CurrentPremera BluecrossPolicy N/A

IL-5 Inhibitors

Defines medical necessity, site-of-service review rules, age limits, indication-specific coverage criteria, dosing limits, exclusions (investigational uses), documentation requirements, benefit management (pharmacy vs medical), and coding for IL-5 inhibitors Cinqair (reslizumab), Fasenra (benralizumab), and Nucala (mepolizumab). Applies site-of-service medical necessity to medical benefit reviews (except Alaska fully-insured members).

Policy Summary

PayerPremera Bluecross

PolicyIL-5 Inhibitors

Policy CodePolicy N/A

Change TypeMultiple material updates (age, eosinophil thresholds, site-of-service, indications)

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionSubmit office visit notes with diagnosis, history, labs, physical exam, and medication history to support medical necessity.

POLICY UPDATE CHANGES

Updated Fasenra (benralizumab) age requirement from 12 years to 6 years (June 2024 effective).

Updated asthma eosinophil count criteria multiple times: changed 150→300 cells/µL effective Jan 3, 2025, then changed back to 150 cells/µL effective Feb 1, 2025; later allowed >=150 cells/µL and exceptions for corticosteroid-dependent individuals (Feb 1, 2026).

Added Cinqair (reslizumab) coverage criteria as add-on maintenance treatment (effective Aug 7, 2020).

Prohibited combination use across listed biologics (omalizumab, dupilumab, reslizumab, benralizumab, tezepelumab, mepolizumab) for asthma.

Clarified that Site of Service Medical Necessity criteria can apply to injection drugs and added site-of-service review for Fasenra and Nucala with various effective dates in 2025-2026.

Updated Nucala (mepolizumab) criteria to include treatment of certain individuals with COPD and CRSwNP changes (removal of some prior surgical requirements and addition of systemic corticosteroid requirement or prior surgery).

Updated EGPA criteria for Fasenra and Nucala to clarify that presence of ANCA meets the requirement and lowered eosinophil thresholds for EGPA from 1500 to 1000 cells/µL.

Clarified that medications are subject to product FDA dosage and administration prescribing information and non-formulary exception review authorizations may be approved up to 12 months.

3Drugs addressed

MultipleIndications covered

12Typical authorization (months)

AddedSite-of-service reviews

ProhibitedCombination biologics

Coverage Summary

This policy covers the IL-5 inhibitors Cinqair (reslizumab), Fasenra (benralizumab), and Nucala (mepolizumab) for their labeled indications including asthma, and, where specified, COPD, EGPA, HES, and CRSwNP.

Site-of-service rules apply to medical benefit reviews for IV/injectable administration (with a statutory exception for Alaska fully‑insured members); age 13+ triggers SOS review. Managed benefit assignments: Cinqair is medical‑benefit only; Fasenra and Nucala may be managed under pharmacy and medical benefits.

Typical authorization duration is up to 12 months for initial and re‑authorizations when criteria are met; reauthorization requires documentation of clinical response per indication. Combination biologic therapy is prohibited for asthma: these agents are not to be used in combination with each other or with specified biologics (omalizumab, dupilumab, tezepelumab) when used for asthma or nasal polyps.

High‑level dosing and age highlights: Cinqair IV dosing limited to 3 mg/kg every 4 weeks and is for individuals aged ≥18 years; Fasenra approved for asthma in individuals aged ≥6 years with a maintenance dose of 30 mg every 8 weeks; Nucala approved for asthma in individuals aged ≥6 years with maintenance doses typically 100 mg every 4 weeks (other indication‑specific doses apply).

Medical-Necessity Criteria

Site of Service Medical Necessity (general)

Site of Service criteria applies to medical benefit reviews; does NOT apply to Alaska fully-insured members. For age 13+ site of service review applies.

ALL of the following

General SOS application: Site of service medical necessity criteria applies to IV and injectable drugs for medical benefit reviews; SOS review applies for individuals aged 13 years and older. SOS does not apply to Alaska fully-insured members.
Medically necessary sites of service include physician's office, infusion center, home infusion, outpatient hospital IV infusion department, and hospital-based outpatient clinical level of care.
Hospital outpatient initial/re-initiation: Hospital-based outpatient setting is considered medically necessary for the initial 90 days for the initial course of infusion/injection or re-initiation after >= 6 months following discontinuation (does not include standard dosing intervals of 6 months or longer).90 days
Distance/availability exception: Hospital-based outpatient setting is considered medically necessary when no outpatient infusion center is within 50 miles and no contracted home infusion agency will travel, or when the hospital is the only place offering the infusion/injection of this drug.

