Nucala Drug Information

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. 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. 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. 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.

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. Table 2. Adverse Reactions with NUCALA with ≥3% Incidence and More Common than Placebo in Patients with Severe Asthma (MENSA and SIRIUS) 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 most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving NUCALA 100 mg included rash, pruritus, headache, 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 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. 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. Adverse Reactions in Adult Patients with 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. Table 3 summarizes adverse reactions that occurred in ≥3% of patients treated with NUCALA and more frequently than in patients treated with placebo in the CRSwNP trial.

Table 3. Adverse Reactions with NUCALA with ≥3% Incidence and More Common than Placebo in Patients with Chronic Rhinosinusitis with Nasal Polyps Systemic Reactions, including Hypersensitivity Reactions: In the 52-week trial, the percentage of patients who experienced systemic (allergic and other) reactions was <1% in the group receiving NUCALA 100 mg and <1% 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. Adverse Reactions in Adults with Chronic Obstructive Pulmonary Disease The safety data below reflects the safety of NUCALA in adults with inadequately controlled COPD and an eosinophilic phenotype.

Trial 3 enrolled COPD adults with a peripheral blood eosinophil count ≥150 cells/µL at screening or ≥300 cells/µL in the year prior. Table 4 summarizes adverse reactions that occurred in ≥3% of patients treated with NUCALA and more frequently than in patients treated with placebo in COPD trials. Table 4.

Adverse Reactions in Patients with Eosinophilic Granulomatosis with Polyangiitis A total of 136 patients with EGPA were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. 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. 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. 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.

Adverse Reactions in Adult and Adolescent Patients with 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 must have been on a stable dose of background HES therapy for the 4 weeks prior to randomization.

Systemic Reactions, including Hypersensitivity Reactions: In the trial, no systemic allergic (type I hypersensitivity) reactions were reported. 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.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post-approval 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.

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 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.

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. 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. Patients had a reduction in the rate of exacerbations that trended in favor of NUCALA. The safety profile observed in adolescents was generally similar to that of the overall population in the Phase 3 studies.

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. 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.

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. 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. 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.

NUCALA is contraindicated in patients with a history of hypersensitivity to mepolizumab or excipients in the formulation.

There is no specific treatment for an overdose with mepolizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.