Nucala (Mepolizumab)
mepolizumab — humanized anti-IL-5 monoclonal antibody
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Severe eosinophilic asthma | Adults and children ≥6 years | Add-on maintenance | FDA Approved |
| Chronic rhinosinusitis with nasal polyps (CRSwNP) | Adults ≥18 years | Add-on maintenance (inadequate response to nasal corticosteroids) | FDA Approved |
| Chronic obstructive pulmonary disease (COPD) — eosinophilic phenotype | Adults | Add-on maintenance | FDA Approved (May 2025) |
| Eosinophilic granulomatosis with polyangiitis (EGPA) | Adults | Treatment (with background therapy) | FDA Approved |
| Hypereosinophilic syndrome (HES) | Adults and adolescents ≥12 years (≥6 months duration, no identifiable non-hematologic secondary cause) | Treatment | FDA Approved |
Mepolizumab is the first anti-IL-5 biologic approved across five eosinophil-driven conditions. In asthma, it targets the subset of patients with persistent eosinophilic inflammation who remain uncontrolled despite high-dose inhaled corticosteroids and additional controllers. The COPD indication, added in May 2025, makes it the first approved biologic for COPD with eosinophilic phenotype, defined by blood eosinophil count ≥150 cells/μL. Mepolizumab is not indicated for the relief of acute bronchospasm or status asthmaticus.
Eosinophilic esophagitis (EoE): Small trials have shown reductions in esophageal eosinophil counts, but clinical symptom improvement has been inconsistent. Evidence quality: Low.
Allergic bronchopulmonary aspergillosis (ABPA): Case series report steroid-sparing benefit in patients with severe ABPA and blood eosinophilia. Evidence quality: Very low.
Chronic eosinophilic pneumonia: Individual case reports describe favorable responses in relapsing disease. Evidence quality: Very low.
Dosing
Adult & Adolescent Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Severe eosinophilic asthma — adults & adolescents ≥12 y | 100 mg SC q4wk | 100 mg SC q4wk | 100 mg SC q4wk | No titration required; flat dose Self-administration via AI or PFS after training |
| Severe eosinophilic asthma — children 6–11 y | 40 mg SC q4wk | 40 mg SC q4wk | 40 mg SC q4wk | Weight-independent dose; gives comparable exposure to adult 100 mg 40 mg/0.4 mL PFS only; administered by HCP or caregiver |
| CRSwNP — inadequate response to nasal corticosteroids | 100 mg SC q4wk | 100 mg SC q4wk | 100 mg SC q4wk | Continue background nasal corticosteroid Assess response at 24–52 weeks; prior surgery required for indication |
| Eosinophilic COPD — add-on to triple inhaled therapy | 100 mg SC q4wk | 100 mg SC q4wk | 100 mg SC q4wk | Requires BEC ≥150 cells/μL; continue ICS/LABA/LAMA Not for acute bronchospasm |
| EGPA — relapsing or refractory disease | 300 mg SC q4wk | 300 mg SC q4wk | 300 mg SC q4wk | Administered as 3 separate 100 mg injections, each ≥5 cm apart Continue background OCS; taper under supervision |
| HES — adults & adolescents ≥12 y with ≥6 months duration | 300 mg SC q4wk | 300 mg SC q4wk | 300 mg SC q4wk | Administered as 3 separate 100 mg injections, each ≥5 cm apart FIP1L1-PDGFRα-positive HES excluded from trials |
Unlike many biologics, mepolizumab uses a fixed-dose strategy in adults and adolescents across all indications. Population PK analyses confirmed that body weight does not clinically alter mepolizumab exposure sufficiently to warrant dose adjustment. The only weight-related consideration is in children aged 6–11 years, where 40 mg was selected to match adult exposure rather than using weight-based scaling.
If a dose is missed, administer it as soon as possible and then resume the regular 4-week schedule. If the next scheduled dose is already due, give it as planned. Do not double the dose.
