mepolizumab: prescribing information – dosing, contraindications, interactions, side effects

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 disease control.

Chronic obstructive pulmonary disease (COPD)

Nucala is indicated in adults as an add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils 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).

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 in adults as an add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils 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).

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 over

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.

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.

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 aged 6 to 11 years old

Nucala 100 mg powder for solution for injection and 40 mg solution for injection in pre-filled syringe are appropriate for administration to this population.

Nucala 100 mg solution for injection in pre-filled pen and 100 mg solution for injection in pre-filled syringe are not indicated for administration to this population.

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.

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 100 mg solution for injection in pre-filled pen or pre-filled syringe

The pre-filled pen or pre-filled syringe must be used for subcutaneous injection only.

Nucala may be self-administered by the patient or administered by a caregiver if their healthcare professional determines that it is appropriate, and the patient or caregiver are trained in injection techniques.

For children aged 6 to 11 years old, administration must be carried out by a healthcare professional or a trained caregiver.

For self-administration the recommended injection sites are the abdomen or thigh. A caregiver can also inject Nucala into the upper arm.
For doses which require more than one injection, it is recommended that each injection is administered at least 5 cm apart.

Comprehensive instructions for subcutaneous administration of Nucala in a pre-filled pen or pre-filled syringe are provided in the instructions for use in the package leaflet.

Nucala 40 mg solution for injection in pre-filled syringe

The pre-filled syringe must be used for subcutaneous injection only.

Nucala must be administered by a healthcare professional or a caregiver. It may be administered by a caregiver if a healthcare professional determines that it is appropriate, and the caregiver is trained in injection techniques.

The recommended injection sites are the upper arm, abdomen or thigh.

Comprehensive instructions for subcutaneous administration of Nucala in a pre-filled syringe are provided in the instructions for use in the package leaflet.

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.

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.

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.

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

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 and COPD 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 52- to 104-week placebo-controlled study, 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 occurred in 2% of patients receiving mepolizumab 100 mg compared with 2% in patients receiving placebo. The most common manifestations reported were pain, swelling, itching and erythema.

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 for an average of 21.5 months. 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 the national reporting system listed in Appendix V.

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)***
Common

System Organ Class
Adverse reactions
Frequency
Local injection site reactions
Pyrexia
* Systemic reactions including hypersensitivity have been reported at an overall incidence comparable to that of placebo in the severe eosinophilic asthma and COPD 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 52- to 104-week placebo-controlled study, 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 occurred in 2% of patients receiving mepolizumab 100 mg compared with 2% in patients receiving placebo. The most common manifestations reported were pain, swelling, itching and erythema.

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 for an average of 21.5 months. 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 the national reporting system listed in Appendix V.

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.

COPD patients with low blood eosinophil counts

Data do not support the use of Nucala in patients with COPD with blood eosinophil count <150 cells/mcL and no evidence of blood eosinophil count ≥300 cells/mcL in the previous 12 months.

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”.

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.

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).

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX09.

Mechanism of action

Mepolizumab is an IL-5 antagonist (IgG1 kappa) that binds to IL-5, inhibiting its bioactivity with nanomolar potency by blocking its binding to the IL-5R alpha complex on the cell surface. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. In patients where their disease is driven by type 2 inflammation, IL-5 is an important component of the processes driving the pathogenesis of asthma, CRSwNP, COPD, EGPA and HES.
Additional structural and inflammatory cell types also express the IL-5R alpha e.g., epithelial cells, mast cells, plasma cells, basophils, ILC-2 cells, T cells, smooth muscle cells, neutrophils and fibroblasts. In severe asthma and CRSwNP, inhibition of IL-5 has been associated with an improvement in aspects of airway remodelling. However, the mechanism of action in these cells and across the different diseases has not been definitively established.

