Nucala

Mepolizumab.

Each vial contains 100 mg mepolizumab. After reconstitution, each ml of solution contains 100 mg mepolizumab.
Each 1 ml pre-filled pen contains 100 mg of mepolizumab.
Mepolizumab is a humanised monoclonal antibody produced in Chinese hamster ovary cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Vial: Sucrose, Sodium phosphate dibasic heptahydrate, Polysorbate 80.
Pre-filled pen: Sucrose, Sodium phosphate dibasic heptahydrate, Citric acid monohydrate, Polysorbate 80, EDTA disodium dihydrate, Water for injections.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases. ATC code: R03DX09.
Pharmacology: Pharmacodynamics: 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: 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 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.
EGPA: In patients with EGPA, following a 300 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline of 177 (n=68) to 38 cells/μL (n=64) at week 52. There was a geometric mean reduction of 83% compared to placebo and this magnitude of reduction was observed within 4 weeks of treatment.
HES: In patients with HES (adults/adolescents), following a 300 mg dose of mepolizumab administered subcutaneously every 4 weeks for 32 weeks, blood eosinophil reduction was observed within 2 weeks of treatment. At week 32, blood eosinophils were reduced from a geometric mean count at baseline of 1460 (n=54) to 70 cells/μL (n=48) and a geometric mean reduction of 92% compared to placebo was observed. This magnitude of reduction was maintained for a further 20 weeks in patients that continued mepolizumab treatment in the open-label extension study.
Immunogenicity: Severe eosinophilic asthma, CRSwNP, EGPA and HES: 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 adults and adolescents with severe refractory eosinophilic asthma treated with 100 mg dose, 6/196 (3%) of adults with CRSwNP treated with 100 mg dose, 1/68 (<2%) of adults with EGPA treated with 300 mg dose and 1/53 (2%) of adults and adolescents with HES treated with 300 mg dose of mepolizumab subcutaneously had detectable anti-mepolizumab antibodies after having received at least one dose of mepolizumab.
The immunogenicity profile of mepolizumab in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) or in HES patients (n=102) treated for 20 weeks in open-label extension studies was similar to that observed in the placebo-controlled studies.
Neutralising antibodies were detected in one adult patient with severe refractory eosinophilic asthma and in no patients with CRSwNP, EGPA or HES. 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: Severe eosinophilic asthma: The efficacy of mepolizumab in the treatment of a targeted group of patients with severe refractory eosinophilic asthma was evaluated 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).

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Exacerbation reduction MEA115588 (MENSA) study: MEA115588 was a randomised, double-blind, placebo-controlled, parallel-group, multi-centre study which evaluated 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. (See Table 2.)

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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. (See Table 3.)

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Oral corticosteroid reduction study MEA115575 (SIRIUS): MEA115575 evaluated 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). (See Table 4.)

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Open-label extension studies in severe refractory eosinophilic asthma MEA115666 (COLUMBA), MEA115661 (COSMOS) and 201312 (COSMEX): The long-term efficacy profile of mepolizumab 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 MEA115666, MEA115661 and 201312 was generally consistent with the 3 placebo-controlled studies.
Chronic Rhinosinusitis with Nasal Polyps (CRSwNP): Study 205687 (SYNAPSE) was a 52-week, randomised, double-blind, placebo-controlled study which evaluated 407 patients aged 18 years and older with CRSwNP.
Patients enrolled in the study were required to have a nasal obstruction VAS (Visual Analogue Scale) symptom score of >5 out of a maximum score of 10, an overall VAS symptom score >7 out of a maximum score of 10 and an endoscopic bilateral NP score of ≥5 out of a maximum score of 8 (with a minimum score of 2 in each nasal cavity). Patients must also have had a history of at least one prior surgery for nasal polyps in the previous 10 years.
Key baseline characteristics included total endoscopic NP score mean (SD) 5.5 (1.29), nasal obstruction VAS score mean (SD) 9.0 (0.83), overall VAS symptom score mean (SD) 9.1 (0.74), loss of smell VAS score mean (SD) 9.7 (0.72) and Sino-Nasal Outcome Test (SNOT-22) mean (SD) 64.1 (18.32). The geometric mean eosinophil count was 390 cells/mcL (95% CI: 360, 420). In addition, 27% of patients had aspirin-exacerbated respiratory disease (AERD) and 48% of patients had at least 1 course of OCS for CRSwNP in the past 12 months.
Patients received a 100 mg dose of mepolizumab or placebo, administered subcutaneously once every 4 weeks in addition to background intranasal corticosteroid therapy.
The co-primary endpoints were change from baseline in total endoscopic NP score at week 52 and change from baseline in mean nasal obstruction VAS score during weeks 49-52. The key secondary endpoint was the time to first NP surgery up to Week 52 (surgery was defined as any procedure involving instruments resulting in incision and removal of tissue [e.g. polypectomy] in the nasal cavity). Patients who received mepolizumab had significantly greater improvements (decreases) in total endoscopic NP score at Week 52 and in nasal obstruction VAS score during weeks 49-52 compared to placebo, and all secondary endpoints were statistically significant in favour of mepolizumab (see Table 5 and Figure 1).

