Nucala 100 mg powder for solution for injection

Each vial contains 100 mg mepolizumab. After reconstitution, each ml of solution contains 100 mg mepolizumab.

Mepolizumab is a humanised monoclonal antibody produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder for solution for injection.

Lyophilised white powder.

Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adult patients (see section 5.1).

Nucala should be prescribed by physicians experienced in the diagnosis and treatment of severe refractory eosinophilic asthma.

Posology

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 should 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.

Special populations

Paediatric population

The safety and efficacy of Nucala in children and adolescents under 18 years of age has not yet been established. Very limited data are currently available in children 12 to 18 years old (see sections 4.8, 5.1 and 5.2) therefore no recommendations can be made.

Elderly patients

No dose adjustment is required for elderly patients (see section 5.2).

Renal and hepatic impairment

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

Method of administration

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

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.

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

Nucala should not be used to treat acute asthma exacerbations.

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

Abrupt discontinuation of corticosteroids after initiation of Nucala therapy is not recommended. Reduction in corticosteroid doses, if required, should 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. urticaria, angioedema, rash, bronchospasm, hypotension), have occurred following administration of Nucala. 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).

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 Nucala and do not respond to anti-helminth treatment, temporary discontinuation of therapy should be considered.

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 asthma is minimal and there is no evidence of IL-5 receptor alpha expression on hepatocytes. The potential for drug-drug 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 cynomolgous 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.

Summary of the safety profile

In clinical studies in subjects with severe refractory eosinophilic asthma, the most commonly reported adverse reactions during treatment were headache, injection site reactions and back pain.

Tabulated list of adverse reactions

A total of 915 subjects with severe refractory eosinophilic asthma have received either a subcutaneous or an intravenous dose of mepolizumab during clinical studies of 24 to 52 weeks duration. The table below presents the adverse reactions from the two placebo controlled studies in patients receiving mepolizumab 100 mg subcutaneously (n=263).

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.

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

** The most common manifestations associated with reports of systemic non-allergic administration-related reactions were rash, flushing and myalgia; these manifestations were reported infrequently and in <1% of subjects receiving mepolizumab 100 mg subcutaneously.

Description of selected adverse reaction

Local injection site reactions

In 2 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.

Paediatric population

The clinical trial data currently available in paediatric patients is too limited to characterise the safety profile of mepolizumab in this population (see section 5.1). However, the frequency, type and severity of adverse reactions in the paediatric population are expected to be similar to those seen in adults.

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:

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie

United Kingdom

The Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

There is no clinical experience with overdose of mepolizumab.

Single doses of up to 1500 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, the patient should 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.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: not yet assigned .

Mechanism of action

Mepolizumab is a humanised monoclonal antibody (IgG1, kappa), which targets human interleukin-5 (IL-5) with high affinity and specificity. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. Mepolizumab inhibits the bioactivity of IL-5 with nanomolar potency by blocking the binding of IL-5 to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface, thereby inhibiting IL-5 signalling and reducing the production and survival of eosinophils.

Pharmacodynamic effects

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 reduction was observed within 4 weeks of treatment.

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide therapeutics, patients may develop antibodies to mepolizumab following treatment. In the placebo-controlled trials, 15/260 (6%) of subjects treated with 100 mg dose subcutaneously developed anti-mepolizumab antibodies after having received at least one dose of mepolizumab. Neutralising antibodies were detected in one subject. Anti-mepolizumab antibodies did not discernibly impact the pharmacokinetics and pharmacodynamics of mepolizumab in the majority of patients and there was no evidence of a correlation between antibody titres and change in blood eosinophil level.

Clinical efficacy

The efficacy of mepolizumab in the treatment of a targeted group of patients with severe refractory eosinophilic asthma was eva luated in 3 randomised, double-blind, parallel-group clinical studies of between 24-52 weeks duration, in patients aged 12 years and older. These patients either remained uncontrolled (at least two severe exacerbations in the previous 12 months) on their current standard of care, including at least high doses of inhaled corticosteroids (ICS) plus an additional maintenance treatment(s), or were dependent on systemic corticosteroids. Additional maintenance treatments included long-acting beta₂ -adrenergic agonists (LABA), leukotriene modifiers, long-acting muscarinic antagonists (LAMA), theophylline, and oral corticosteroids (OCS).

The two exacerbations studies MEA112997 and MEA115588 enrolled a total of 1192 patients, 60% females, with a mean age of 49 years (range 12– 82). The proportion of patients on maintenance OCS was 31% and 24%, respectively. Patients were required to have a history of two or more severe asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV₁<80% in adults and <90% in adolescents).The mean number of exacerbations in the previous year was 3.6 and the mean predicted pre-bronchodilator FEV₁ was 60%. Patients continued to receive their existing asthma medicine during the studies.

