Nucala

Mepolizumab.

Mepolizumab is a humanised monoclonal antibody (IgG1, kappa), directed against human interleukin-5 (IL-5) produced in Chinese hamster ovary cells by recombinant DNA technology.
NUCALA is supplied as a sterile lyophilised powder for subcutaneous injection after reconstitution. Upon reconstitution with 1.2 mL of Sterile Water for Injection, the resulting concentration is 100 mg/mL and delivers 1 mL, with a pH of 7.0.
Excipients/Inactive Ingredients: Sucrose, Sodium phosphate dibasic heptahydrate, Polysorbate 80, Hydrochloric acid.

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 humanized 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 signaling and reducing the production and survival of eosinophils.
Pharmacodynamic effects: Severe asthma: In clinical trials, reduction in blood eosinophils was observed consistently following treatment with NUCALA. The magnitude and duration of this reduction was dose-dependent. Following a dose of 100 mg administered subcutaneously every 4 weeks for 32 weeks, the blood eosinophils were reduced to a geometric mean count of 40 cells/μL. This corresponds to a geometric mean reduction of 84% compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment. This magnitude of blood eosinophils reduction was maintained in severe asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies.
Immunogenicity: Severe asthma: Consistent with the potentially immunogenic properties of protein and peptide therapeutics, patients may develop antibodies to mepolizumab following treatment. Overall, 15/260 (6%) of subjects with severe asthma treated with 100 mg dose subcutaneously developed anti-mepolizumab antibodies after having received at least one dose of mepolizumab. The immunogenicity profile of mepolizumab in severe asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies was similar to that observed in the placebo-controlled studies.
Neutralizing antibodies were detected in one subject receiving mepolizumab. Anti-mepolizumab antibodies did not discernibly impact the PK or PD of mepolizumab treatment in the majority of patients and there was no evidence of a correlation between antibody tires and change in eosinophil level.
Clinical Studies: Severe asthma: The efficacy of NUCALA in the treatment of a targeted group of subjects with severe eosinophilic asthma was evaluated in 3 randomized, double-blind, parallel-group clinical studies of between 24-52 weeks duration, in patients aged 12 years and older. These studies were designed to evaluate the efficacy of NUCALA administered once every 4 weeks by subcutaneous or intravenous injection in severe eosinophilic asthma patients not controlled on their standard of care [e.g., inhaled corticosteroids (ICS), oral corticosteroids (OCS), combination ICS and long-acting beta₂-adrenergic agonists (LABA), leukotriene modifiers, short-acting beta₂-adrenergic agonists (SABA)].
Placebo Controlled Studies: Dose-ranging Efficacy MEA112997 (DREAM) Study: In MEA112997, a randomized, double-blind, placebo-controlled, parallel-group, multi-center study of 52 weeks duration in 616 patients, results demonstrated that mepolizumab (75 mg, 250 mg or 750 mg) significantly reduced asthma exacerbations when administered intravenously compared to placebo. There was no statistically significant difference in effect seen between the 3 studied doses. Blood eosinophil counts greater than or equal to 150 cells/μl at screening; or blood eosinophils ≥300 cells/μl in the past 12 months predicted subjects who would benefit most from NUCALA therapy. Results from this study were used to determine dose selection for the studies using subcutaneous mepolizumab administration. NUCALA is not indicated for intravenous use, and should only be administered by the subcutaneous route.
Exacerbation Reduction MEA115588 (MENSA) Study: MEA115588 was a randomized, double-blind, placebo-controlled, parallel-group, multi-center study which evaluated the efficacy and safety of mepolizumab as add-on therapy in 576 patients with severe eosinophilic asthma. This study evaluated the frequency of clinically significant exacerbations of asthma, defined as: worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits.
Patients were aged 12 years of age or older, with a history of two or more asthma exacerbations in the past 12 months and not controlled on their current asthma drug therapies [i.e., high-dose inhaled corticosteroids (ICS) in combination with at least another controller such as long-acting beta₂-adrenergic agonists (LABA) or leukotriene modifiers]. Patients were allowed to be on oral corticosteroid therapy and continued to receive their existing asthma medication during the study. Severe eosinophilic asthma patients were identified by peripheral blood eosinophils greater than or equal to 150 cells/μl within 6 weeks of randomization (first dose) or blood eosinophils greater than or equal to 300 cells/μl within the past 12 months of randomization.
Patients received either NUCALA 100 mg administered subcutaneously (SC), mepolizumab 75 mg administered intravenously (IV), or placebo treatment once every 4 weeks over 32 weeks. The primary endpoint, reduction in the frequency of clinically significant exacerbations of asthma was statistically significant (p<0.001). Table 1, provides the results of the primary endpoint and secondary endpoints of MEA115588. (See Table 1.)

