CurrentBlue Cross Blue Shield - North CarolinaPolicy N/A

Complement C5 Inhibitors 'Notification'

Defines medical necessity notification/authorization criteria, site-of-care rules, duration, continuation requirements, combination-agent exclusions, HCPCS codes and maximum units for restricted complement C5 inhibitor products used for PNH, aHUS, gMG, and NMOSD for Blue Cross NC.

Policy Summary

PayerBlue Cross Blue Shield - North Carolina

PolicyComplement C5 Inhibitors 'Notification'

Policy CodePolicy N/A

Change TypeConsolidation & criteria standardization

Effective DateJan 1, 2026

Next Review Date

Key ActionSubmit medical record documentation confirming diagnosis, diagnostic test results, prior therapy history or intolerances, specialist prescriber/consultation, and evidence of signs/symptoms as specified.

SourceLink

POLICY UPDATE CHANGES

Consolidated individual product policies into a single 'Complement C5 Inhibitors' medical policy effective 1/1/2026.

For PNH applied consistent diagnostic requirements of flow cytometry, LDH level, and PNH signs/symptoms.

For eculizumab products for PNH, added requirement for trial of iptacopan (Fabhalta) in addition to pegcetacoplan (Empaveli) and ravulizumab (Ultomiris).

For aHUS added requirement for differential diagnosis demonstrating complement-mediated HUS and ADAMTS13 activity >5%.

For NMOSD added requirement of at least one attack/relapse in past 12 months and rule out alternative diagnoses.

Added requirement to try preferred eculizumab biosimilar eculizumab-aagh (Epysqli) before non-preferred eculizumab products, with exception pathways including MedWatch submission for serious AEs.

Added requirement that prescriber be a specialist or have consulted a specialist.

Restricted Products Listed

4Indications Covered

180Initial Approval Duration (days)

365Continuation Approval Duration (days)

Coverage Summary

This policy is the consolidated Corporate Medical Policy titled Complement C5 Inhibitors effective January 1, 2026 (notification given 11/1/2025) and replaces separate product policies for crovalimab, eculizumab (and biosimilars), and ravulizumab. It applies to the restricted products crovalimab-akkz (PiaSky), eculizumab (Soliris) and eculizumab biosimilars (eculizumab-aeeb [Bkemv], eculizumab-aagh [Epysqli]), and ravulizumab-cwvz (Ultomiris) for the indications of PNH, aHUS, gMG, and NMOSD and defines standardized diagnostic, prior-therapy, site-of-care, and approval/continuation criteria. Coverage stance: covered_with_criteria per the policy framework.

Policy-level stats and thresholds

Restricted Products Listed5 (crovalimab, eculizumab, eculizumab-aeeb, eculizumab-aagh, ravulizumab)

Indications Covered4 (PNH, aHUS, gMG, NMOSD)

Initial Approval Duration180 days (6 months)

Continuation Approval Duration365 days (1 year)

LDH baseline threshold>= 1.5 x ULN (prior to starting therapy)

ADAMTS13 activity threshold> 5%

MG-ADL thresholdMG-ADL total score >= 6

Initial Criteria for Approval

Initial Criteria for Approval - General structure

The restricted product(s) may be considered medically necessary when the following criteria are met:

Diagnosis confirmation: Flow cytometry with at least 2 independent reagents on at least 2 cell lineages demonstrating GPI-AP deficiency [medical record documentation required].

LDH threshold: Baseline LDH >= 1.5 times the upper limit of normal prior to starting complement inhibitor therapy [medical record documentation required].LDH >= 1.5 x ULN

PNH signs/symptoms: At least one PNH-related sign or symptom in the past 3 months prior to starting therapy (e.g., fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin < 10 g/dL], history of major adverse vascular event including thrombosis, dysphagia, erectile dysfunction, or history of RBC transfusion due to PNH) [medical record documentation required].

Continuation Criteria for Approval

Conditions required to continue therapy after initial approval

Continuation overall: Requests for continuation must meet the following general criteria (patient approved through initial criteria or would have met initial criteria at therapy start) [medical record documentation required].

Evidence of clinical benefit by diagnosis

PNH continuation: For PNH: patient has had stabilization or improvement of symptoms from baseline while using the requested agent (e.g., reduced RBC transfusion requirements, stabilization/improvement of hemoglobin, reduction of LDH, no thromboembolism events persisting) [medical record documentation required].
aHUS continuation: For aHUS: request is for an eculizumab product or ravulizumab AND patient has demonstrated positive clinical response measured by hematological parameters or TMA response (e.g., improved platelet count, reduction of LDH, stabilization/improvement of renal function) [medical record documentation required].