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Time to First NP surgery: Across the 52-week treatment period, patients in the mepolizumab group had a lower probability of undergoing NP surgery than patients in the placebo group. The risk of surgery over the treatment period was significantly lower by 57% for patients treated with mepolizumab compared with placebo (Hazard Ratio: 0.43; 95% CI 0.25, 0.76; p=0.003).

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A post-hoc analysis of the proportion of patients with surgery showed a 61% reduction in the odds of surgery versus placebo (OR: 0.39, 95% CI: 0.21, 0.72; p=0.003).
CRSwNP patients with co-morbid asthma: In 289 (71%) patients with co-morbid asthma, pre-specified analyses showed improvements in the co-primary endpoints consistent with those seen in the overall population in the patients who received mepolizumab 100 mg compared with placebo. Additionally in these patients, there was a greater improvement from baseline at Week 52 in asthma control as measured by the Asthma Control Questionnaire (ACQ-5) for mepolizumab 100 mg compared with placebo (median change [Q1, Q3] of -0.80 [-2.20, 0.00] and 0.00 [-1.10, 0.20], respectively).
Eosinophilic Granulomatosis with Polyangiitis (EGPA): MEA115921 was a randomised, double-blind, placebo-controlled, 52-week study which evaluated 136 adult patients with EGPA, who had a history of relapsing or refractory disease, and who were on stable oral corticosteroid therapy (OCS; ≥7.5 to ≤50 mg/day prednisolone/prednisone), with or without stable immunosuppressant therapy (excluding cyclophosphamide). Other background standard of care therapy was allowed during the study. Fifty-three percent (n=72) were also on concomitant stable immunosuppressant therapy. Patients with organ-threatening or life-threatening EGPA were excluded from study MEA115921.
Patients either received a 300 mg dose of mepolizumab or placebo administered subcutaneously once every 4 weeks in addition to their background prednisolone/prednisone with or without immunosuppressive therapy. The OCS dose was tapered at the discretion of the investigator.
Remission: The co-primary endpoints were the total accrued duration of remission, defined as a Birmingham Vasculitis Activity Score (BVAS)=0 plus prednisolone/prednisone dose ≤4 mg/day, and the proportion of patients in remission at both 36 and 48 weeks of treatment. BVAS=0 represents no active vasculitis.
Compared with placebo, patients receiving mepolizumab 300 mg achieved a significantly greater accrued time in remission. Additionally, compared to placebo, a significantly higher proportion of patients receiving mepolizumab 300 mg achieved remission at both Week 36 and Week 48 (Table 6).
For both co-primary endpoints, compared with placebo, the beneficial effect observed following mepolizumab 300 mg treatment was present irrespective of if patients were receiving immunosuppressant therapy in addition to background corticosteroids.
Using the secondary endpoint remission definition of BVAS=0 plus prednisolone/prednisone ≤7.5 mg/day, patients receiving mepolizumab 300 mg also achieved significantly greater accrued time in remission (p<0.001), and a higher proportion of patients were in remission at both Week 36 and Week 48 (p<0.001), compared to placebo. (See Table 6.)