Pharmacology
Mechanism of Action
Mepolizumab is a humanized IgG1 kappa monoclonal antibody that binds human interleukin-5 (IL-5) with high affinity (dissociation constant ~100 pM). IL-5 is the principal cytokine governing the maturation, recruitment, activation, and survival of eosinophils. By preventing IL-5 from engaging the alpha subunit of the IL-5 receptor on eosinophil surfaces, mepolizumab disrupts downstream signaling cascades that sustain eosinophil-driven tissue inflammation. This leads to a rapid and sustained reduction in circulating eosinophils — typically an 80–85% decrease from baseline within four weeks. Although eosinophil depletion is the pharmacodynamic hallmark, the precise downstream mechanisms by which this translates into clinical benefit in each approved condition remain an area of active investigation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~80% (SC); Tmax 4–8 days; ~2-fold accumulation at steady state with q4wk dosing | Slow absorption supports the 4-week dosing interval; injection site (arm, abdomen, thigh) does not meaningfully alter exposure |
| Distribution | Vd ~3.6 L (70 kg); distribution half-life 1–2 days; Vss 1.5–2× plasma volume | Primarily confined to plasma and extracellular fluid, consistent with IgG1 antibody distribution |
| Metabolism | Degraded by ubiquitous proteolytic enzymes; not hepatically restricted; no CYP involvement; no target-mediated clearance | No dose adjustment for hepatic impairment; no cytochrome-mediated drug interactions expected |
| Elimination | Terminal t½ 16–22 days; apparent CL 0.28 L/day (70 kg); not renally excreted | No dose adjustment for renal impairment; long half-life supports monthly dosing |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | 19% (vs 18% placebo) | Marginal excess over placebo; generally mild and self-limiting; reported across asthma trials (MENSA, SIRIUS) |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site reactions | 8% (vs 3% placebo) in asthma; 15% (vs 13%) in EGPA | Pain, erythema, swelling, itching, burning; higher with 300 mg dose (3 injections); most reactions mild |
| Back pain | 5–7% (vs 4–6% placebo) | Reported across asthma and COPD trials; not clearly dose-related |
| Fatigue | 5% (vs 4% placebo) | Generally mild; reported predominantly in asthma trials |
| Oropharyngeal pain | 4–8% (vs 2–5% placebo) | More common in CRSwNP (8%) and COPD (4%) populations |
| Arthralgia | 6% (vs 2% placebo) | Notable signal in CRSwNP trial; monitor if persistent |
| Diarrhea | 3–5% (vs 2–4% placebo) | Emerged prominently in COPD pooled safety data |
| Cough | 5% (vs 4% placebo) | Reported in COPD trials; distinguish from underlying disease exacerbation |
| Urinary tract infection | 3–4% (vs 2–3% placebo) | Reported across asthma and COPD populations |
| Pruritus | 3% (vs 2% placebo) | May reflect mild hypersensitivity; distinguish from injection site pruritus |
| Eczema | 3% (vs <1% placebo) | Notable imbalance versus placebo; monitor skin for new or worsening dermatitis |
| Muscle spasms | 3% (vs <1% placebo) | Signal from asthma trials; generally mild and transient |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis / severe hypersensitivity | Rare (<1%) | Hours to days post-injection | Discontinue permanently; treat per anaphylaxis protocol; do not re-challenge |
| Angioedema | Rare (postmarketing reports) | Hours post-injection | Discontinue; emergency management; permanent discontinuation |
| Herpes zoster reactivation | ~1% (vs 0.7% placebo in COPD) | Variable; ongoing treatment | Treat with antivirals; consider varicella vaccination before starting therapy; continue or hold mepolizumab based on severity |
| Systemic hypersensitivity reactions (non-anaphylactic) | 1–6% (higher with 300 mg dose) | Day of dosing (majority) | Assess severity; mild reactions may allow continuation with monitoring; rash, flushing, pruritus, dyspnea, stridor reported |
| Opportunistic infections (helminth) | Very rare (theoretical) | Any time during treatment | Screen and treat pre-existing helminth infections before initiation; discontinue mepolizumab if infection does not respond to anti-helminth therapy |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hypersensitivity reactions | <1% | Across all indications; protocol-mandated discontinuation for anaphylaxis |
| Injection site reactions | Rare | Infrequent cause of discontinuation despite relatively common occurrence |
| Herpes zoster | <1% | Serious events requiring discontinuation were uncommon in trials |
Injection site reactions are the most frequently reported adverse event exceeding placebo, particularly with the 300 mg dose requiring three separate injections. Rotating injection sites, allowing the prefilled device to reach room temperature for 30 minutes before use, and ensuring proper technique can minimize discomfort. Most reactions are mild and self-limiting. Persistent severe reactions warrant clinical reassessment.
