4.1. Therapeutic indications

Severe eosinophilic asthma

Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older (see section 5.1).

Chronic rhinosinusitis with nasal polyps (CRSwNP)

Nucala is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate control.

Chronic obstructive pulmonary disease (COPD)

Nucala is indicated as add-on maintenance treatment of adult patients with uncontrolled COPD of an eosinophilic phenotype on a combination of an inhaled corticosteroid (ICS), a long acting beta2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA). (see section 5.1).

Eosinophilic granulomatosis with polyangiitis (EGPA)

Nucala is indicated as an add-on treatment for patients aged 6 years and older with relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA).

Hypereosinophilic syndrome (HES)

Nucala is indicated as an add-on treatment for adult patients with inadequately controlled hypereosinophilic syndrome without an identifiable non-haematologic secondary cause (see section 5.1).

4.2. Posology and method of administration

It is recommended that Nucala is prescribed by physicians experienced in the diagnosis and treatment of severe refractory eosinophilic asthma, CRSwNP, COPD, EGPA or HES.

Posology

Severe eosinophilic asthma

Adults and adolescents aged 12 years and older

The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks.

Children aged 6 to 11 years old

The recommended dose of mepolizumab is 40 mg administered subcutaneously once every 4 weeks.

Nucala is intended for long-term treatment. The need for continued therapy is to be considered at least on an annual basis as determined by physician assessment of the patient's disease severity and level of control of exacerbations.

CRSwNP

Adults

The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks.

Nucala is intended for long-term treatment. Consideration can be given to alternative treatments in patients who have shown no response after 24 weeks of treatment for CRSwNP. Some patients with initial partial response may subsequently improve with continued treatment beyond 24 weeks.

COPD

Adults

The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks.

EGPA

Adults and adolescents aged 12 years and older

The recommended dose of mepolizumab is 300 mg administered subcutaneously once every 4 weeks.

The posology of mepolizumab in children and adolescents aged 6 to 17 years old with EGPA was supported by modelling and simulation data (see section 5.2).

Children aged 6 to 11 years old weighing ≥ 40 kg

The recommended dose of mepolizumab is 200 mg administered subcutaneously once every 4 weeks.

Children aged 6 to 11 years old weighing < 40 kg

The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks.

Nucala is intended for long-term treatment. The need for continued therapy is to be reviewed at least on an annual basis as determined by physician assessment of the patient's disease severity and improvement of symptom control.

Patients who develop life-threatening manifestations of EGPA must also be evaluated for the need for continued therapy, as Nucala has not been studied in this population.

HES

Adults

The recommended dose of mepolizumab is 300 mg administered subcutaneously once every 4 weeks.

Nucala is intended for long-term treatment. The need for continued therapy is to be reviewed at least on an annual basis as determined by physician assessment of the patient's disease severity and level of symptom control.

Patients who develop life-threatening manifestations of HES must also be evaluated for the need for continued therapy, as Nucala has not been studied in this population.

Special populations

Elderly patients

No dose adjustment is required for elderly patients aged ≥65 years old (see section 5.2).

Renal and hepatic impairment

No dose adjustment is required in patients with renal or hepatic impairment (see section 5.2).

Paediatric population

Severe eosinophilic asthma

Children less than 6 years old

The safety and efficacy of mepolizumab in children less than 6 years old have not yet been established.

No data are available.

Children aged 6 to 17 years old

The posology of mepolizumab in children and adolescents aged 6 to 17 years old with severe refractory eosinophilic asthma has been determined by limited efficacy, pharmacokinetic and pharmacodynamic studies and supported by modelling and simulation data (see sections 5.1 and 5.2).

CRSwNP in children less than 18 years old

The safety and efficacy in children with CRSwNP below the age of 18 years have not been established. No data are available.

COPD in children less than 18 years old

There is no relevant use of mepolizumab in the paediatric population (under 18 years of age) for the indication of COPD.

EGPA in children less than 6 years old

The safety and efficacy of mepolizumab has not been established in children below the age of 6 years old.

No data are available.

HES in children aged less than 18 years old

The safety and efficacy of mepolizumab in children and adolescents aged less than 18 years old have not yet been established.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Nucala is for subcutaneous injection only and must be administered by a healthcare professional. It may be injected into the upper arm, thigh, or abdomen.

For doses which require more than one injection, it is recommended that each injection is administered at least 5 cm apart.

The powder should be reconstituted prior to administration and the reconstituted solution should be used immediately. For instructions on the reconstitution of the medicinal product before administration, see section 6.6.

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

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Asthma or COPD exacerbations

Mepolizumab must not be used to treat acute asthma or COPD exacerbations.

Asthma-related or COPD-related adverse symptoms or exacerbations may occur during treatment. Patients must be instructed to seek medical advice if their asthma or COPD remains uncontrolled or worsens after initiation of treatment.

Corticosteroids

Abrupt discontinuation of corticosteroids after initiation of mepolizumab therapy is not recommended. Reduction in corticosteroid doses, if required, must be gradual and performed under the supervision of a physician.