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Relapse: Compared with placebo, the time to first relapse was significantly longer for patients receiving mepolizumab 300 mg (p<0.001). Additionally, patients receiving mepolizumab had a 50% reduction in annualised relapse rate compared with placebo: 1.14 vs 2.27, respectively.
Oral corticosteroid reduction: Patients treated with mepolizumab had a significantly lower average daily OCS during Weeks 48-52 compared with patients who received placebo. During Weeks 48 to 52, 59% and 44% of patients treated with mepolizumab achieved an average daily OCS dose of ≤7.5 mg and ≤4 mg, respectively, compared with 33% and 7% in the placebo group. 18% of patients in the mepolizumab group were able to taper off OCS completely compared with 3% in the placebo group.
Asthma Control Questionnaire - 6 (ACQ-6): Patients treated with mepolizumab had significant improvements in mean ACQ-6 score during Weeks 49-52 compared with patients who received placebo.
Hypereosinophilic syndrome (HES): Study 200622 was a randomised, double-blind, placebo-controlled, 32-week study which evaluated 108 patients ≥12 years old with HES. Patients received 300 mg of mepolizumab, or placebo administered subcutaneously once every 4 weeks while continuing their HES therapy. In study 200622, HES therapy included but was not limited to OCS, immunosuppressive, cytotoxic therapy or other symptomatic therapies associated with HES such as omeprazole.
Patients entering the study had experienced at least two HES flares within the past 12 months and had a blood eosinophil count ≥1000 cells/μL during screening. Patients who were FIP1L1-PDGFRα kinase-positive were excluded from the study.
The primary endpoint of study 200622 was the proportion of patients who experienced a HES flare during the 32-week treatment period. A HES flare was defined as worsening of clinical signs and symptoms of HES resulting in the need to increase OCS or increase/add cytotoxic or immunosuppressive HES therapy or receiving blinded active OCS due to increased blood eosinophils (on ≥2 occasions).
The primary analysis compared patients who experienced a HES flare or withdrew from the study in the mepolizumab and placebo treatment groups. Over the 32-week treatment period, 50% fewer patients experienced a HES flare or withdrew from the study when treated with 300 mg mepolizumab compared with placebo; 28% versus 56%, respectively (OR 0.28, 95% CI: 0.12, 0.64) (see Table 7).
Secondary endpoints were time to first HES flare, proportion of patients who experienced a HES flare during Week 20 through Week 32, rate of HES flares and change from baseline in fatigue severity. All secondary endpoints were statistically significant and provided support for the primary endpoint (see Figure 2 and Table 8).

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Time to First Flare: Patients who received 300 mg mepolizumab had a significant increase in the time to first HES flare compared with placebo. The risk of first HES flare over the treatment period was 66% lower for patients treated with Nucala compared with placebo (Hazard Ratio: 0.34; 95% CI 0.18, 0.67; p=0.002).

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Open-label extension (OLE): Study 205203 was a 20-week open-label extension of Study 200622. HES therapy was allowed to be adjusted per local standard of care while maintaining mepolizumab 300 mg treatment starting at Week 4. In this study, the effect of treatment with mepolizumab on the reduction of HES flares reported during Study 200622 was sustained for patients who continued mepolizumab treatment in study 205203, in which 94% (47/50) of patients did not experience a flare.
In the 72 patients requiring OCS during Weeks 0 to 4 of the OLE, 28% of patients achieved a mean daily dose OCS dose reduction of ≥50% during Weeks 16 to 20.
Paediatric population: Severe refractory eosinophilic asthma: In MEA115588 and in the double-blind placebo-controlled study 200862, there were 34 adolescents (12 to 17 years old). Of these 34 subjects: 12 received placebo, 9 received mepolizumab 75 mg intravenously, and 13 received 100 mg subcutaneously. In a combined analysis of these studies, a 40% reduction in clinically significant exacerbations was observed in adolescents following mepolizumab treatment compared to placebo (rate ratio 0.60; 95% CI: 0.17, 2.10).
Eosinophilic Granulomatosis with Polyangiitis (EGPA): There are no clinical data available in children and adolescents aged 6 to 17 years old.
HES: Four adolescents (12 to 17 years old) were enrolled in study 200622; one adolescent received mepolizumab 300 mg, and 3 adolescents received placebo for 32 weeks. The one adolescent treated with mepolizumab in the 32-week Study 200622 did not have a HES flare. All 4 adolescents that completed study 200622 continued into a 20-week open-label extension study 205203 in which one of the 4 adolescents experienced one HES flare.
Pharmacokinetics: 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. 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 (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.
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.
Paediatric population: Severe eosinophilic asthma and HES: There are limited pharmacokinetic data available in the paediatric population (59 patients with eosinophilic esophagitis, 55 patients with severe refractory eosinophilic asthma and 1 patient with HES). Intravenous mepolizumab pharmacokinetics was evaluated by population pharmacokinetic analysis in a paediatric study conducted in patients aged 2-17 years old with eosinophilic esophagitis. Paediatric pharmacokinetics was largely predictable from adults, after taking into account bodyweight. Mepolizumab pharmacokinetics in adolescent patients with severe refractory eosinophilic asthma or HES included in the phase 3 studies were consistent with adults (see Dosage & Administration).
Toxicology: Preclinical safety data: 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.