Pharmacodynamic effects

Severe eosinophilic asthma

In patients with severe refractory eosinophilic asthma (adults/adolescents), following a dose of 100 mg administered subcutaneously every 4 weeks for 32 weeks, blood eosinophils were reduced from a geometric mean count at baseline of 290 to 40 cells/μL at week 32 (n=182), a reduction of 84% compared to placebo. This magnitude of blood eosinophils reduction was maintained in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies.
In children aged 6 to 11 years old with severe refractory eosinophilic asthma administered mepolizumab subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 306 (n=16) to 48 (n=15) following 40 mg (for a weight < 40kg) and 331 to 44 cells/µL (n=10) following 100 mg (for a weight ≥ 40 kg), a reduction from baseline of 85% and 87%, respectively.
In adults, adolescents and children, this magnitude of reduction was observed within 4 weeks of treatment.

CRSwNP

In patients with CRSwNP, following a 100 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 390 (n=206) to 60 cells/µL (n=126), which corresponds to a geometric mean reduction of 83% compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period of 52 weeks.

COPD

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX09.

Mechanism of action

Mepolizumab is an IL-5 antagonist (IgG1 kappa) that binds to IL-5, inhibiting its bioactivity with nanomolar potency by blocking its binding to the IL-5R alpha complex on the cell surface. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. In patients where their disease is driven by type 2 inflammation, IL-5 is an important component of the processes driving the pathogenesis of asthma, CRSwNP, COPD, EGPA and HES.
Additional structural and inflammatory cell types also express the IL-5R alpha e.g., epithelial cells, mast cells, plasma cells, basophils, ILC-2 cells, T cells, smooth muscle cells, neutrophils and fibroblasts. In severe asthma and CRSwNP, inhibition of IL-5 has been associated with an improvement in aspects of airway remodelling. However, the mechanism of action in these cells and across the different diseases has not been definitively established.

Pharmacodynamic effects

Severe eosinophilic asthma

In patients with severe refractory eosinophilic asthma (adults/adolescents), following a dose of 100 mg administered subcutaneously every 4 weeks for 32 weeks, blood eosinophils were reduced from a geometric mean count at baseline of 290 to 40 cells/µL at week 32 (n=182), a reduction of 84% compared to placebo.
This magnitude of blood eosinophils reduction was maintained in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies.
In children aged 6 to 11 years old with severe refractory eosinophilic asthma administered mepolizumab subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 306 (n=16) to 48 (n=15) following 40 mg (for a

weight < 40kg) and 331 to 44 cells/µL (n=10) following 100 mg (for a weight ≥ 40 kg), a reduction from baseline of 85% and 87%, respectively.
In adults, adolescents and children, this magnitude of reduction was observed within 4 weeks of treatment.

CRSwNP

In patients with CRSwNP, following a 100 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 390 (n=206) to 60 cells/µL (n=126), which corresponds to a geometric mean reduction of 83% compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period of 52 weeks.

COPD

Following subcutaneous dosing in patients with asthma and CRSwNP, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 mg to 250 mg.
Subcutaneous administration of mepolizumab 300 mg had approximately three times the systemic exposure of mepolizumab 100 mg. Mepolizumab pharmacokinetics were consistent in patients with asthma, CRSwNP, COPD, EGPA or HES. Following administration of a single 100 mg subcutaneous dose in healthy subjects, mepolizumab systemic exposure was comparable between formulations.

Absorption

Following subcutaneous administration to healthy subjects or patients with asthma, mepolizumab was absorbed slowly with a median time to reach maximum plasma concentration (Tmax) ranging from 4 to 8 days.

Following a single subcutaneous administration in the abdomen, thigh or arm of healthy subjects, mepolizumab absolute bioavailability was 64%, 71% and 75%, respectively. In patients with asthma the absolute bioavailability of mepolizumab administered subcutaneously in the arm ranged from 74- 80%. Following repeat subcutaneous administration every 4 weeks, there is approximately a two-fold accumulation at steady state.

Distribution

Following a single intravenous administration to patients with asthma, mepolizumab distributes into a mean volume of distribution of 55 to 85 mL/kg.

Biotransformation

Mepolizumab is a humanised IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.

Elimination

Following a single intravenous administration to patients with asthma, the mean systemic clearance (CL) ranged from 1.9 to 3.3 mL/day/kg, with a mean terminal half-life of approximately 20 days.
Following subcutaneous administration of mepolizumab the mean terminal half-life (t1/2) ranged from 16 to 22 days. In the population pharmacokinetic analysis estimated mepolizumab systemic clearance was 3.1 mL/day/kg.

Special populations