Cinqair (reslizumab) — asthma (labeled indication)

Cinqair IV may be considered medically necessary for add-on maintenance treatment of severe eosinophilic asthma when ALL criteria are met:

Cinqair asthma criteria

Age: Individual is aged 18 years or older.>= 18 years
Background therapy: Using maximum tolerated doses of an inhaled corticosteroid.
Background therapy 2: Using an inhaled long-acting beta-agonist (LABA).
Asthma severity/diagnostic criteria (meets one)

Fasenra (benralizumab) — asthma and EGPA

Fasenra SC may be considered medically necessary for labeled indications when ALL criteria are met:

Fasenra asthma branch

Age: Individual aged 6 years or older.>= 6 years
Background ICS: Using maximum tolerated doses of an inhaled corticosteroid.
Background LABA: Using an inhaled long-acting beta-agonist (LABA).
Asthma severity/diagnostic criteria (meets one)

Nucala (mepolizumab) — asthma, COPD, EGPA, HES, CRSwNP

Nucala may be considered medically necessary for multiple labeled indications when the following indication-specific criteria are met:

Nucala asthma branch

Age: Individual aged 6 years or older.>= 6 years
Background ICS: Using maximum tolerated doses of an inhaled corticosteroid.
Background LABA: Using an inhaled long-acting beta-agonist (LABA).
Asthma severity/diagnostic criteria (meets one)

Investigational / Not covered uses

All other uses not outlined in this policy are considered investigational.

Investigational uses: All other uses of Cinqair, Fasenra, and Nucala for conditions not outlined in this policy are investigational, including treatment of other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus.

Provider Actions & Requirements

Prior Authorization

Prior authorization required / duration limits

Non-formulary exception reviews and all other reviews for drugs listed in this policy may be approved up to 12 months. Re-authorization requires chart documentation demonstrating positive clinical response per indication (examples: decreased oral steroid requirement, reduced exacerbation frequency/ER visits/hospitalizations, decreased symptom frequency/severity, improved quality-of-life or ability to perform activities of daily living; HES: decreased number/severity of flares; CRSwNP: decrease in nasal polyp size AND improvement in nasal congestion).

Documentation Required

Office visit documentation required

Submit office visit notes that contain the diagnosis, relevant history, laboratory values, physical evaluation, and medication history to support medical necessity.

Diagnosis

Coding

HCPCS/J-codes for IL-5 inhibitorsHCPCS

J0517	Injection, benralizumab (Fasenra) 1 mg
J2182	Injection, mepolizumab (Nucala) 1 mg
J2786	Injection, reslizumab (Cinqair) 1 mg

HCPCS and coding updates referenced in historyHCPCS

J2182	HCPCS code added effective 1/1/17 (document references coding update)
J0517	HCPCS code added effective 1/1/19 (document references coding update)
J2786	HCPCS code for Cinqair (reslizumab) referenced as added (coverage effective Aug 7, 2020 per history)

Background & Evidence

IL‑5 inhibitors act by reducing eosinophil numbers: mepolizumab and reslizumab bind circulating IL‑5 while benralizumab targets the IL‑5 receptor alpha, producing rapid eosinophil depletion. They are used as add‑on therapies to reduce severe asthma exacerbations in eosinophilic phenotypes.

The policy covers the agents for their labeled indications (asthma; and where specified, COPD, EGPA, HES, and CRSwNP) and describes when use is considered medically necessary as add‑on therapy to inhaled corticosteroids/LABA and other background therapy.

DREAM (mepolizumab): reduced exacerbation rates by up to 52% vs placebo depending on dose in refractory eosinophilic asthma.

MENSA (mepolizumab): 100 mg SQ showed a 53% reduction in exacerbations vs placebo at 32 weeks.

SYNAPSE (Nucala, CRSwNP): significant improvement in bilateral nasal polyp score at Week 52, improved nasal obstruction VAS, and a 57% reduction in proportion requiring surgery (HR 0.43).