Drug Interactions
Mepolizumab has a low drug interaction potential. As a monoclonal antibody, it is degraded by ubiquitous proteolytic enzymes rather than by CYP-mediated hepatic metabolism, and no formal drug interaction studies have been performed. Population pharmacokinetic analyses from Phase 3 trials found no evidence that commonly co-administered small molecule drugs alter mepolizumab exposure. The key considerations relate to concomitant biologics and immunomodulatory therapies rather than classical pharmacokinetic interactions.
Monitoring
-
Blood Eosinophil Count
Baseline, then q3–6 months
Routine Confirm eosinophilic phenotype before initiation. Track pharmacodynamic response; an 80–85% reduction is expected. Persistently elevated eosinophils may suggest non-adherence or non-response. -
Post-Injection Observation
Each administration
Routine Monitor for hypersensitivity reactions following injection, per standard biologic administration practice. Reactions may be immediate or delayed (days). -
Asthma / COPD Control
Every visit
Routine Use ACQ, ACT, or SGRQ scores to assess clinical response. Track exacerbation frequency. Assess corticosteroid tapering progress in EGPA and OCS-dependent asthma. -
Corticosteroid Tapering
At each visit during taper
Routine Particularly important in EGPA and OCS-dependent asthma. Monitor for adrenal insufficiency symptoms: fatigue, hypotension, nausea. Taper gradually. -
Herpes Zoster Symptoms
Ongoing
Trigger-based Counsel patients to report new vesicular rash or dermatomal pain promptly. Consider recombinant zoster vaccine (Shingrix) before initiating mepolizumab, particularly in patients ≥50 years or immunocompromised. -
Parasitic Infections
Baseline; as clinically indicated
Trigger-based Screen patients in endemic areas. If helminth infection arises during therapy and does not respond to treatment, discontinue mepolizumab until resolved. -
Nasal Polyp Score / Symptoms (CRSwNP)
q3–6 months
Routine Track endoscopic NPS and VAS symptom scores (obstruction, loss of smell, discharge). Assess need for surgery. Response assessed optimally at 24–52 weeks.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to mepolizumab or any excipient in the formulation (polysorbate 80, sodium phosphate dibasic heptahydrate, sucrose, citric acid monohydrate, EDTA disodium dihydrate).
Relative Contraindications (Specialist Input Recommended)
- Active helminth infection: Treat and resolve parasitic infections before initiation. If infection occurs during treatment and fails anti-helminth therapy, discontinue mepolizumab until infection clears.
- FIP1L1-PDGFRα-positive HES: These patients were excluded from the pivotal HES trial; mepolizumab is not established in this subgroup, which typically responds to imatinib.
- Pregnancy (2nd/3rd trimester): Monoclonal antibodies cross the placenta with increasing transfer as pregnancy progresses. Use only if potential benefit justifies potential risk to the fetus.
Use with Caution
- Patients at high risk for herpes zoster: Consider vaccination with recombinant zoster vaccine before starting treatment, particularly patients ≥50 years and those on concurrent immunosuppression.
- Elderly patients (≥65 years): No dose adjustment needed, but greater sensitivity in some individuals cannot be ruled out.
- Corticosteroid-dependent patients: Do not abruptly discontinue systemic or inhaled corticosteroids upon starting mepolizumab. Gradual tapering under supervision is essential to avoid adrenal crisis and disease flare.
Hypersensitivity reactions including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, and rash have been reported with mepolizumab both in clinical trials and in postmarketing experience. These reactions can occur within hours of administration or may have delayed onset over several days. Mepolizumab should be permanently discontinued in the event of anaphylaxis or severe hypersensitivity reaction. Healthcare professionals should be prepared to manage anaphylaxis when administering mepolizumab.
Patient Counselling
Purpose of Therapy
Mepolizumab works by blocking a specific protein (IL-5) that promotes the growth of eosinophils, a type of white blood cell that drives inflammation in conditions like asthma, nasal polyps, COPD, EGPA, and HES. By reducing eosinophil counts, mepolizumab helps prevent flare-ups and may allow reduction of steroid medications over time. It is a maintenance treatment — it does not treat sudden breathing emergencies or acute attacks.
