IL-5 Inhibitors (reslizumab, benralizumab, mepolizumab, depemokimab) coverage and site-of-service criteria
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Defines medical necessity, site-of-service review, and coverage criteria for IL-5 inhibitor drugs for severe eosinophilic asthma and related eosinophilic conditions; applies to providers requesting medical benefit reviews and site-of-service determinations.
Added coverage criteria for Exdensur (depemokimab-ulaa).
Updated criteria to include Exdensur in the list of medications not to be used concurrently with other listed biologics.
Updated eosinophil count thresholds and other asthma criteria in prior 2024–2025 updates, including changes between 150 and 300 cells/µL and modifications to inhaled corticosteroid dosing language and FEV1/FVC criteria.
Added coverage criteria for Exdensur (depemokimab-ulaa).
Updated Fasenra (benralizumab) age requirement from 12 years or older to 6 years or older.
Eosinophil threshold and asthma diagnostic criteria have been adjusted multiple times (150 to 300 then back to 150 cells/mcL; addition of exacerbation/FEV1-based diagnostic requirements).
Added coverage criteria for Nucala (mepolizumab) for treatment of certain individuals with COPD and for Fasenra for hypereosinophilic syndrome (HES).
Clarified that medications in this policy are subject to the product's FDA dosage and administration prescribing information and quantity limits per prescribing information were added.
Drug- and Indication-Specific Coverage Criteria
Cinqair (reslizumab) — severe eosinophilic asthma (age >=18)
Covered when ALL of the following are met
Not to be used concurrently with other listed biologics; prescriber specialty required; dose limit per policy
Exdensur (depemokimab-ulaa) and Fasenra (benralizumab) — severe eosinophilic asthma
Covered when ALL of the following are met (product-specific age and dosing vary)
Not to be used concurrently with other listed biologics; prescriber specialty required
Not to be used concurrently with other listed biologics; prescriber specialty required
Fasenra indications — EGPA and HES
Covered when ALL of the following are met
Prescriber specialty requirement; specific vasculitis/organ criteria listed in policy
Hematology prescriber requirement; genetic testing requirement; duration and flare thresholds specified
Nucala (mepolizumab) — asthma, COPD, EGPA
Covered when ALL of the following are met
Not to be used concurrently with other listed biologics; prescriber specialty required
COPD-specific background therapy and exacerbation history required
Prescriber specialty requirement; EGPA organ/vasculitis criteria mirror Fasenra requirements
Site-of-Service (SOS) medical necessity rules for IV/ injectable administration
Covered when ALL of the following are met
Site-of-service criteria also apply for CRS grade 3–4 per policy; Alaska exception described in history
Nucala for eosinophilic COPD (Initial Therapy)
Covered when ALL of the following are met
COPD initial criteria
- Age: Individual is aged 18 years or older
- Diagnosis: Diagnosed with inadequately controlled COPD
- Eosinophil threshold: Blood eosinophil >=150 cells/mcL within previous 12 months>=150 cells/mcL
- Prior therapy: Tried a LAMA/LABA combination for >=90 days unless not tolerated>=90 days
- Exacerbation history: Either: 2 or more COPD exacerbations treated with systemic corticosteroid and/or antibiotic in prior 12 months OR 1 or more COPD exacerbation requiring hospitalization in prior 12 months
- Prescriber: Prescribed by or in consultation with an allergist, immunologist or pulmonologist
- Dose limit: Maintenance dose limited to 100 mg every 4 weeks100 mg q4w
Nucala for eosinophilic granulomatosis with polyangiitis (EGPA)
Covered when ALL of the following are met
EGPA initial criteria
- Age: Individual is aged 18 years or older
- Asthma history: History or presence of asthma
- Background steroids: Stable dose of prednisone or prednisolone between 7.5 mg and 50 mg with or without immunosuppressive therapy7.5-50 mg
- Eosinophil threshold: Blood eosinophils >=10% OR absolute eosinophil count >=1000 cells/microL>=10% or >=1000 cells/microL