Hypersensitivity and administration-related reactions

Acute and delayed systemic reactions, including hypersensitivity reactions (e.g. anaphylaxis, urticaria, angioedema, rash, bronchospasm, hypotension), have occurred following administration of mepolizumab. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., typically within several days). These reactions may occur for the first time after a long duration of treatment (see section 4.8). In the event of a hypersensitivity reaction, appropriate treatment as clinically indicated must be initiated.

Parasitic infections

Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre-existing helminth infections should be treated before starting therapy. If patients become infected whilst receiving treatment with mepolizumab and do not respond to anti-helminth treatment, temporary discontinuation of therapy should be considered.

Organ threatening or life-threatening EGPA

Nucala has not been studied in patients with organ threatening or life-threatening manifestations of EGPA (see section 4.2).

Life-threatening HES

Nucala has not been studied in patients with life-threatening manifestations of HES (see section 4.2).

Excipients

This medicinal product contains polysorbate 80 (see section 2), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of mepolizumab. Increased levels of pro-inflammatory cytokines (e.g. IL-6), via interaction with their cognate receptors on hepatocytes, have been shown to suppress the formation of CYP450 enzymes and drug transporters, however, elevation of systemic pro-inflammatory markers in severe refractory eosinophilic asthma is minimal and there is no evidence of IL-5 receptor alpha expression on hepatocytes. The potential for interactions with mepolizumab is therefore considered low.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of mepolizumab in pregnant women.

Mepolizumab crosses the placental barrier in monkeys. Animal studies do not indicate reproductive toxicity (see section 5.3). The potential for harm to a human fetus is unknown.

As a precautionary measure, it is preferable to avoid the use of Nucala during pregnancy.

Administration of Nucala to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

Breast-feeding

There are no data regarding the excretion of mepolizumab in human milk. However, mepolizumab was excreted into the milk of cynomolgus monkeys at concentrations of less than 0.5% of those detected in plasma.

A decision must be made whether to discontinue breast-feeding or to discontinue Nucala therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data in humans. Animal studies showed no adverse effects of anti-IL5 treatment on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Nucala has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Severe eosinophilic asthma

In placebo-controlled studies in adult and adolescent patients with severe refractory eosinophilic asthma, the most commonly reported adverse reactions during treatment were headache (20%), injection site reactions (8%) and back pain (6%).

CRSwNP

In a placebo-controlled study in patients with CRSwNP, the most commonly reported adverse reactions during treatment were headache (18%) and back pain (7%).

COPD

In three placebo-controlled studies in patients with COPD, the most commonly reported adverse reactions during treatment were headache (10%), back pain (7%) and arthralgia (5%).

EGPA

In a placebo-controlled study in patients with EGPA, the most commonly reported adverse reactions during treatment were headache (32%), injection site reactions (15%) and back pain (13%). Systemic allergic/hypersensitivity reactions were reported by 4% of EGPA patients.

HES

In a placebo-controlled study in patients with HES, the most commonly reported adverse reactions during treatment were headache (13%), urinary tract infection (9%), injection site reactions and pyrexia (7% each).

Tabulated list of adverse reactions

The table below presents the adverse reactions from placebo-controlled severe eosinophilic asthma studies from patients receiving mepolizumab 100 mg subcutaneously (SC) (n=263), from a randomised, double-blind placebo-controlled 52-week study in patients with CRSwNP receiving mepolizumab 100 mg SC (n=206), in three double-blind placebo-controlled 52- to 104-week studies in patients with COPD receiving mepolizumab 100 mg SC (n=1043), in patients with EGPA receiving mepolizumab 300 mg SC (n=68), in a double-blind placebo-controlled 32-week study in patients with HES receiving mepolizumab 300 mg SC (n= 54), and from spontaneous post-marketing reports. Safety data is also available from open-label extension studies in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years).The safety profile of mepolizumab in HES patients (n=102) enrolled in a 20-week open label extension study was similar to the safety profile of patients in the pivotal placebo-controlled study.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Adverse reactions

Frequency

Infections and infestations

Lower respiratory tract infection

Urinary tract infection

Pharyngitis

Herpes zoster**

Common

Immune system disorders

Hypersensitivity reactions (systemic allergic)*

Anaphylaxis**

Common

Rare

Nervous system disorders

Headache

Very common

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Common

Gastrointestinal disorders

Abdominal pain upper

Common

Skin and subcutaneous tissue disorders

Eczema

Common

Musculoskeletal and connective tissue disorders

Back pain

Arthralgia**

Common

General disorders and administration site conditions

Administration-related reactions (systemic non allergic)***

Local injection site reactions

Pyrexia

Common

* Systemic reactions including hypersensitivity have been reported at an overall incidence comparable to that of placebo in the severe eosinophilic asthma studies. For examples of the associated manifestations reported and a description of the time to onset, see section 4.4.