CALIMA and SIROCCO (benralizumab): significant placebo‑adjusted reductions in exacerbation rates in high‑eosinophil subgroups (>300 cells/µL) with FEV1 improvements (~0.10–0.16 L); subgroup analyses show benefit at ≥150 cells/µL.

MATINEE and METREX (Nucala, COPD): statistically significant reduction in annualized moderate/severe exacerbation rate when added to triple therapy.

Mepolizumab steroid‑sparing trials (e.g., ZONDA/MATINEE context in policy): demonstrated reductions in oral corticosteroid requirements.

Reslizumab pivotal trials (3082/3083): ~50% reduction in exacerbation rate (rate ratio 0.46, 95% CI 0.37–0.58, p<0.0001) and FEV1 improvement of about +110 mL.

Definitions

Revision History

08/07/2020added

Added Cinqair (reslizumab) coverage criteria as add-on maintenance treatment; coverage effective August 7, 2020.

10/01/2020revised

Prohibited combination use of IL‑5 inhibitors with Dupixent (dupilumab) and Xolair (omalizumab) for asthma (policy update disallowing combination therapy).

06/01/2024revised

Updated Fasenra (benralizumab) age requirement from 12 years to 6 years (approved May 24, 2024; effective per May/June 2024 history).

Policy Summary

PayerPremera Bluecross

PolicyIL-5 Inhibitors

Policy CodePolicy N/A

Change TypeMultiple material updates (age, eosinophil thresholds, site-of-service, indications)

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionSubmit office visit notes with diagnosis, history, labs, physical exam, and medication history to support medical necessity.

On This Page

Clinical risk conditions: Hospital-based outpatient setting is considered medically necessary when the individual has a clinical condition increasing risk of complications for infusion/injection, including any of: known cardiac condition (e.g., symptomatic arrhythmia) or pulmonary condition (e.g., significant respiratory disease, serious obstructive airway disease, %FVC <= 40%), unstable renal function reducing ability to respond to fluids, difficult/unstable vascular access, acute mental status/cognitive conditions impacting safety, or known history of severe adverse drug reactions/anaphylaxis to related/similar drug.%FVC <= 40%

CRS exception: Hospital-based outpatient setting considered medically necessary for cytokine release syndrome (CRS) when ALL CRS severity criteria are met: temperature >= 38°C; hypotension requiring >=1 vasopressors; hypoxia requiring oxygen via high-flow nasal cannula, face mask, non-rebreather, Venturi mask OR positive pressure (CPAP, BiPAP, intubation, mechanical ventilation). AND the individual will be admitted to an inpatient setting as soon as criteria are met.Temp >= 38°C; vasopressors; advanced oxygen/ventilatory support

CRS grade 3 or 4

Not medically necessary: Hospital-based/outpatient/home/physician office sites are NOT medically necessary when the site-of-service criteria in this policy are not met.

Exacerbations >=2: 2 or more asthma exacerbations in the previous 12 months requiring use of oral or systemic corticosteroids.2 in 12 months

Exacerbation with visit: 1 or more asthma exacerbations requiring hospitalization, emergency department visit, or urgent care visit in the previous 12 months.1 in 12 months

FEV1: Forced expiratory volume in 1 second (FEV1) less than 80% predicted.FEV1 < 80% predicted

FEV1/FVC: FEV1/forced vital capacity (FVC) less than 0.80.FEV1/FVC < 0.80

OCS taper worsening: Asthma that worsens upon tapering of oral corticosteroid therapy.

Eosinophil criteria

Blood eos >=150: Blood eosinophil count >= 150 cells/mcL.>= 150 cells/mcL
Sputum eos >=3%: Sputum eosinophil count >= 3%.>= 3%
OCS dependent unable to test: Oral or systemic corticosteroid dependent asthma and unable to discontinue oral/systemic corticosteroids for blood or sputum eosinophil tests.

Combination prohibition: Will not be used in combination with Dupixent (dupilumab), Fasenra (benralizumab), Nucala (mepolizumab), Tezspire (tezepelumab-ekko), or Xolair (omalizumab) for asthma.

Prescriber requirement: Prescribed by or in consultation with an allergist/immunologist or pulmonologist.