- Vasculitis evidence: Presence of at least one vasculitis/organ-involvement criterion (e.g., biopsy showing necrotizing vasculitis, alveolar hemorrhage, palpable purpura, myocardial infarction from coronary arteritis, hematuria with red cell casts, leukocytoclastic vasculitis on biopsy, mononeuritis multiplex, ANCA)
Details listed in policy text
- Prescriber: Prescribed by or in consultation with an allergist, immunologist, pulmonologist, or rheumatologist
- Dose limited to 300 mg every 4 weeks300 mg q4w
Nucala for hypereosinophilic syndrome (HES)
Covered when ALL of the following are met
HES initial criteria
- Age: Individual is aged 12 years or older>=12 years
- Duration: Documented history of at least 6 months without identifiable non-hematologic secondary cause>=6 months
Examples: drug hypersensitivity, parasitic infection, HIV, non-hematologic malignancy
- FIP1L1-PDGFRA negative: Negative for FIP1L1-PDGFRA kinase-positive HES by FISH or RT-PCR
- Eosinophil threshold: Blood eosinophil >=1000 cells/microL>=1000 cells/microL
- Flare history: 2 or more HES flares in past 12 months requiring escalation in therapy>=2 flares/12 months
- Background therapy: Receiving background HES therapy for at least 4 weeks prior to initiating Nucala>=4 weeks
- Prescriber: Prescribed by or in consultation with a hematologist
- Dose limited to 300 mg every 4 weeks300 mg q4w
Nucala for chronic rhinosinusitis with nasal polyps (CRSwNP)
Covered when ALL of the following are met
NPS and VAS trial-specific measures supported by SYNAPSE; prior surgical or systemic steroid history required where specified
General coverage stance / investigational uses
Initial approvals limited to indications and criteria specified in this policy; other uses excluded
Coverage aligned to trial populations (initial therapy/indication-specific)
Coverage considerations reflect populations enrolled in pivotal trials and key eligibility elements used to demonstrate benefit.
Trial-based eligibility reflected in policy requirements
Trial populations guided asthma coverage criteria
Benralizumab pivotal trials inform Fasenra criteria
Trial efficacy and safety observations incorporated into Cinqair criteria
Exdensur (depemokimab-ulaa) efficacy and safety basis
Covered when supported by evidence from phase III trials demonstrating clinical benefit in severe eosinophilic asthma on standard-of-care therapy.
Trials randomized ~792 individuals; primary endpoint annualized exacerbation rate
Monitor liver tests per trial discontinuation criteria; antibody development reported
Reslizumab (Cinqair) efficacy and safety observations
Clinical trial evidence and safety signals relevant to coverage decisions.
Pooled rate ratio ~0.46; FEV1 improvements observed
Anaphylaxis and CPK elevations were notable safety findings
Asthma and related eosinophilic condition coverage criteria (summary of recent policy criteria changes)
Covered when ALL/selected conditions defined by drug-specific criteria are met (policy contains distinct drug-specific criteria across document). Highlights from recent updates:
Policy-wide requirement
Diagnostic options clarified in 2024–2025 updates
See policy history for timeline of changes
Explicit prohibition across indications
Documented in policy history
Policy prohibits concurrent use of IL-5 pathway biologics with other specified biologic therapies when used for asthma or related indications. Specifically, Cinqair (reslizumab), Exdensur (depemokimab-ulaa), Fasenra (benralizumab), and Nucala (mepolizumab) will not be used in combination with Dupixent (dupilumab), Tezspire (tezepelumab-ekko), omalizumab, or other listed IL-5 agents when the medications are being used for the treatment of asthma. This prohibition is an explicit coverage exclusion and may result in denial of requests for concurrent therapy.
Any use of Cinqair (reslizumab), Exdensur (depemokimab-ulaa), Fasenra (benralizumab), or Nucala (mepolizumab) for conditions not described within this policy is considered investigational and excluded from coverage. Examples include treatment of other eosinophilic conditions not listed in the drug-specific criteria and use for relief of acute bronchospasm. Coverage is limited to indications and criteria explicitly detailed in the policy and to dosing consistent with FDA prescribing information.