For the oral corticosteroid-sparing study MEA115575, a total of 135 patients were enrolled (55% were female; mean age of 50 years) who were being treated daily with OCS (5-35 mg per day), and high-dose ICS plus an additional maintenance medicine.

Dose-ranging efficacy MEA112997 (DREAM) study

In MEA112997, a randomised, double-blind, placebo-controlled, parallel-group, multi-centre study of 52 weeks duration in 616 patients with severe refractory eosinophilic asthma, mepolizumab significantly reduced clinically significant asthma exacerbations (defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalisation and/or emergency department visits) when administered in doses of 75 mg, 250 mg or 750 mg intravenously compared to placebo (see Table 1).

Table 1: Frequency of clinically significant exacerbations at week 52 in the intent to treat population

Exacerbation reduction (MEA115588) MENSA study

MEA115588 was a randomised, double-blind, placebo-controlled, parallel-group, multi-centre study which eva luated the efficacy and safety of mepolizumab as add-on therapy in 576 patients with severe refractory eosinophilic asthma defined as peripheral blood eosinophils greater than or equal to 150 cells/μL at initiation of treatment or greater than or equal to 300 cells/μL within the past 12 months.

Patients received mepolizumab 100 mg administered subcutaneously, mepolizumab 75 mg administered intravenously or placebo treatment once every 4 weeks over 32 weeks. The primary endpoint was the frequency of clinically significant exacerbations of asthma and the reductions for both mepolizumab treatment arms compared to placebo were statistically significant (p<0.001). Table 2 provides the results of the primary and secondary endpoints for patients treated with subcutaneous mepolizumab or placebo.

Table 2: Results of primary and secondary endpoints at week 32 in the intent to treat population (MEA115588)

Reduction of exacerbation rate by baseline blood eosinophil count

Table 3 shows the results of a combined analysis of the two exacerbation studies (MEA112997 and MEA115588) by baseline blood eosinophil count. The rate of exacerbations in the placebo arm increased with increasing baseline blood eosinophil count. The reduction rate with mepolizumab was greater in patients with higher blood eosinophil counts.

Table 3: Combined analysis of the rate of clinically significant exacerbations by baseline blood eeosinophil count in patients with severe refractory eosinophilic asthma

Oral corticosteroid reduction study MEA115575 (SIRIUS)

MEA115575 eva luated the effect of mepolizumab 100 mg administered subcutaneously on reducing the requirement for maintenance oral corticosteroids (OCS) while maintaining asthma control in subjects with severe refractory eosinophilic asthma. Patients had a blood eosinophil count of ≥150/μL at baseline or a blood eosinophil count of ≥300/μL in the 12 months prior to screening. Patients were administered mepolizumab or placebo treatment once every 4 weeks over the treatment period. Patients continued to receive their existing asthma medicine during the study with the exception of their OCS dose which was reduced every 4 weeks during the OCS reduction phase (Weeks 4-20), as long as asthma control was maintained.

A total of 135 patients were enrolled: mean age was 50 years, 55% were female, and 48% had been receiving oral steroid therapy for at least 5 years. The baseline mean prednisone equivalent dose was approximately 13 mg per day.

The primary endpoint was the percent reduction in daily OCS dose (weeks 20-24), whilst maintaining asthma control by defined dose reduction categories (see Table 4). Predefined categories included percent reductions ranging from 90-100% reduction, to no decrease in the prednisone dose from the end of the optimisation phase. The comparison between mepolizumab and placebo was statistically significant (p=0.008).

Table 4: Results of the primary and secondary endpoints in MEA115575

Paediatric population

There were 25 adolescents 13 girls and 12 boys, 9 aged 12 -14 years and 16 aged 15-17 years enrolled in study MEA115588. Of the total 25 subjects: 9 received placebo, 9 received mepolizumab 75 mg intravenously, and 7 received 100 mg subcutaneously. The same proportion of subjects (3/9) receiving placebo and mepolizumab intravenously reported clinically significant exacerbations; no exacerbations were reported in those receiving mepolizumab subcutaneously.

Following subcutaneous dosing in patients with asthma, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 mg to 250 mg.

Absorption

Following subcutaneous administration to healthy subjects or patients with asthma, mepolizumab was absorbed slowly with a median time to reach maximum plasma concentration (T_max) 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 humanized 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.