Dose limited to 3 mg/kg every 4 weeks.3 mg/kg q4w

Exacerbations >=2: 2 or more asthma exacerbations in the previous 12 months requiring oral/systemic corticosteroids.2 in 12 months

Exacerbation with visit: 1 or more asthma exacerbations requiring hospitalization, ED visit, or urgent care in previous 12 months.1 in 12 months

FEV1: Forced expiratory volume in 1 second (FEV1) < 80% predicted.FEV1 < 80% predicted

FEV1/FVC < 0.80.FEV1/FVC < 0.80

OCS taper worsening: Asthma that worsens upon tapering of oral corticosteroid therapy.

Eosinophil criteria

Blood eos >=150: Blood eosinophil count >= 150 cells/mcL.>= 150 cells/mcL
Sputum eos >=3%: Sputum eosinophil count >= 3%.>= 3%
OCS dependent unable to test: Oral/systemic corticosteroid-dependent asthma and unable to discontinue for eosinophil testing.

Combination prohibition: Will not be used in combination with Cinqair, Dupixent, Nucala, Tezspire, or Xolair for asthma.

Prescriber requirement: Prescribed by or in consultation with an allergist/immunologist or pulmonologist.

Dose limit: Maintenance dose limited to 30 mg every 8 weeks.30 mg q8w

Fasenra EGPA branch

Age: Individual aged 18 years or older.>= 18 years
Asthma history: History or presence of asthma.
OCS stable dose: Taking stable dose of prednisone or prednisolone between 7.5 mg and 50 mg with or without additional immunosuppressive therapy.7.5-50 mg
EGPA eosinophil threshold: Blood eosinophil level >= 10% OR absolute eosinophil count >= 1000 cells/microL.>= 10% OR >= 1000 cells/microL
Vasculitis diagnostic criteria
- Polyangiitis documented by biopsy showing necrotizing vasculitis; biopsy showing necrotizing or crescentic glomerulonephritis; alveolar hemorrhage; palpable purpura; or myocardial infarction due to proven coronary arteritis.
- Vasculitis supported by hematuria with red cell casts or >10% dysmorphic erythrocytes; hematuria with 2+ proteinuria; or leukocytoclastic vasculitis/eosinophilic infiltration of arterial wall on biopsy.
- Neurologic involvement: Mononeuritis or mononeuritis multiplex.
- ANCA: Anti-neutrophil cytoplasmic antibody (ANCA).
Prescriber requirement EGPA: Prescribed by or in consultation with an allergist/immunologist, pulmonologist, or rheumatologist.

Exacerbations >=2: 2 or more asthma exacerbations in the previous 12 months requiring oral/systemic corticosteroids.2 in 12 months

Exacerbation with visit: 1 or more asthma exacerbations requiring hospitalization, ED, or urgent care visit in previous 12 months.1 in 12 months

FEV1 < 80% predicted.FEV1 < 80% predicted

FEV1/FVC < 0.80.FEV1/FVC < 0.80

OCS taper worsening: Asthma that worsens upon tapering of oral corticosteroid therapy.

Eosinophil criteria

Blood eos >=150: Blood eosinophil count >= 150 cells/mcL.>= 150 cells/mcL
Sputum eos >=3%: Sputum eosinophil count >= 3%.>= 3%
OCS dependent unable to test: Oral/systemic corticosteroid-dependent asthma and unable to discontinue for eosinophil testing.

Combination prohibition: Will not be used in combination with Cinqair, Dupixent, Fasenra, Tezspire, or Xolair for asthma.

Prescriber requirement: Prescribed by or in consultation with an allergist/immunologist or pulmonologist.

