Interleukin-5 Antagonists (benralizumab, depemokimab, mepolizumab, reslizumab) — Notification / Coverage Criteria
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Medical necessity and notification criteria for administration and coverage of IL-5 antagonist biologics for eosinophilic asthma and other eosinophilic conditions for Blue Cross Blue Shield North Carolina members.
Added requirement for trial and failure of Cinqair prior to use of Exdensur within initial and continuation criteria.
For EGPA indication: removed required trial and failure of an oral immunosuppressant and added diagnostic requirement of baseline eosinophil count ≥ 1000 cells/µL or ≥ 10%; added use-limits for relapsing/refractory disease or maintenance of remission.
For CRSwNP: added requirement of at least 2 inadequately controlled symptoms for ≥12 consecutive weeks and objective diagnostic confirmation by rhinoscopy, endoscopy, or sinus CT; removed trials of Xhance/oral systemic corticosteroids and replaced with intranasal corticosteroid trial requirement.
Added Exdensur (depemokimab-ulaa) initial criteria, dosing, HCPCS codes, and maximum units.
Site-of-care criteria clarified and expanded to allow outpatient hospital administration when specific risk or practical criteria are met; otherwise administration is in office/home.
Coverage Criteria and Clinical Requirements
Initial Therapy — Covered when ALL of the following are met for the requested agent and indication
Covered when ALL of the following are met for the requested agent and indication
Root
Diagnosis and age limits
Severe eosinophilic asthma
- Eosinophil threshold for asthma: For benralizumab, depemokimab, or mepolizumab: blood eosinophils >=150 cells/µL at initiation (within past 6 weeks) OR >=300 cells/µL in past 12 months; For reslizumab: blood eosinophils >=400 cells/µL at initiation (within past 6 weeks) OR >=400 cells/µL in past 12 monthssee above
Medical record documentation required (eosinophil counts)
- Background therapy and control: Patient is currently treated with and adherent to maximally tolerated conventional therapies: (a) an inhaled corticosteroid regimen for past 3 months OR documented clinical intolerance/contraindication to ALL inhaled corticosteroids; AND (b) a regimen containing a LABA, LTRA, LAMA, theophylline, or zileuton for past 3 months OR documented clinical intolerance/contraindication to ALL agents in that class
Medical record documentation required
- Evidence of uncontrolled disease: One of: two or more severe asthma exacerbations requiring systemic corticosteroid bursts in past 12 months; OR one or more serious exacerbation requiring hospitalization, mechanical ventilation, or ER/urgent care in past 12 months; OR controlled asthma that worsens when corticosteroids are tapered; OR baseline pre-treatment FEV1 <80% predicted
Medical record documentation required
- EGPA: Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA); request for benralizumab or mepolizumab; age >=18; AND baseline eosinophils >=1000 cells/µL OR >=10% on differential; AND patient is stable on and currently taking oral corticosteroids; AND disease is not severe organ- or life-threatening vasculitis; AND agent will be used for relapsing/refractory disease or maintenance of remission
Medical record documentation required
- HES: Diagnosis of hypereosinophilic syndrome (HES); request for mepolizumab; age >=12; diagnosed >=6 months; no non-hematologic secondary HES or FIP1L1-PDGFRα-positive HES; patient on stable HES therapy and has had >=2 HES flares in past 12 months (one not due to recent therapy decrease); AND blood eosinophils >=1000 cells/µL
Medical record documentation required
- CRSwNP: Diagnosis of chronic rhinosinusitis with nasal polyposis (CRSwNP); request for mepolizumab; age >=18; at least TWO CRS symptoms for >=12 consecutive weeks (e.g., nasal obstruction, discharge, facial pain/pressure, reduction/loss of smell); AND objective confirmation by anterior rhinoscopy, nasal endoscopy, or sinus CT; AND prior surgery for nasal polyps OR not a surgical candidate; AND trial of intranasal corticosteroid for >=4 consecutive weeks within 12 weeks prior to initiation OR documented intolerance/contraindication to all intranasal corticosteroids; AND patient will continue intranasal corticosteroid therapy unless contraindicated
Medical record documentation required
- COPD: Diagnosis of COPD; request for mepolizumab; age >=18; eosinophilic phenotype demonstrated by eosinophils >=150 cells/µL at initiation (within past 6 weeks) OR >=300 cells/µL in past 12 months; AND symptoms of chronic bronchitis (productive cough >=3 months in past year); AND post-bronchodilator FEV1/FVC <0.70 and post-bronchodilator FEV1 >30% to ≤70% predicted; AND currently receiving maintenance triple therapy (ICS, LABA, LAMA) for past 3 months OR documented intolerance/contraindication to each; AND history of two or more moderate exacerbations or one severe exacerbation in past 12 months
Medical record documentation required
- Safety and administrative requirements: Patient will not receive the requested agent in combination with another biologic for the same indication; prescriber is a specialist or has consulted a specialist; no FDA-labeled contraindications; for mepolizumab or benralizumab, if patient cannot self-administer, documentation of inability and lack of caregiver required; requested quantity does not exceed maximum units allowed; site-of-care criteria applies for inpatient or outpatient hospital administration
Includes product-specific maximum units and site-of-care rules (see coding/dosing table)