**From spontaneous post marketing reporting. Herpes zoster was reported uncommonly in severe asthma studies.

*** The most common manifestations associated with reports of systemic non-allergic administration-related reactions from patients in the severe eosinophilic asthma and COPD studies were rash, flushing , myalgia and fatigue; these manifestations were reported infrequently and in <1% of patients receiving mepolizumab 100 mg subcutaneously.

Description of selected adverse reactions

Systemic reactions, including hypersensitivity reactions, in CRSwNP

In the 52-week placebo-controlled study, systemic allergic (type I hypersensitivity) reactions were reported in 2 patients (<1%) in the group receiving mepolizumab 100 mg and in no patients in the placebo group. Other systemic reactions were reported by no patients in the group receiving mepolizumab 100 mg and in 1 patient (<1%) in the placebo group.

Systemic reactions, including hypersensitivity reactions, in COPD

In the placebo-controlled study of 52 to 104 weeks duration, systemic allergic (type I hypersensitivity) reactions were reported in 1 patient (<1%) in the group receiving mepolizumab 100 mg and in no patients in the placebo group. Other systemic reactions were reported by 4 patients (<1%) in the group receiving mepolizumab 100 mg and in 4 patients (<1%) in the placebo group.

In the two 52-week placebo-controlled studies, systemic allergic/hypersensitivity reactions were reported in 4 patients (<1%) in the groups receiving mepolizumab 100 mg and in 3 patients (<1%) in the placebo groups. Systemic non-allergic reactions were reported by 7 patients (1%) in the groups receiving mepolizumab 100 mg and in 10 patients (2%) in the placebo groups.

Systemic reactions, including hypersensitivity reactions, in EGPA

In the 52-week placebo-controlled study the percentage of patients who experienced systemic (allergic and non‑allergic) reactions was 6% in the group receiving 300 mg of mepolizumab and 1% in the placebo group. Systemic allergic/hypersensitivity reactions were reported by 4% of patients in the group receiving 300 mg of mepolizumab and 1% of patients in the placebo group. Systemic non-allergic reactions (angioedema) were reported by 1 (1%) patient in the group receiving 300 mg of mepolizumab and no patients in the placebo group.

Systemic reactions, including hypersensitivity reactions, in HES

In the 32-week placebo-controlled study, 1 patient (2%) reported a systemic (other) reaction in the group receiving 300 mg of mepolizumab (multifocal skin reaction) and no patients in the placebo group.

Local injection site reactions

Severe eosinophilic asthma

In placebo-controlled studies the incidence of local injection site reactions with mepolizumab 100 mg subcutaneous and placebo was 8% and 3%, respectively. These events were all non-serious, mild to moderate in intensity and the majority resolved within a few days. Local injection site reactions occurred mainly at the start of treatment and within the first 3 injections with fewer reports on subsequent injections. The most common manifestations reported with these events included pain, erythema, swelling, itching, and burning sensation.

CRSwNP

In the placebo-controlled study, local injection site reactions (e.g., erythema, pruritus) occurred in 2% of patients receiving mepolizumab 100 mg compared with <1% in patients receiving placebo.

COPD

In the placebo-controlled studies, local injection site reactions (e.g., erythema, haematoma, swelling, pruritus) occurred in 2% of patients receiving mepolizumab 100 mg compared with 2% in patients receiving placebo.

EGPA

In the placebo-controlled study, local injection site reactions (e.g., pain, erythema, swelling) occurred at a rate of 15% in patients receiving mepolizumab 300 mg compared with 13% in patients receiving placebo.

HES

In the placebo-controlled study, local injection site reactions (e.g., burning, itching) occurred at a rate of 7% in patients receiving mepolizumab 300 mg compared with 4% in patients receiving placebo.

Paediatric population

Severe eosinophilic asthma

Thirty-seven adolescents (aged 12-17) were enrolled in four placebo-controlled studies (25 mepolizumab treated intravenously or subcutaneously) of 24 to 52 weeks duration. Thirty -six paediatric patients (aged 6-11) received mepolizumab subcutaneously in an open-label study for 12 weeks. After a treatment interruption of 8 weeks, 30 of these patients, received mepolizumab for a further 52 weeks. The safety profile was similar to that seen in adults. No additional adverse reactions were identified.

In addition, the long-term safety of mepolizumab was assessed in 9 adolescent patients (aged 12-17) and 15 paediatric patients (aged 6-11) who were enrolled in an open-label extension study (201956). In this study, patients received mepolizumab subcutaneously and were followed for up to 6.4 years. The safety profile was similar to that seen in pivotal asthma studies. No additional adverse reactions were identified.

HES

Four adolescents aged 12 to 17 years were enrolled in the placebo-controlled study 200622, one adolescent received 300 mg of mepolizumab, and 3 adolescents received placebo for 32 weeks. All 4 adolescents continued into a 20-week open-label extension study 205203 (see Section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Single doses of up to 1,500 mg were administered intravenously in a clinical trial to patients with eosinophilic disease without evidence of dose-related toxicities.

There is no specific treatment for an overdose with mepolizumab. If overdose occurs, it is recommended that the patient be treated supportively with appropriate monitoring as necessary.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.