Coverage decisions reflect the populations and subgroups that demonstrated benefit in pivotal trials. For reslizumab (Cinqair), subgroup analyses showed no established efficacy in adolescents (age 12–17) and limited or no meaningful benefit in some subgroups (e.g., certain regional and racial subgroups). When trial evidence does not demonstrate benefit for a subgroup, coverage for that subgroup is not supported unless additional evidence is provided.
The policy disallows concurrent administration of IL-5 inhibitors with each other or with other biologics listed for asthma management. As updated in the 2026 review, Exdensur (depemokimab-ulaa) has been added to the list of agents that must not be used concurrently with reslizumab, benralizumab, mepolizumab, dupilumab, tezepelumab, or omalizumab. Requests for simultaneous therapy with any combination of these agents for asthma will be reviewed and are subject to denial.
Concurrent use of two or more biologic therapies from the agents referenced in this policy for the treatment of asthma is excluded. The policy explicitly states that combination therapy with multiple biologic products listed (including Xolair/omalizumab, Dupixent/dupilumab, Tezspire/tezepelumab, and the IL-5 agents) is not permitted and may trigger denial of coverage for the concurrent regimens.
Hospital-based outpatient infusion or other higher-acuity infusion sites may be considered not medically necessary when the policy’s Site-of-Service (SOS) criteria are not met. The policy specifies that SOS administration is only medically necessary for initial courses or re-initiation after ≥6 months when there is no outpatient infusion center within 50 miles, no contracted home infusion agency available, or when specific clinical risk conditions (e.g., unstable cardiac/pulmonary status, difficult vascular access, prior severe adverse reactions) are present. If these SOS criteria are not satisfied, use of hospital outpatient or similar infusion settings is considered not medically necessary and subject to denial.
Any use of the listed IL-5 agents outside the indications and clinical scenarios specified in this policy is considered investigational or not medically necessary. The policy requires that requests align with the drug-specific coverage criteria (indication, age, documented exacerbation history, eosinophil thresholds, background therapy, and prescriber requirements); uses not meeting those criteria are not covered.
Coverage exclusions include populations not represented or without demonstrated benefit in clinical trials. For example, reslizumab’s pivotal trial subgroup analyses found no established efficacy in adolescents (age 12–17) and limited benefit in certain regional and racial subgroups; safety concerns (anaphylaxis, CPK elevations) further inform noncoverage in populations where benefit–risk is not established. Requests for these populations will be assessed against trial evidence and may be denied.
Combination therapy with multiple biologic products listed in this policy for asthma is prohibited. The policy gives examples of disallowed combinations (e.g., using two or more of Nucala, Fasenra, Cinqair, Exdensur, Dupixent, Xolair, Tezspire) and clarifies that adding Exdensur to the list of non-concurrent agents was an interim 2026 update. Such combination therapy is not supported by the evidence and is subject to denial.
Use of the listed IL-5 agents outside their FDA dosing and administration instructions or without meeting the required clinical criteria (age, exacerbation history, eosinophil thresholds, background controller therapy, and prescriber qualifications) is considered not medically necessary. The policy requires adherence to FDA prescribing information and documents dosing limits for specific indications; deviations from those parameters will not be covered.
See the coding section for HCPCS and billing cross-references relevant to authorization and claim processing. The policy references reviewed HCPCS codes (for example, J2182, J0517, J2786, J2361) and indicates that coding tables are included elsewhere in the document for use during prior authorization and billing review.
Billing and HCPCS/CPT Codes
Prior Authorization, Documentation, and Provider Requirements
Prior authorization required; provider must document clinical criteria
Prior authorization is required for IL‑5 inhibitors; requests are subject to site‑of‑service review and must document that the individual meets the policy’s clinical criteria (age, concurrent controller therapy, specified exacerbation or spirometry findings, and eosinophil thresholds) for the drug and indication.