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Oral Corticosteroid Reduction MEA115575 (SIRIUS) Study: MEA115575 evaluated the effect of NUCALA 100 mg SC on reducing the use of maintenance oral corticosteroids (OCS) while maintaining asthma control in subjects with severe eosinophilic asthma who were dependent on systemic corticosteroids.
Patients had a peripheral blood eosinophil count of ≥300/μL in the 12 months prior screening or a peripheral blood eosinophil count of ≥150/μL at baseline. Patients were administered NUCALA or placebo treatment once every 4 weeks over the treatment period. The OCS dose was reduced every 4 weeks during the OCS reduction phase (Weeks 4-20), as long as asthma control was maintained. During the study patients continued their baseline asthma therapy [i.e., high-dose inhaled corticosteroids (ICS) in combination with at least another controller such as long-acting beta₂-adrenergic agonists (LABA) or leukotriene modifiers].
This study enrolled a total of 135 patients: mean age of 50 years, 55% were female, 48% had been receiving oral steroid therapy for at least 5 years, and had a baseline mean prednisone equivalent dose of approximately 13 mg per day.
The primary endpoint was the reduction in daily OCS dose (weeks 20-24) whilst maintaining asthma control compared with patients treated with placebo (see Table 2).

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Additionally, health-related quality of life was measured using SGRQ. At Week 24, there was a statistically significant improvement in the mean SGRQ score for NUCALA compared with placebo: -5.8 (95% CI: -10.6, -1.0; P=0.019). At Week 24, the proportion of subjects with a clinically meaningful decrease in SGRQ score (defined as a decrease of at least 4 units from baseline) was greater for NUCALA (58%, 40/69) compared with placebo (41%, 27/66).
The long-term efficacy profile of NUCALA in severe 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.
Open Label Extension Study MEA115661 (COSMOS) Study: Following completion of the double-blind MEA115575 and MEA115588 studies, all patients were offered the opportunity to participate in MEA115661, a 52-week open-label extension (OLE) study, during which time all patients received open-label mepolizumab (100 mg SC). In total, 651 patients (126 subjects who had previously participated in study MEA115575 and 525 subjects who had previously participated in Study MEA115588), received 100 mg SC of mepolizumab every 4 weeks. During open-label treatment of all subjects with mepolizumab in MEA115661, the rates of exacerbations per year remained low in the subjects who were previously treated with mepolizumab and were consistent with results demonstrated during the 32-week double-blind period of study MEA115588. In addition, the impact of mepolizumab on steroid reduction was maintained following MEA115575 with average daily steroid dose remaining consistent with the level achieved with mepolizumab treatment at Weeks 20-24 during MEA115575.
Pharmacokinetics: Following subcutaneous dosing in subjects with moderate/severe 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 of mepolizumab to patients with asthma, the mean volume of distribution is 55 to 85 mL/kg.
Metabolism: 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 Patient Populations: The population pharmacokinetics of mepolizumab were analyzed to evaluate the effects of demographic characteristics. Analyses of these limited data suggest that no dose adjustments are necessary for race or gender.
Elderly patients (> 65 years old): No formal studies have been conducted in elderly patients. However, in the population pharmacokinetic analysis, there was no indication of an effect of age (12-82 years of age) on the pharmacokinetics of mepolizumab.
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.
Toxicology: Pre-clinical Safety Data: Carcinogenesis/mutagenesis: As mepolizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Reproductive Toxicology: 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 F1 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 crosses the placenta. Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers for several months post-partum and did not affect the immune system of the infants.
Animal toxicology and 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 have been 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.

Severe Eosinophilic Asthma: NUCALA is indicated as an add-on maintenance treatment for patients aged 12 years old and older with severe eosinophilic asthma who: have at least two exacerbations in the preceding 12 months on current standard of care (high doses of inhaled corticosteroids plus additional maintenance treatment) and/or requirement for treatment with systemic corticosteroids, and have a blood eosinophil count of ≥ 150 cells/μL (0.15 GI/L) at initiation of treatment with NUCALA OR ≥ 300 cells/μL (0.3 GI/L) in the past 12 months.
NUCALA is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus (see Precautions).