Severe eosinophilic asthma: Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adults and adolescents aged 12 years and older (see Pharmacology: Pharmacodynamics under Actions).
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.
Eosinophilic granulomatosis with polyangiitis (EGPA): Nucala is indicated as an add-on treatment for adult patients 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 Pharmacology: Pharmacodynamics under Actions).

Nucala should be prescribed by physicians experienced in the diagnosis and treatment of severe refractory eosinophilic asthma, CRSwNP, 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.
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.
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.
EGPA: 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 should 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 should 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 should 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 should 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 (see Pharmacology: Pharmacokinetics under Actions).
Renal and hepatic impairment: No dose adjustment is required in patients with renal or hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Severe eosinophilic asthma: Children less than 12 years old: The safety and efficacy of mepolizumab in children and adolescents less than 12 years old have not yet been established.
CRSwNP: 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.
EGPA: Children less than 18 years old: The safety and efficacy of mepolizumab has not been established in children below the age of 18 years old. No data are available.
HES: 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 Adverse Reactions, and Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions but no recommendation on a posology can be made.
Method of administration: Vial: 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. 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 Special precautions for disposal and other handling under Cautions for Usage.
Each vial of mepolizumab should be used for a single patient, and any remainder of the vial should be discarded.
Pre-filled pen: The Nucala pre-filled pen should 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 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 are provided in the instructions for use under Patient Counselling Information.

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, 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.

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

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 exacerbations: Nucala should not be used to treat acute asthma exacerbations.
Asthma-related adverse symptoms 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.
Corticosteroids: 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. anaphylaxis, 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 Adverse Reactions). In the event of a hypersensitivity reaction, appropriate treatment as clinically indicated should 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 Dosage & Administration).
Life-threatening HES: Nucala has not been studied in patients with life-threatening manifestations of HES (see Dosage & Administration).
Effects on ability to drive and use machines: Nucala has no or negligible influence on the ability to drive and use machines.
Pre-filled pen: Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, that is to say essentially "sodium-free".

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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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-IL-5 treatment on fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

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%).
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: Severe eosinophilic asthma, CRSwNP and EGPA: Table 9 presents the adverse reactions from placebo-controlled severe eosinophilic asthma studies with frequencies 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 patients with EGPA receiving mepolizumab 300 mg SC (n=68) 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).
HES: In a double-blind placebo-controlled 32-week study in patients with HES receiving mepolizumab 300 mg SC (n=54), no additional adverse reactions were identified to those reported in the severe eosinophilic asthma studies.
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. (See Table 9.)

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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 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.
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. The safety profile was similar to that seen in adults. 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 Pharmacology: Pharmacodynamics under Actions).
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.

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 drug-drug interactions with mepolizumab is therefore considered low.

Special precautions for disposal and other handling: Vial: Reconstitution should be carried out under aseptic conditions.
Instructions for reconstitution for each vial: 1. Reconstitute the contents of the vial with 1.2 mL of sterile water for injections preferably using a 2 to 3 mL syringe and a 21 gauge 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 not be used.
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 of 100mg dose: 1. For subcutaneous administration, a 1 mL polypropylene syringe fitted with a disposable needle 21 gauge to 27 gauge 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.
If more than one vial is required for administration of the prescribed dosage, repeat steps 1 to 3. It is recommended that individual injection sites are separated by at least 5 cm.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Pre-filled pen: Before administration, the solution should be inspected visually. The liquid should be clear to opalescent, colourless to pale yellow to pale brown. If the solution is cloudy, discoloured or contains particles, the solution should not be used.
After removing the pre-filled pen from the refrigerator, allow the pen to reach room temperature for at least 30 minutes before injecting Nucala.
Comprehensive instructions for subcutaneous administration of Nucala in a pre-filled pen are provided under Patient Counselling Information.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products.

Vial: Store as directed on outer package.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Shelf life: 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.
Pre-filled pen: The storage conditions are detailed on the packaging.
If necessary, the Nucala pre-filled pen can be removed from the refrigerator and kept in the unopened pack for up to 7 days at room temperature (up to 30°C), when protected from light. The pack should be discarded if left out of the refrigerator for more than 7 days.
The pre-filled pen must be administered within 8 hours once the pack is opened. The pack should be discarded if not administered within 8 hours.