- PA required for listed IL‑5 agents (e.g., Nucala, Cinqair)
- Clinical criteria to include age, use of maximum tolerated inhaled corticosteroid + LABA, exacerbation or FEV1/FEV1‑FVC findings, and eosinophil/sputum results
Provide trial‑aligned eligibility elements (eosinophils, exacerbations, spirometry)
Prior authorization requests must include trial‑aligned eosinophil test results and other trial‑based eligibility elements (e.g., baseline blood eosinophil counts per indication and history of recurrent exacerbations or spirometry evidence) as specified by the drug criteria.
- Document blood eosinophil count (policy references thresholds used in trials: primary analyses ≥300 cells/µL; policy commonly uses ≥150 cells/mcL for many indications)
- Document history of recurrent exacerbations despite high‑dose/maximum tolerated ICS ± other controllers (or steroid dependence when indicated)
- Provide spirometry or exacerbation details used to mirror trial eligibility (FEV1 <80% predicted or FEV1/FVC <0.80 when listed)
Follow site‑of‑service rules; Alaska exception applies to fully‑insured members
Site‑of‑service review applies to certain agents (including Nucala and Fasenra): initial infusion/injection or re‑initiation after ≥6 months may require hospital‑based outpatient administration when no outpatient infusion center is available within 50 miles or clinical risk factors are present. Alaska fully‑insured members are excepted from SOS criteria per Alaska HB 226.
- SOS medically necessary for initial course or re‑initiation if no outpatient infusion center within 50 miles and no home infusion vendor
- SOS may be required when clinical conditions increase infusion risk (e.g., significant respiratory disease, unstable renal function, difficult vascular access, prior severe adverse reactions)
- Alaska fully‑insured members: SOS medical necessity criteria do not apply per Alaska HB 226
Use updated HCPCS codes (including J2361) on PA and claims
Prior authorization and billing must reflect coding updates; ensure the PA and claims use the current HCPCS codes (including newly added J2361 for depemokimab effective 07/01/26) and the code(s) associated with the specific product being requested.
Document maximum tolerated ICS + LABA before IL‑5 initiation
For asthma indications, document that the patient is on maximum tolerated inhaled corticosteroid therapy plus an inhaled LABA prior to initiating an IL‑5 inhibitor; PA will require this background controller therapy to be shown.
- Record the agent and dose demonstrating maximum tolerated ICS and concurrent LABA use
- If not on these controllers, document intolerance or contraindication
Show ≥90‑day LAMA/LABA trial before Nucala for COPD
For COPD indications, document a trial of a LAMA/LABA combination for ≥90 days (unless not tolerated) prior to initiating Nucala; include dates and response to therapy in the PA submission.
- Provide documentation of LAMA/LABA use for ≥90 days or reason for intolerance
- Include COPD exacerbation history (≥2 treated exacerbations or ≥1 hospitalization in prior 12 months)
Document trials of standard controller therapies before biologic
Demonstrate prior use and failure (or intolerance) of standard guideline‑based controller therapies (e.g., high‑dose/maximum tolerated ICS ± OCS, LABA, leukotriene modifiers) before biologic initiation, consistent with pivotal trial prerequisites.
- Document duration and doses of prior controller therapies and reason for inadequate control
- If OCS dependent, document inability to taper and OCS dose history
Indicate IL‑5 therapy as step‑5 add‑on per GINA 2024
Policy aligns IL‑5 inhibitors with GINA placement: these agents are considered step‑5 add‑on treatments for asthma; include guideline rationale and prior steps tried in the record when requesting PA.
- State that IL‑5 therapy is being considered as add‑on step‑5 therapy per GINA 2024
- Document prior step‑based therapies attempted and outcomes
Provide documentation of background therapy trials and documented failure/intolerance
The policy requires documented trials of appropriate background therapy and evidence of failure or intolerance (e.g., maximum tolerated ICS + other guideline therapy, exacerbation history, or objective measures such as FEV1 or FEV1/FVC) before coverage is approved.
- Provide objective measures used to define failure (exacerbation counts, hospital/ED visits, FEV1 <80% predicted, FEV1/FVC <0.80)
- Document attempts to optimize background therapy and reasons for inadequate control
Submit required clinical documentation with PA (age, meds, eosinophils, exacerbations, spirometry)
Include the following required clinical documentation with the PA: patient age, diagnosis, medication history showing maximum tolerated ICS + LABA, blood or sputum eosinophil values (with dates), and exacerbation history or spirometry results as specified for the indication.