Dose limit asthma: Dose limited to 100 mg every 4 weeks (maintenance dose for asthma).100 mg q4w

Nucala COPD branch

Age: Individual aged 18 years or older.>= 18 years
Diagnosis: Diagnosed with inadequately controlled COPD.
Blood eos >=150: Blood eosinophil level >= 150 cells/mcL within the previous 12 months.>= 150 cells/mcL
LAMA/LABA trial: Tried a combination LAMA/LABA product for >= 90 days unless not tolerated and continues to have documented symptom control issues.>= 90 days
COPD exacerbation history
- COPD exacerbations >=2: 2 or more COPD exacerbations requiring treatment with systemic corticosteroid and/or antibiotic in previous 12 months.2 in 12 months
- COPD hospitalization: 1 or more COPD exacerbations requiring hospitalization in previous 12 months.1 in 12 months
Combination prohibition COPD: Will not be used in combination with Dupixent or Ohtuvayre when used for COPD.
Prescriber requirement COPD: Prescribed by or in consultation with an allergist/immunologist or pulmonologist.
Dose limit COPD: Maintenance dose prescribed is 100 mg every 4 weeks.100 mg q4w

Nucala EGPA branch

Age: Individual aged 18 years or older.>= 18 years
Asthma history EGPA: History or presence of asthma.
OCS stable dose EGPA: Taking stable dose of prednisone or prednisolone between 7.5 mg and 50 mg with or without additional immunosuppressive therapy.7.5-50 mg
EGPA eos threshold: Has a blood eosinophil level >= 10% OR absolute eosinophil count >= 1000 cells/microL.>=10% OR >=1000 cells/microL
EGPA diagnostic criteria: Presence of at least one diagnostic criterion: biopsy documented polyangiitis/necrotizing vasculitis/crescentic GN/alveolar hemorrhage/palpable purpura/myocardial infarction due to coronary arteritis; OR vasculitis supported by hematuria with red cell casts or >10% dysmorphic erythrocytes or hematuria with 2+ proteinuria or leukocytoclastic vasculitis/eosinophilic arterial wall infiltration on biopsy; OR mononeuritis/mononeuritis multiplex; OR ANCA.
Prescriber EGPA: Prescribed by or in consultation with an allergist/immunologist, pulmonologist, or rheumatologist.
Dose limit EGPA: Dose limited to 300 mg every 4 weeks (for EGPA indication).300 mg q4w

Nucala HES branch

Age HES: Individual aged 12 years or older.>= 12 years
Secondary cause excluded: Documented history of at least 6 months without an identifiable non-hematologic secondary cause (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy).6 months
FIP1L1-PDGFRA negative: Without FIP1L1-PDGFRA kinase-positive HES as confirmed by FISH or RT-PCR genetic testing.
Blood eos >=1000: Blood eosinophil level >= 1,000 cells/microL.>= 1000 cells/microL
HES flares: 2 or more HES flares in past 12 months resulting in worsening clinical symptoms or blood eosinophil counts requiring escalation in therapy.2 in 12 months
Background therapy HES: Prior to initiating Nucala, individual is receiving background HES therapy for at least 4 weeks.>= 4 weeks
Prescriber HES: Prescribed by or in consultation with a hematologist.

Nucala CRSwNP branch

Age CRSwNP: Individual aged 18 years or older.>= 18 years
Diagnosis CRSwNP: Diagnosed with inadequately controlled bilateral CRSwNP.
Symptoms (n_of 2)
- Facial pressure or pain.
- Nasal congestion: Moderate to severe nasal congestion or obstruction.
- Loss of smell: Significant loss of smell.
INCS trial: Had an adequate trial and failure of an intranasal corticosteroid as monotherapy.
Concomitant INCS: Nucala prescribed in combination with an intranasal corticosteroid.
Prior systemic steroid or surgery: Has one of: prior use of systemic corticosteroids to treat nasal polyps in the last 2 years OR previous surgical removal of bilateral nasal polyps.
Dose CRSwNP: Prescribed dose 100 mg subcutaneously once every 4 weeks.100 mg q4w
Combination prohibition CRSwNP: Will not be used in combination with Dupixent, Tezspire, or Xolair for CRSwNP.
Prescriber CRSwNP: Prescribed by or in consultation with an allergist/immunologist or pulmonologist.

Laboratory values (include eosinophil counts within 12 months)

Physical exam / evaluation

Billing Rule

Site-of-service review for administration

For individuals age 13 and older, the site-of-service for medical necessity will be reviewed. Hospital-based outpatient site is medically necessary only in specified circumstances (initial course or re-initiation after ≥6 months, no outpatient infusion center within 50 miles/no home infusion available, clinical conditions increasing risk of complications, or CRS meeting specified severity criteria). The Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members (see exception).

