Nucala
Nucala
Generic Name
Nucala
Brand Names
for dupilumab—a fully human IgG4 monoclonal antibody that selectively inhibits IL‑4/IL‑13 signaling by targeting the IL‑4 receptor α (IL‑4Rα) subunit.
Mechanism
Dupilumab binds to the shared IL‑4Rα chain, blocking:
• IL‑4 from signaling via both the type‑I and type‑II receptors
• IL‑13 from signaling via the type‑II receptor
This dual blockade interrupts the Th2 cytokine cascade responsible for eosinophilic inflammation, IgE production, and airway/skin remodeling. The result is a marked reduction in airway hyper‑responsiveness, mucus hypersecretion, and cutaneous inflammation.
Pharmacokinetics
| Parameter | Approximate Value | Notes |
| Absorption | Slow; 75–84 % bioavailability after subcutaneous injection | Peak concentration ~7–10 days post‑dose |
| Distribution | Volume ≈ 20 L; bound to plasma proteins (~10 %) | Distribution limited to vascular and interstitial spaces |
| Metabolism | Proteolytic degradation to peptides | No significant hepatic metabolism |
| Elimination | Clearance ~1 mL/kg/h; half‑life ≈ 17–20 days (steady state) | Dose sparing possible after trough maintenance |
| Food effect | None | Can be given 24 h before/after food |
> Clinical Tip: Because dupilumab accumulates slowly, a loading dose (two 300 mg subcutaneous injections one week apart) is recommended for most indications.
Indications
- Severe asthma (≥12 years) uncontrolled on high‑dose inhaled corticosteroids ± LABA
- Moderate‑to‑severe atopic dermatitis (≥6 years) with inadequate response or contraindication to other systemic therapies
- Chronic rhinosinusitis with nasal polyposis (≥12 years) not controlled by intranasal corticosteroids or surgery
- Eosinophilic esophagitis (clinical trials) – investigational use
> FDA approval in 2017 for asthma, 2020 for atopic dermatitis, and 2022 for chronic rhinosinusitis with nasal polyposis.
Contraindications
- Positive allergy to dupilumab or any excipient (e.g., benzyl alcohol)
- Active infection requiring systemic antibiotics
- History of severe conjunctivitis with ocular complications
- Ongoing uncontrolled eosinophilic disorders (e.g., hypereosinophilic syndrome) – monitor closely
Dosing
| Indication | Initial Dose | Maintenance Dose | Administration | Notes |
| Severe Asthma | 300 mg SC every 2 weeks (loading 2 doses) | 300 mg SC every 4 weeks | Subcutaneous | Can convert to 150 mg SC q 2 wks without loss of efficacy |
| Atopic Dermatitis | 300 mg SC every 4 weeks (loading 2 doses) | 300 mg SC every 4 weeks | Subcutaneous | Weight <60 kg: 150 mg SC q 4 wks |
| Chronic Rhinosinusitis | 300 mg SC every 2 weeks (loading 2 doses) | 300 mg SC every 2 weeks | Subcutaneous | Nonsignificant safety differences compared with asthma dosing |
| Eosinophilic Esophagitis (clinical) | 300 mg SC every 2 weeks | 300 mg SC q 2 weeks | Subcutaneous | Monitor for endoscopic remission |
• Premedication: None required
• Breaks in therapy: Avoid sudden discontinuation; consider tapering over 4–8 weeks to prevent rebound eosinophilia
Adverse Effects
- Injection‑site reactions (pruritus, erythema, swelling) – 20–30 %
- Conjunctivitis / Dry eye – 8–15 %
- Upper respiratory tract infections – 5–7 %
- Eosinophilia (mild elevation) – ≤5 %
- Headache – 3–5 %
- Asthma exacerbation (in patients with uncontrolled asthma) – <1 %
Serious events (≤1 %):
• Anaphylaxis – rare; use caution in patients with previous IgE‑mediated reactions
• Severe ocular complications (keratitis, corneal ulceration) – monitor eye symptoms
• Parasitic infections (especially in endemic regions) – screen and treat pre‑initiation
Monitoring
| Parameter | Frequency | Rationale |
| Blood eosinophils | Baseline, month 1, then every 3 months | Detect eosinophil‑mediated complications |
| IgE levels | Baseline, every 6 months | For pharmacodynamic correlation |
| Liver enzymes (ALT/AST) | Baseline, then every 6 months | Rare elevation with dupilumab |
| Ophthalmologic assessment | Baseline, then every 6 months or sooner if symptoms | Conjunctivitis monitoring |
| Asthma control questionnaire (AQLQ/PAY‑7) | Every visit | Quantify symptom relief |
| Skin assessment (EASI score) | Every visit for atopic dermatitis | Measure disease severity |
Clinical Pearls
- Inflammation timing: A loading dose as two 300 mg injections spaced 7 days apart dramatically shortens onset of action; omit the loading dose in patients with major contraindications (e.g., active infection).
- Dose conversion: Switching from 300 mg q 4 weeks to 150 mg q 4 weeks (or 300 mg q 2 weeks) is safe and cost‑effective for lighter‑weight patients (3 × 10⁹/L or systemic symptoms warrant evaluation for IL‑5‑mediated disorders.
- Vaccination: Live‑attenuated vaccines are contraindicated; immunizations should be administered at least 4 weeks before initiating dupilumab.
- Pregnancy: No definitive teratogenic data; use only if benefit outweighs risk and no alternatives.
- Drug interactions: None directly; however, concomitant systemic steroids may mask eosinophil elevations, delaying detection of serious AEs.
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• Recap: Dupilumab (Nucala) remains a cornerstone for Th2‑driven diseases—sevre asthma, atopic dermatitis, and chronic rhinosinusitis with polyposis—providing robust clinical benefit with a favorable safety profile when monitored appropriately.