- Office visit notes with diagnosis, medication history, and physical exam
- Laboratory reports showing blood eosinophil counts (date and value) or sputum eosinophils
- Documentation of exacerbations, ED/hospital visits, and spirometry (FEV1, FEV1/FVC)
Attach office notes, labs, imaging, and med history to support PA
Submit office visit notes, labs, medication history, and physical evaluation to demonstrate medical necessity; include prior background therapy details and any prior nasal polyp measures or surgeries when relevant to CRSwNP requests.
- Office visit notes showing diagnosis and clinical course
- Lab results, imaging or endoscopy for CRSwNP (CT, nasal endoscopy) and history of prior nasal polyp surgery or systemic steroid use
Provide chart‑note evidence of clinical response for re‑authorization
For re‑authorization/continuation, submit chart notes documenting clinical response such as decreased oral steroid requirement, reduced exacerbation frequency, fewer ER/hospital visits, symptom improvement, or quality‑of‑life gains compared with baseline.
- Document change from baseline in exacerbations, steroid use, ER/hospital visits
- Include symptom scores or QOL measures showing improvement
Document baseline trial measures (NPS, VAS) and prior background therapy
When baseline trial measures were used to establish eligibility (e.g., nasal polyp score, nasal obstruction VAS, or other validated scales), include the baseline values and the method used (NPS, VAS) and prior background therapy (e.g., ≥8 weeks nasal corticosteroid for CRSwNP) in the PA submission.
- Report baseline NPS and VAS values and how they were measured for CRSwNP
- Include documentation of ≥8 weeks nasal corticosteroid use prior to trial eligibility when relevant
Prescribe within FDA dosing and abide by quantity limits per PI
Follow FDA prescribing information and the policy’s quantity limits: prescribe within the labeled dose and frequency (e.g., Nucala maintenance dose limited to 100 mg every 4 weeks; Fasenra 30 mg dosing limits specified) and adhere to product‑specific dosing restrictions when submitting PA/claims.
- Adhere to product dose limits (Nucala 100 mg q4w; Fasenra 30 mg q4w or Q8wk regimens as indicated; Cinqair IV 3 mg/kg q4w dosing limitation)
- Note that Exdensur has HCPCS J2361 effective 07/01/26 for billing
Match documentation to FDA PI and prescriber/diagnosis requirements
Ensure submitted documentation is consistent with FDA prescribing information and includes any prescriber requirements or diagnostic confirmations specified by indication (e.g., nasal polyposis confirmed by exam/CT for CRSwNP).
- Provide diagnostic confirmation where required (e.g., CRSwNP by exam, CT, or endoscopy)
- Include prescriber specialty when required (allergist/immunologist, pulmonologist, hematologist, or otolaryngologist as specified)
SOS requests risk denial if SOS criteria are not met
Site‑of‑service PA or medical‑benefit SOS requests may be denied if the site‑of‑service criteria are not met (for example, outpatient hospital or other hospital‑based sites are considered not medically necessary when SOS criteria are unmet).
- Requests for hospital outpatient administration without meeting SOS medical necessity criteria risk denial
- Ensure documentation proving lack of local infusion/home infusion options or presence of qualifying clinical risk factors
Do not combine IL‑5 agents with other listed biologics for asthma (prohibited)
Combination therapy with other listed biologics for asthma is prohibited: Nucala (mepolizumab) and other IL‑5 agents must not be used concurrently with Dupixent (dupilumab), Exdensur (depemokimab), Fasenra (benralizumab), Cinqair (reslizumab), Tezspire (tezepelumab), or omalizumab; concurrent use may trigger non‑coverage or denial.
