Nucala

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 , Clinical Studies ].

Limitations of Use

NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions ].

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)].

Eosinophilic Granulomatosis with Polyangiitis

NUCALA is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA).

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.

2.1 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

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 ].

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 0.4 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 0.4 mL injection (equivalent to 40 mg of mepolizumab) subcutaneously into the upper arm, thigh, or abdomen.

Each vial of NUCALA for injection should be used for a single patient, and any remainder of the contents should be discarded.

Preparation and Administration of NUCALA Injection Prefilled Autoinjector and Prefilled Syringes

NUCALA injection is intended for use under the guidance of a healthcare provider.

The 100 mg/mL prefilled autoinjector and 100 mg/mL prefilled syringe are only for use in adults and adolescents aged 12 years and older. A patient may self-inject, or the patient caregiver may administer NUCALA injection 100 mg/mL subcutaneously after the healthcare provider determines it is appropriate.

The 40 mg/0.4 mL prefilled syringe is only for use in children aged 6 to 11 years and must be administered by the healthcare provider or the patient caregiver. The patient caregiver may administer NUCALA injection 40 mg/0.4 mL subcutaneously after the healthcare provider determines it is appropriate.

Provide proper training in subcutaneous injection technique and on the preparation and administration of NUCALA injection prior to use [see Instructions for Use].

1.

Remove the prefilled autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for 30 minutes prior to injection. Do not warm NUCALA injection in any other way.

2.

Prior to administration, visually inspect the window of the prefilled autoinjector or the prefilled syringe for particulate matter or discoloration. NUCALA injection should be clear to opalescent, colorless to pale yellow to pale brown in color. Do not use NUCALA injection if the product exhibits discoloration, cloudiness, or particulate matter. Do not use the NUCALA prefilled autoinjector or prefilled syringe if dropped on a hard surface.

3.

Administer the subcutaneous injection into the thigh or abdomen, avoiding the 5 cm (approximately 2 inches) around the navel. The upper arm can also be used if a caregiver administers the subcutaneous injection.

4.

For use in EGPA and HES, ensure injection sites for each subcutaneous injection are separated by at least 5 cm (approximately 2 inches).

5.

Never give injections into areas where the skin is tender, bruised, red, or hard.

6.

If a dose is missed, administer a dose as soon as possible. Thereafter, the patient can resume dosing on the usual day of administration. If the next dose is already due, then administer as planned.

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.

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 ]. 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.

Pediatric Use

Severe Asthma

The safety and effectiveness of NUCALA for severe asthma, and with an eosinophilic phenotype, have been established in pediatric patients aged 6 years and older.

Use of NUCALA in adolescents aged 12 to 17 years is supported by evidence from adequate and well-controlled trials in adults and adolescents. A total of 28 adolescents aged 12 to 17 years with severe asthma were enrolled in the Phase 3 asthma trials. Of these, 25 were enrolled in the 32-week exacerbation trial (MENSA) and had a mean age of 14.8 years. Patients had a history of 2 or more exacerbations in the previous year despite regular use of medium- or 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 .] Patients had a reduction in the rate of exacerbations that trended in favor of NUCALA. Of the 19 adolescents who received NUCALA, 9 received 100 mg and the mean apparent clearance in these patients was 35% less than that of adults. The safety profile observed in adolescents was generally similar to that of the overall population in the Phase 3 studies [see Adverse Reactions ].

Use of NUCALA in pediatric patients aged 6 to 11 years with severe asthma, and with an eosinophilic phenotype, is supported by evidence from adequate and well-controlled trials in adults and adolescents with additional pharmacokinetic, pharmacodynamic, and safety data in children aged 6 to 11 years. A single open-label clinical trial was conducted in 36 children aged 6 to 11 years (mean age: 8.6 years, 31% female) with severe asthma. Enrollment criteria were the same as for adolescents in the 32-week exacerbation trial (MENSA). Based upon the pharmacokinetic data from this trial, a subcutaneous dose of 40 mg every 4 weeks was determined to have similar exposure to adults and adolescents administered a subcutaneous dose of 100 mg [see Clinical Pharmacology ].

The effectiveness of NUCALA in pediatric patients aged 6 to 11 years is extrapolated from efficacy in adults and adolescents with support from pharmacokinetic analyses showing similar drug exposure levels for 40 mg administered subcutaneously every 4 weeks in children aged 6 to 11 years compared with adults and adolescents [see Clinical Pharmacology ]. The safety profile and pharmacodynamic response observed in this trial for children aged 6 to 11 years were similar to that seen in adults and adolescents [see Adverse Reactions , Clinical Pharmacology ].

The safety and effectiveness in pediatric patients aged younger than 6 years with severe asthma have not been established.

Chronic Rhinosinusitis with Nasal Polyps

The safety and effectiveness in patients aged younger than 18 years with CRSwNP have not been established.

Chronic Obstructive Pulmonary Disease

The safety and effectiveness in pediatric patients aged younger than 18 years with COPD have not been established. COPD is largely a disease of adult patients.

Eosinophilic Granulomatosis with Polyangiitis

The safety and effectiveness in patients aged younger than 18 years with EGPA have not been established.

Hypereosinophilic Syndrome

The safety and effectiveness of NUCALA for HES have been established in adolescent patients aged 12 years and older. The safety and effectiveness in pediatric patients aged younger than 12 years with HES have not been established.

Use of NUCALA for this indication is supported by evidence from an adequate and well-controlled study (NCT02836496) in adults and adolescents and an open-label extension study (NCT03306043). One adolescent received NUCALA during the controlled study and this patient and an additional 3 adolescents received NUCALA during the open-label extension study [see Clinical Studies ]. The 1 adolescent treated with NUCALA in the 32-week trial did not have a HES flare or an adverse event reported. All adolescents received 300 mg of NUCALA for 20 weeks in the open-label extension.

Geriatric Use

Of the total number of patients treated with NUCALA (n = 4106) for severe asthma, HES, EGPA, CRSwNP, and COPD, 1073 (26%) were 65 years of age and older and 241 (6%) were 75 years of age and older [see Clinical Studies ]. No overall differences in safety and effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity in some older individuals cannot be ruled out.

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 ].

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.

Opportunistic Infections: Herpes Zoster

Herpes zoster has occurred in subjects receiving NUCALA 100 mg in controlled clinical trials [see Adverse Reactions ]. Consider vaccination if medically appropriate.

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.

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.