org/asthma [see Use in Specific Populations (8.1)].

Nucala is a registered trademark of the GSK group of companies.

Manufactured by

GlaxoSmithKline LLC

Philadelphia, PA 19112

U.S. License Number 1727

Distributed by

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 the GSK group of companies. All rights reserved.

NCL:2PI

PRINCIPAL DISPLAY PANEL

NDC 0173-0881-01

Nucala®

(mepolizumab)

for Injection

100 mg/vial

Rx Only

For subcutaneous injection after reconstitution.

Single-use vial. Discard unused portion.

Contents: Each vial delivers mepolizumab 100 mg, polysorbate 80 (0.67 mg), sodium phosphate dibasic heptahydrate (7.14 mg), and sucrose (160 mg). After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the reconstituted solution concentration is 100 mg/mL and delivers 1 mL.

No preservative.

No U.S. standard of potency.

1 vial

Do not accept if plastic overseal is missing or not securely fitted.

©2015 the GSK group of companies

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Usual Adult Dose of Nucala for Asthma -- Maintenance:

100 mg subcutaneously every 4 weeks

Comment:
-This drug should be administered in the upper arm, thigh, or abdomen.
-The need for continued therapy with this drug should be assessed at least annually.

Use: Add-on maintenance treatment for severe asthma with an eosinophilic phenotype

Usual Pediatric Dose for Asthma -- Maintenance:

12 years or older:
100 mg subcutaneously every 4 weeks

Comment:
-This drug should be administered in the upper arm, thigh, or abdomen.

Use: Add-on maintenance therapy for severe asthma with an eosinophilic phenotype

Call your doctor for instructions if you miss a dose of Nucala.

More frequent side effects include: injection site reaction. See below for a comprehensive list of adverse effects.