- Do not request coverage for concurrent use of Nucala or other IL‑5 agents with dupilumab, tezepelumab, omalizumab, or other IL‑5 agents for asthma
- State if prior biologic was discontinued and provide dates if switching therapy
Do not combine Nucala with specified therapies for COPD or CRSwNP
Combination therapy prohibitions also apply by indication: Nucala must not be combined with Dupixent (dupilumab) or ensifentrine (Ohtuvayre) for COPD, and must not be used with Dupixent, Tezspire, or omalizumab for CRSwNP; such combination requests can be denied.
- For COPD, do not combine Nucala with Dupixent or Ohtuvayre when seeking coverage
- For CRSwNP, do not request concurrent coverage with Dupixent, Tezspire, or omalizumab
Requests may be denied when patient subgroup lacks trial‑demonstrated benefit or safety concerns exist
Lack of demonstrated efficacy in specific subgroups (e.g., reslizumab showed no meaningful benefit in U.S. subjects, adolescents, and some racial subgroups) or known safety concerns may affect coverage decisions and could lead to denial if the patient’s profile does not match trial populations.
- If requesting reslizumab for adolescents or subgroups without demonstrated benefit, include supporting evidence because the policy notes lack of established efficacy in adolescents
- Be aware safety signals (anaphylaxis, CPK elevations with reslizumab) are noted and may influence decisions
Exdensur (depemokimab) cannot be used concurrently with other listed biologics
Concurrent use of newly added Exdensur (depemokimab‑ulaa) with other listed biologics is prohibited; prior authorization requests for concurrent biologic therapy involving Exdensur will be denied.
- Exdensur was added to the policy’s list of agents not to be used concurrently with other listed biologics
- Do not request concurrent coverage of Exdensur with other IL‑5 or related biologics
No concurrent biologic therapy for same indication—requests risk denial
The policy explicitly prohibits concurrent use of IL‑5 therapies with other biologics (e.g., Xolair/omalizumab, Dupixent/dupilumab, Tezspire/tezepelumab‑ekko); submitting requests for simultaneous biologic therapies may result in denial.
- Ensure only one biologic from the listed agents is requested for the same indication at a time
- If switching biologics, document discontinuation date and reason
Clinical Background and Evidence Summary
Eosinophils are circulating white blood cells that contribute to airway inflammation in eosinophilic asthma. The IL-5 signaling pathway is central to eosinophil growth, activation, and survival; therefore, targeting IL-5 or the IL-5 receptor reduces eosinophil counts and associated airway inflammation. IL-5 pathway inhibitors (e.g., mepolizumab, benralizumab, reslizumab, depemokimab) are used as add-on maintenance therapy to reduce exacerbations in individuals with severe eosinophilic asthma, aligning with trial populations and guideline positioning.
Key Terms and Thresholds
Policy Changes and Effective Dates
Policy effective date updated to 2026-08-01; added Exdensur (depemokimab-ulaa) to the policy and added HCPCS code J2361 (effective 07/01/2026).
Approved interim review adding Fasenra coverage criteria for hypereosinophilic syndrome (HES) and clarifying Nucala CRSwNP diagnosis confirmation by exam/CT; administrative coding and content updates noted.
Updated asthma criteria to allow oral/systemic corticosteroids for eosinophil testing and lowered EGPA eosinophil threshold from 1500 to 1000 cells/µL; expanded Nucala CRSwNP combination prohibition to include Tezspire.
Added site-of-service review for Fasenra and Nucala and added FEV1/FVC <0.80 and worsening on OCS taper as diagnostic options; effective following provider notification on 10/03/2025.
Reverted baseline eosinophil requirement from 300 cells/mcL back to 150 cells/mcL and updated prescriber and inhaled corticosteroid language (maximum tolerated dose); added exceptions to site-of-service and clarified other criteria.
Increased asthma eosinophil threshold from 150 to 300 cells/mcL (effective 01/03/2025) and standardized asthma diagnostic criteria and prescriber requirements for Nucala, Fasenra, and Cinqair.
The policy history documents interim reviews through 2026 that added Exdensur (depemokimab-ulaa) to the policy and updated the list of medications that are not to be used concurrently. These interim updates were effective prior to the policy effective date and are reflected in the concurrent-use prohibitions and coverage criteria now in place.
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