Continuation Therapy — Continuation therapy covered when ALL of the following are met
Continuation therapy covered when ALL of the following are met
Continuation Root
- Eligibility: Patient was approved through Blue Cross NC initial criteria OR would have met initial criteria at therapy start
- Clinical response for severe eosinophilic asthma: For severe eosinophilic asthma, patient has improvement or stabilization from baseline as demonstrated by one or more: decreased rescue medication use, decreased frequency of exacerbations, increased predicted FEV1, or reduction in asthma-related symptoms; AND remains on and compliant with asthma control therapy
Medical record documentation required
- EGPA continuation: For EGPA treated with benralizumab or mepolizumab, patient is stable on oral corticosteroids and has improvement or stabilization from baseline demonstrated by remission, decreased maintenance oral corticosteroid dose, decreased hospitalizations, or no increase in maintenance corticosteroid/immunosuppressant dose
Medical record documentation required
- HES continuation: For HES on mepolizumab, patient has demonstrated one or more specified clinical benefits while using the medication (e.g., reduction in number of flares or improvement in clinical symptoms such as fatigue, cough, breathlessness)
Medical record documentation required
Continuation Therapy Criteria — Continuation therapy is covered when ALL of the following are met (per indication-specific requirements):
Continuation therapy is covered when ALL of the following are met (per indication-specific requirements):
Nested, indication-specific logic included
These interleukin‑5 antagonist agents are not indicated for relief of acute bronchospasm or status asthmaticus. Additionally, reslizumab (Cinqair) is not indicated for treatment of other eosinophilic conditions outside its approved use. These limitations reflect the FDA‑labeled indications and are required considerations when evaluating requests for coverage of any IL‑5 antagonist product.
For reslizumab specifically, ensure the patient meets the drug’s age requirement (adult patients ≥18 years) and the policy’s eosinophil thresholds and other asthma‑specific eligibility criteria before approval; reslizumab should not be used as rescue therapy for acute bronchospasm or status asthmaticus.
A prior policy exclusion for the presence of neoplastic disease or known/suspected parasitic infection was removed in the July 2026 updates. The current policy text does not reintroduce a new absolute exclusion for these conditions in the cited sections; reviewers should apply the updated criteria without automatically denying requests solely for these historical concerns.
Use of these IL‑5 antagonists that does not meet the documented medical necessity criteria in this policy is considered not medically necessary. Common denial triggers include failure to meet age limits for the requested agent, not meeting the agent‑specific eosinophil thresholds at initiation or within the prior 12 months, lack of required prior therapies or documented adherence to background controller regimens, absence of specialty prescriber documentation when required, or concurrent use with another biologic for the same indication.
For initial approvals, the policy requires documentation of relevant baseline labs and treatment history (e.g., eosinophil counts, inhaled corticosteroid use, LABA/LTRA/LAMA/theophylline/zileuton where applicable). Requests that omit this documentation or that do not meet the stated thresholds and prior‑therapy requirements are at risk for denial as not medically necessary.
Injection or infusion administration in an inpatient setting that is arranged solely for the purpose of administering the drug is not medically necessary. Inpatient administration may be permitted only when the patient meets the medical necessity criteria and the inpatient admission is for reasons other than just giving the injection or infusion.
If inpatient or outpatient hospital administration is requested, the request must meet the site‑of‑care medical necessity criteria (e.g., history of severe adverse event, increased risk conditions, inability to adhere, new to therapy or re‑initiation, or formulation change); otherwise the administration should occur in a home‑based infusion or physician office setting.
HCPCS / Coding and Clinical Thresholds
| affected codes | Policy references administration in healthcare setting and site-of-care criteria; specific procedure or HCPCS/CPT codes not listed in this document portion. |
| J0517 | benralizumab (Fasenra) HCPCS code |
| J2182 | mepolizumab (Nucala) HCPCS code |
| J2786 | reslizumab (Cinqair) HCPCS code |
Prior Authorization, Documentation, and Operational Requirements
Prior authorization required; approval valid 365 days; site-of-care applies
Prior authorization/notification is required for all requests; when criteria are met approval duration is 365 days. Site-of-care rules apply for inpatient or outpatient hospital administration and must be considered when requesting facility-based administration.
- Duration of approval: 365 days when criteria are met (initial and continuation).
- Site-of-care criteria apply for inpatient or outpatient hospital administration (see site-of-care medical necessity criteria).
Prior authorization must reference FDA dosing, indication criteria, and HCPCS codes
Prior authorization must be obtained referencing the agent-specific FDA-labeled dosing and indication criteria and the HCPCS codes listed for each agent (e.g., J0517 for benralizumab; J2182 for mepolizumab; J2786 for reslizumab; C9399/J3490/J3590 for depemokimab).