Documentation Required

Specialist prescribing requirement

Prescriptions must be by or in consultation with specified specialists depending on indication.

Asthma / COPD / CRSwNP: allergist/immunologist or pulmonologist
HES: hematologist
EGPA: rheumatologist (in consultation) and allergist/immunologist or pulmonologist as specified

Prior Authorization

Site of Service and prior authorization requirements

Site-of-Service Medical Necessity criteria and site-of-service review apply to the drugs listed and reference specific HCPCS/J-codes. Affected J-codes include J2786 (reslizumab), J2182 (mepolizumab), and J0517 (benralizumab). History entries cite effective dates when site-of-service reviews and related updates were added (see history for dates).

Affected J-codes: J2786, J2182, J0517
Refer to history entries for effective dates of site-of-service reviews and related updates

Documentation Required

Eosinophil test timing and corticosteroid exception

Eosinophil blood counts must be documented within the last 12 months for coverage criteria. An exception is allowed when the individual is oral or systemic corticosteroid-dependent and is unable to discontinue corticosteroids for eosinophil testing.

Billing Rule

Quantity limits

Quantity limits have been added and align with the product prescribing information for each agent (Cinqair, Nucala, Fasenra).

Quantity limits per FDA prescribing information for Cinqair (reslizumab), Nucala (mepolizumab), and Fasenra (benralizumab)

Prior Authorization

Combination therapy restriction

Concurrent use of two or more of the listed biologics for asthma is prohibited. Specifically, the policy disallows combination therapy with Xolair (omalizumab), Dupixent (dupilumab), Cinqair (reslizumab), Fasenra (benralizumab), Tezspire (tezepelumab), and Nucala (mepolizumab) when used for asthma.

Denial Risk

Alaska fully-insured members site-of-service exception

The Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members pursuant to Alaska HB 226 (effective Jan 3, 2025). Failure to recognize this exception when evaluating site-of-service requirements may affect coverage decisions for Alaska fully-insured members.

Safety signals for reslizumab: identified risks include anaphylaxis (several treatment‑related cases) and CPK elevations/muscle toxicity (~0.8% vs 0.4% placebo); most common AE included oropharyngeal pain.

Overall safety summaries for mepolizumab and benralizumab show generally acceptable tolerability in trials with noted AE profiles and ongoing long‑term safety monitoring.

Guideline alignment: IL‑5 inhibitors are recommended as add‑on treatment in Step 5 of GINA 2024.

01/03/2025revised

Material change (is_material true): Increased asthma blood eosinophil threshold from >=150 cells/µL to >=300 cells/µL for Nucala, Fasenra, and Cinqair (effective January 3, 2025) — provider notification period applied.

02/01/2025revised

Material change (is_material true): Reverted asthma blood eosinophil threshold from >=300 cells/µL back to >=150 cells/µL for Nucala, Fasenra, and Cinqair (effective February 1, 2025); clarified Site of Service does not apply to Alaska fully‑insured members per Alaska HB 226 and added prescriber requirements and other administrative clarifications.

04/01/2025revised

Updated asthma coverage criteria to remove requirement for documentation of eosinophilic phenotype within prior 12 months and changed 'maximum doses' to 'maximum tolerated doses' of inhaled corticosteroid.

07/01/2025revised

Added FEV1/FVC < 0.80 and 'asthma that worsens upon tapering of oral corticosteroid therapy' to asthma diagnostic options; announced future site-of-service additions (provider notification timeline).

10/03/2025added

Site-of-service review added for Fasenra and Nucala (effective October 3, 2025 after provider notification); clarified Site of Service criteria can apply to injection drugs.

11/01/2025revised

Updated Nucala nasal polyps criteria (removed prior requirement of at least one surgery in last 10 years; required prior systemic corticosteroid use in last 2 years or prior surgical removal); clarified EGPA criteria that presence of ANCA meets the requirement.

02/01/2026revisedLatest

Material change (is_material true): Updated asthma criteria to allow oral/systemic corticosteroids for exacerbations, allow blood eosinophil count >=150 cells/mcL, and permit exceptions for individuals unable to discontinue corticosteroids for eosinophil testing; lowered EGPA eosinophil threshold from >=1500 to >=1000 cells/µL and clarified site-of-service applicability to injection drugs.