How to Take
Mepolizumab is given as an injection under the skin once every four weeks. Depending on the indication and patient age, the injection can be self-administered at home using a prefilled syringe or autoinjector after proper training. The injection should be given in the upper arm, thigh, or abdomen. For the 300 mg dose (EGPA and HES), three separate injections are needed at sites at least 5 cm apart. The prefilled device should sit at room temperature for 30 minutes before use.
Sources
- NUCALA (mepolizumab) for injection, for subcutaneous use. Full Prescribing Information. GlaxoSmithKline. Revised 08/2025. gskpro.com Primary source for all dosing, indications, adverse events, PK parameters, and contraindication data in this monograph.
- FDA Approval Letter: Nucala sBLA for COPD. May 22, 2025. accessdata.fda.gov Documents the fifth approved indication (eosinophilic COPD) for mepolizumab.
- Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651-659. doi:10.1016/S0140-6736(12)60988-X 52-week dose-ranging trial establishing the pharmacodynamic basis for the 100 mg SC dose.
- Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma (MENSA). N Engl J Med. 2014;371(13):1198-1207. doi:10.1056/NEJMoa1403290 Pivotal confirmatory exacerbation-reduction trial demonstrating a 53% reduction in exacerbations with mepolizumab 100 mg SC vs placebo.
- Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma (SIRIUS). N Engl J Med. 2014;371(13):1189-1197. doi:10.1056/NEJMoa1403291 Demonstrated significant corticosteroid dose reduction in OCS-dependent severe asthma patients.
- Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376(20):1921-1932. doi:10.1056/NEJMoa1702079 52-week pivotal trial showing significantly greater accrued remission time and reduced relapse rates in EGPA.
- Han JK, Bachert C, Fokkens W, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021;9(10):1141-1153. doi:10.1016/S2213-2600(21)00097-7 52-week trial establishing efficacy in CRSwNP with significant improvements in nasal polyp score and obstruction symptoms.
- Roufosse F, Kahn JE, Rothenberg ME, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;146(6):1397-1405. doi:10.1016/j.jaci.2020.08.037 Pivotal HES trial showing 50% relative reduction in flares with mepolizumab 300 mg vs placebo over 32 weeks.
- Sciurba FC, Criner GJ, Christenson SA, et al. Mepolizumab to prevent exacerbations of COPD with an eosinophilic phenotype (MATINEE). N Engl J Med. 2025;392(17):1710-1720. doi:10.1056/NEJMoa2413181 Phase 3 trial supporting the COPD indication, showing 21% reduction in moderate/severe exacerbations in patients with BEC ≥300 cells/μL.
- Greenfeder S, Umland SP, Cuss FM, Chapman RW, Egan RW. Th2 cytokines and asthma—the role of interleukin-5 in allergic eosinophilic disease. Respir Res. 2001;2(2):71-79. doi:10.1186/rr41 Foundational review of IL-5 biology and its role in eosinophil maturation and tissue recruitment.
- Smith DA, Minthorn EA, Beerahee M. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Clin Pharmacokinet. 2011;50(4):215-227. doi:10.2165/11584340-000000000-00000 Comprehensive PK/PD review establishing the two-compartment model and dose-proportional PK across dose ranges.
- Pouliquen IJ, Kornmann O, Barber R, Muschin H, Lecomte F, Shabbir A. Pharmacokinetics and absolute bioavailability of mepolizumab following administration at subcutaneous and intramuscular sites. Clin Pharmacol Drug Dev. 2016;5(Suppl 1):26. doi:10.1002/cpdd.263 Bioavailability study confirming 64–75% SC bioavailability and similar PK across injection sites.
- Shabbir A, Goulding R, Engel B, et al. The pharmacokinetics and relative bioavailability of mepolizumab 100 mg liquid formulation administered subcutaneously. Clin Pharmacol Drug Dev. 2020;9(5):656-662. doi:10.1002/cpdd.726 Bridging study confirming bioequivalence between liquid prefilled devices and the reconstituted lyophilized formulation.