- Requests must reference FDA-labeled dosing and indication-specific criteria.
- Use the HCPCS codes listed for each agent (see coding table).
Step therapy: required trials/inadequate response to other IL‑5 agents for depemokimab and reslizumab
Prior to approval for depemokimab (Exdensur) or reslizumab (Cinqair), the patient must have tried and had an inadequate response to the specified other IL‑5 agents or have documented intolerance/contraindication to them as described in the policy.
- Reslizumab requests require trial and inadequate response to benralizumab AND mepolizumab unless intolerance/contraindication is documented.
- Depemokimab requests require trials of specified IL‑5 agents per age band (see Exdensur step rules).
Exdensur requires prior trials/failure of Cinqair plus Fasenra and Nucala (age-specific rules apply)
For Exdensur (depemokimab) initial and continuation approvals, adults must have tried and had an inadequate response to reslizumab (Cinqair), benralizumab (Fasenra), AND mepolizumab (Nucala) unless there is documented intolerance, contraindication, or hypersensitivity.
- For patients 12 to <18 years, trial and inadequate response to benralizumab AND mepolizumab (or documented intolerance/contraindication) is required.
- July 2026 change: Exdensur requires trial and failure of Cinqair prior to use (operationalized as trial/failure of Cinqair AND Fasenra and Nucala).
Required documentation: eosinophil counts, prior therapies, adherence, and intolerance
Submit medical records showing required blood eosinophil counts (within policy timeframes), documentation of prior therapies and adherence or documented intolerance/contraindication to those therapies, and objective diagnostic testing where applicable.
- Eosinophil count documentation required (e.g., ≥150/µL at initiation or ≥300/µL in past 12 months for many agents; ≥400/µL for reslizumab; EGPA/HES thresholds as specified).
- Documentation of prior controller therapy use and adherence for prior 3 months or documented intolerance/contraindication.
- Objective diagnostic confirmation required for CRSwNP (anterior rhinoscopy, nasal endoscopy, or sinus CT) and baseline pulmonary function where indicated.
Required medical record documentation to support baseline and response for continuation
Medical records must demonstrate baseline status and clinical improvement or stabilization from baseline for continuation (examples include decreased rescue medication use, decreased exacerbations, increased predicted FEV1, or symptom reduction).
- For severe eosinophilic asthma: show one or more—reduced rescue use, fewer exacerbations, increased predicted FEV1, or reduced asthma symptoms.
- For EGPA: document stability on oral corticosteroids and improvement/stabilization (remission, decreased maintenance steroid dose, fewer hospitalizations).
- For HES, CRSwNP, and COPD: provide the indication-specific clinical response measures listed in policy.
Denial risk if initial criteria (diagnosis, age, eosinophils, prior therapy/adherence/intolerance) are not met
Requests missing required initial criteria (diagnosis, applicable age limits, required eosinophil thresholds, documentation of prior therapy and adherence, or documentation of intolerance/contraindication) are at risk for denial.
- Missing or insufficient eosinophil test results within required timeframes is a common denial trigger.
- Lack of documentation of prior controller therapies or adherence, or missing prescriber specialty documentation, increases denial risk.
Site-of-care denials: inpatient-for-administration-only denied; outpatient hospital allowed only with specified bypass criteria
Requests for inpatient administration solely for the purpose of administering an injection/infusion will be denied; outpatient hospital administration is allowed only when one of the site-of-care bypass criteria is met (e.g., history of severe adverse event, conditions increasing risk, inability to adhere, new-to-therapy, re-initiation, or formulation change).
- If site-of-care criteria are not met, administration should occur in a home-based infusion or physician office setting.
- Outpatient hospital administration requires meeting at least one listed condition (e.g., severe prior adverse event or increased risk conditions).
Denial risk for requests exceeding policy maximum units for approval duration
Requests that exceed the maximum units allowed for the duration of approval per the policy’s dosing/maximum units table may be denied.
- The requested quantity must not exceed the maximum units allowed for the 365‑day approval period (see per‑drug maximum units in coding/continuation tables).
- Exceeding listed maximum units (e.g., per drug/indication) is a basis for denial.
Background and Scope
Interleukin‑5 antagonist biologics (benralizumab, depemokimab, mepolizumab, reslizumab) are FDA‑approved as add‑on maintenance therapy for severe eosinophilic asthma and, for select products, for other eosinophilic conditions (e.g., EGPA, HES, CRSwNP, eosinophilic COPD). These agents are intended to reduce eosinophil‑driven inflammation and to decrease exacerbation frequency or steroid reliance when used in patients meeting product‑specific eligibility criteria.
The agents are not rescue therapies and have specific age and blood eosinophil thresholds that determine eligibility (see coverage criteria). Administration setting and duration of approval follow prior authorization and site‑of‑care rules; continuation of therapy requires documented clinical benefit or stabilization from baseline according to indication‑specific measures.
Key Definitions
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