Step by step instructions for using the pre-filled pen: Follow these instructions on how to use the pre-filled pen. Failure to follow these instructions may affect proper function of the pre-filled pen. You should also receive training on how to use the pre-filled pen.
Before you use Nucala: The pre-filled pen should be used only once and then discarded.
Do not share your Nucala pre-filled pen with another person. Do not shake the pen. Do not use the pen if dropped onto a hard surface. Do not use the pen if it appears damaged. Do not remove the needle cap until just before your injection.
Prepare: 1. Get ready what you need.
Find a comfortable, well-lit and clean surface. Make sure you have within reach: Nucala pre-filled pen; Alcohol wipe (not included); Gauze pad or cotton wool ball (not included). Do not perform the injection if you do not have all these.
2. Take out your pre-filled pen.
Take the carton out of the refrigerator. Remove the tray from the carton. Peel back the film cover from the tray. Holding the middle of the pen, carefully take it out of the tray. Place the pen on a clean, flat surface, at room temperature, away from direct sunlight and out of the reach of children. Do not remove the needle cap at this stage.
3. Inspect and wait 30 minutes before use.
Check the expiry date on the label of the pen. Look in the inspection window to check that the liquid is clear (free from cloudiness or particles) and colourless to pale yellow to pale brown. It is normal to see one or more air bubbles. Wait 30 minutes (and no more than 8 hours) before use.
Do not use if the expiry date has passed. Do not warm the pen in a microwave, hot water, or direct sunlight. Do not inject if the solution looks cloudy or discoloured, or has particles. Do not use the pen if left out of the carton for more than 8 hours. Do not remove the needle cap during this step.
4. Choose your injection site.
You can inject Nucala into your thighs or abdomen. If someone else gives you the injection, they can also use your upper arm. If you need more than one injection to complete your dose, then leave at least 5 cm between each injection site.
Do not inject where your skin is bruised, tender, red or hard. Do not inject within 5 cm of your navel (belly button).
5. Clean your injection site.
Wash your hands with soap and water. Clean your injection site by wiping the skin with an alcohol wipe and allowing the skin to air dry. Do not touch your injection site again until you have finished your injection.
Inject: 6. Remove the clear needle cap.
Remove the clear needle cap from the pen by firmly pulling it straight off. Do not worry if you see a drop of liquid at the end of the needle. This is normal. Inject straight after removing the needle cap, and always within 5 minutes.
Do not touch the yellow needle guard with your fingers. This could activate the pen too soon and may cause a needle injury.
After removal, do not put the needle cap back onto the pen, as it may accidentally start the injection.
7. Start your injection.
Hold the pen with its inspection window facing towards you, so you can see it, and with the yellow needle guard facing down. Place the pen straight onto your injection site with the yellow needle guard flat against the surface of your skin.
To start your injection, push the pen down all the way and keep it held down against your skin. The yellow needle guard will slide up into the pen. You should hear the 1st "click" to tell you your injection has started. The yellow indicator will move down through the inspection window as you receive your dose.
Do not lift the pen from your skin at this stage, as that may mean you don't get your full dose of medicine. Your injection may take up to 15 seconds to complete.
Do not use the pen if the yellow needle guard doesn't slide up as described. Dispose of it (see Step 9 as follows), and start again with a new pen.
8. Hold the pen in place to complete your injection.
Continue to hold the pen down until you hear the 2nd "click", and the stopper and yellow indicator have stopped moving and fill the inspection window. Continue to hold the pen in place while you count to 5. Then lift the pen away from your skin.
If you do not hear the 2nd "click": Check that the inspection window is filled with the yellow indicator. If you are not sure, hold the pen down for another 15 seconds to make sure the injection is complete. Do not lift the pen until you are sure you have completed your injection.
You may notice a small drop of blood at the injection site. This is normal. Press a cotton wool ball or gauze on the area for a few moments if necessary. Do not rub your injection site.
Dispose: 9. Dispose of the used pen.
Dispose of the used pen and needle cap according to local requirements. Ask your doctor or pharmacist for advice if necessary. Keep your used pens and needle caps out of the sight and reach of children.

Antiasthmatic & COPD Preparations / Vaccines, Antisera & Immunologicals

R03DX09 - mepolizumab ; Belongs to the class of other systemic drugs used in the treatment of obstructive airway diseases.

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