Paediatric population

There are limited pharmacokinetic data available in the paediatric population (59 subjects with eosinophilic esophagitis, 19 subjects with severe asthma). Intravenous mepolizumab pharmacokinetics was eva luated by population pharmacokinetic analysis in a paediatric study conducted in subjects aged 2–17 years old with eosinophilic esophagitis. Paediatric pharmacokinetics was largely predictable from adults, after taking into account bodyweight. Mepolizumab pharmacokinetics in adolescent subjects with severe eosinophilic asthma included in the phase 3 studies were consistent with adults (see section 4.2).

Special populations

Elderly patients (≥65 years old)

There are limited pharmacokinetic data available in elderly patients (≥65 years old) across all clinical studies (N=90). However, in the population pharmacokinetic analysis, there were no indications of an effect of age on the pharmacokinetics of mepolizumab over the age range of 12 to 82 years.

Renal impairment

No formal studies have been conducted to investigate the effect of renal impairment on the pharmacokinetics of mepolizumab. Based on population pharmacokinetic analyses, no dose adjustment is required in patients with creatinine clearance values between 50-80 mL/min. There are limited data available in patients with creatinine clearance values <50 mL/min.

Hepatic impairment

No formal studies have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of mepolizumab. Since mepolizumab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, changes in hepatic function are unlikely to have any effect on the elimination of mepolizumab.

As mepolizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.

Animal toxicology and/or pharmacology

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeated dose toxicity studies in monkeys. Intravenous and subcutaneous administration to monkeys was associated with reductions in peripheral and lung eosinophil counts, with no toxicological findings.

Eosinophils are thought to be associated with immune system responses to some parasitic infections. Studies conducted in mice treated with anti-IL-5 antibodies or genetically deficient in IL-5 or eosinophils have not shown impaired ability to clear parasitic infections. The relevance of these findings for humans is unknown.

Fertility

No impairment of fertility was observed in a fertility and general reproduction toxicity study in mice performed with an analogous antibody that inhibits IL-5 in mice. This study did not include a littering or functional offspring assessment.

Pregnancy

In monkeys, mepolizumab had no effect on pregnancy or on embryonic/fetal and postnatal development (including immune function) of the offspring. Examinations for internal or skeletal malformations were not performed. Data in cynomolgus monkeys demonstrate that mepolizumab crossed the placenta. Concentrations of mepolizumab were about 1.2-2.4 times higher in infants than in mothers for several months post partum and did not affect the immune system of the infants.

Sucrose

Sodium phosphate dibasic heptahydrate

Polysorbate 80

This medicinal product must not be mixed with other medicinal products.

2 years.

After reconstitution

Chemical and physical stability of the reconstituted medicinal product have been demonstrated for 8 hours when stored below 30°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of user.

Store below 25°C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Clear, colourless 10 mL type I glass vial, with bromobutyl rubber stopper and a grey aluminium overseal with a plastic flip-cap containing 100 mg powder for solution for injection.

Pack sizes:

1 vial

Multipack comprising 3 (3 packs of 1) vials

Not all pack-sizes may be marketed.

Nucala does not contain a preservative therefore reconstitution should be carried out under aseptic conditions.

Instructions for reconstitution

1. Reconstitute the contents of the vial with 1.2 mL of sterile water for injection preferably using a 2 to 3 mL syringe and a 21G needle. The stream of sterile water should be directed vertically, onto the centre of the lyophilised cake. Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 10 seconds with circular motion at 15-second intervals until the powder is dissolved.

Note: The reconstituted solution must not be shaken during the procedure as this may lead to product foaming or precipitation. Reconstitution is typically complete within 5 minutes after the sterile water has been added, but it may take additional time.

2. If a mechanical reconstitution device (swirler) is used to reconstitute Nucala, reconstitution can be accomplished by swirling at 450 rpm for no longer than 10 minutes. Alternatively, swirling at 1000 rpm for no longer than 5 minutes is acceptable.

3. Following reconstitution, Nucala should be visually inspected for particulate matter and clarity prior to use. The solution should be clear to opalescent, and colourless to pale yellow or pale brown, free of visible particles. 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 be discarded.

4. The reconstituted solution, if not used immediately must be :

• Protected from sunlight

• Stored below 30°C, not frozen

• Discarded if not used within 8 hours of reconstitution

Instructions for administration

1. For subcutaneous administration a 1 mL polypropylene syringe fitted with a disposable needle 21G to 27G x 0.5 inch (13 mm) should preferably be used.

2. Just prior to administration, remove 1 mL of reconstituted Nucala. 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 mepolizumab) subcutaneously into the upper arm, thigh, or abdomen.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

GlaxoSmithKline Trading Services Limited

Currabinny

Carrigaline

County Cork

Ireland.

EU/1/15/1043/001

EU/1/15/1043/002

Date of first authorisation: 02 December 2015

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.