NUCALA should be prescribed by a specialist experienced in the diagnosis and treatment of severe eosinophilic asthma.
NUCALA should be reconstituted and administered by a health care professional.
Following reconstitution, NUCALA should only be administered as a subcutaneous injection (e.g. upper arm, thigh, or abdomen) (see Instructions for Use/Handling under Cautions for Usage).
Posology: Severe Eosinophilic Asthma: Adults and Adolescents (12 years and older): The recommended dose is 100 mg of NUCALA administered by subcutaneous (SC) injection once every 4 weeks.
The safety and efficacy of NUCALA have not been established in adolescents weighing less than 45kg.
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.
Children (up to 12 years of age): The safety and efficacy of NUCALA have not been established in children less than 12 years of age.
Elderly (65 years or older): No dosage adjustment is recommended in patients 65 years or older (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Renal Impairment: Dose adjustments in patients with renal impairment are unlikely to be required (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Hepatic Impairment: Dose adjustments in patients with hepatic impairment are unlikely to be required (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).

There is no clinical experience with overdose of NUCALA.
Single doses of up to 1500 mg of mepolizumab were administered intravenously in a clinical trial to patients with eosinophilic disease without evidence of dose-related toxicities.
Treatment: 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 mepolizumab or to any of the excipients.

NUCALA should not be used to treat acute asthma exacerbations.
Asthma-related adverse events or exacerbations may occur during treatment with NUCALA. Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with NUCALA.
Abrupt discontinuation of corticosteroids after initiation of NUCALA therapy is not recommended. Reductions in corticosteroid doses, if required, should be gradual and performed under the supervision of a physician.
Hypersensitivity and Administration 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 had a delayed onset (i.e., days).
Parasitic Infections: Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre-existing helminth infections were excluded from participation in the clinical programme. Patients with pre-existing helminth infections should be treated for their infection prior to NUCALA therapy. If patients become infected whilst receiving treatment with NUCALA and do not respond to anti-helminth treatment, temporary discontinuation of NUCALA should be considered.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of mepolizumab on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology or adverse reaction profile of NUCALA.

Fertility: There are no fertility data in humans. Animal studies showed no adverse effects of anti-IL5 treatment on fertility (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions).
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: Pre-clinical 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.
Lactation: There are no data regarding the excretion of mepolizumab in human milk. However, mepolizumab was excreted into the milk of cynomolgous monkeys at concentrations that were less than 0.5% of those detected in plasma.
A decision should be made whether to discontinue breast-feeding or discontinue NUCALA, taking into account the importance of breast-feeding to the infant and the importance of the drug to the mother.

Severe asthma: The safety of NUCALA was studied in a clinical development program in severe eosinophilic asthma which included 3 randomized, placebo-controlled, multicenter studies (n=1327). Subjects received either subcutaneous (SC) or intravenous (IV) mepolizumab or placebo during clinical studies of 24-52 weeks duration. Adverse reactions associated with NUCALA 100 mg administered subcutaneously (n=263) are presented in the table as follows. The safety profile of NUCALA in severe asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies was similar to that observed in the placebo-controlled studies.
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) and rare (≥1/10000 to <1/1000). (See Table 3.)

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Post-marketing data: (See Table 4.)

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No formal interaction studies have been performed with mepolizumab.

Incompatibilities: Do not mix the reconstituted solution for injection with other medicinal products.
Instructions for Use/Handling: NUCALA is provided as a lyophilized powder in a single-use vial for subcutaneous injection only. NUCALA does not contain a preservative therefore reconstitution by a healthcare professional should be carried out under aseptic conditions.
Once reconstituted, NUCALA will contain a concentration of 100 mg/mL mepolizumab. The reconstituted solution of mepolizumab, if not used immediately, should be stored below 30°C, and should not be frozen. Any unused concentrate or solution remaining after 8 hours must be discarded.
Instructions for reconstitution of each 100 mg vial: 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 21 gauge needle. The reconstituted solution will contain a concentration of 100 mg/mL mepolizumab.
2. The stream of sterile Water for Injection should be directed vertically onto the center of the lyophilized 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: Do not shake the reconstituted solution during the procedure as this may lead to product foaming or precipitation. Reconstitution is typically complete within 5 minutes after the sterile water has been added, but it may take additional time.
3. 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.
4. Visually inspect the reconstituted solution for particulate matter and clarity prior to use. The solution should be clear to opalescent, and colorless 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.
5. The reconstituted solution of NUCALA, if not used immediately: Store below 30°C.
Discard if not used within 8 hours of reconstitution.
Do not mix with other medications.
Do not freeze.
Instructions for administration: 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.

Unopened Vial: Store at between 2°C and 8°C.
Do not freeze.
Protect from light. Store in the original carton until use.
Reconstituted solution: After reconstitution with Water for Injection the product is stable for up to 8 hours when stored below 30°C.
Do not freeze.
During administration, protection from light is not necessary.

Antiasthmatic & COPD Preparations

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

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