Site of Care Medical Necessity Criteria

Determines acceptable administration setting for injections/infusions

Site of Care options

Inpatient: Injection/infusion may be given in inpatient setting if medical necessity criteria are met AND inpatient admission is NOT for the sole purpose of administering the injection/infusion.
Outpatient hospital: Injection/infusion may be given in outpatient hospital setting if medical necessity criteria are met AND ONE of: history of severe adverse event (anaphylaxis, seizure, thromboembolism, myocardial infarction, renal failure); OR conditions increasing risk for severe adverse event (unstable renal function, cardiopulmonary conditions, unstable vascular access); OR history of mild adverse events not controlled with pre-medication; OR inability to physically/cognitively adhere to regimen; OR new to therapy (initial or <3 months since initial); OR re-initiation of therapy per defined gaps; OR requirement of change in formulation.

Coding (HCPCS / Product mapping)

HCPCS / Product mappingHCPCS

J1307	crovalimab-akkz (PiaSky)
J1299	eculizumab (Soliris)
Q5152	eculizumab-aeeb (Bkemv)
Q5151	eculizumab-aagh (Epysqli)
J1303	ravulizumab-cwvz (Ultomiris)

The policy includes specific maximum units (quantity limits) per product and indication which are provided in the policy tables and are enforced as part of approval (see product-specific "Maximum Units" tables in the policy). Exact numeric tables and per-indication maximums live in the policy (do not duplicate numeric tables here) and will be applied when assessing requested quantities for initial and continuation approvals.

Provider Actions

Prior Authorization

Medical necessity documentation required

Submit medical record documentation confirming the patient’s diagnosis and required diagnostic test results (e.g., flow cytometry demonstrating GPI-AP deficiency, baseline LDH), ADAMTS13 and relevant antibody tests where applicable, documentation of prior therapies or documented intolerances, record of PNH-related signs/symptoms, and evidence that the prescriber is a specialist or consulted a specialist.

Prior Authorization

MedWatch submission for serious adverse event

When requesting a non-preferred eculizumab product because of a documented serious adverse event to the preferred biosimilar eculizumab-aagh (Epysqli), the prescriber must complete and submit an FDA MedWatch Adverse Event Reporting Form as part of the request.

Background & Definitions

Background: The policy consolidates prior separate medical policies for crovalimab (PiaSky), eculizumab (Soliris) and its biosimilars, and ravulizumab (Ultomiris) into a single corporate "Complement C5 Inhibitors" medical policy to standardize diagnostic confirmation, prior-therapy requirements, site-of-care criteria, and continuation rules. Primary reference sources for policy content and diagnostic guidance include FDA package inserts and key peer-reviewed studies and guideline publications cited in the policy.

Definitions (New to therapy; Re-initiation)

New to therapy - definitionInitial injection or infusion OR less than 3 months since initial injection or infusion.

Re-initiation of therapy - definitionFirst injection/infusion after 6 months of no injections for drugs with dosing interval <6 months, OR first after at least 1-month gap outside approved interval for drugs with every 6 months dosing.

Primary references: FDA package inserts for the listed products; selected key peer-reviewed studies and guidelines cited in the policy include Borowitz et al. 2010 (flow cytometry guidance for PNH), Brodsky et al. 2008 (eculizumab in PNH), Howard et al. 2017 (eculizumab in gMG), Kulasekararaj et al. 2019 and Lee et al. 2019 (ravulizumab vs eculizumab in PNH), Legendre et al. 2013 (eculizumab in aHUS), Pittock et al. 2019 (eculizumab in NMOSD), plus international consensus guidance documents referenced in the policy.

Revision History

11/1/2025policy_notification

Policy notification given for consolidated Corporate Medical Policy effective 1/1/2026.

01/01/2026consolidation_effectiveLatest

Consolidated individual product policies (Crovalimab, Eculizumab and biosimilars, Ravulizumab) into single 'Complement C5 Inhibitors' medical policy effective 1/1/2026.

01/2026material_change_standardization

Applied consistent PNH diagnostic requirements across products: flow cytometry, baseline LDH ≥ 1.5 x ULN, and documentation of PNH signs/symptoms.

Policy Summary

PayerBlue Cross Blue Shield - North Carolina

PolicyComplement C5 Inhibitors 'Notification'

Policy CodePolicy N/A

Change TypeConsolidation & criteria standardization

Effective DateJan 1, 2026

Next Review Date

SourceLink

On This Page

Initial Criteria for Approval - Crovalimab pediatric/adult prior therapy requirements

Agent-specific prior therapy or intolerance requirements for crovalimab and adults

Crovalimab pediatric/adult prior therapy rules

For patients 13 to <18 years: Patient is 13 to less than 18 years of age AND (has tried and had an inadequate response to ravulizumab (Ultomiris) OR has an intolerance, FDA labeled contraindication, or hypersensitivity to ravulizumab (Ultomiris)) [medical record documentation required].
For patients 18 years or older: Patient is 18 years of age or older AND (has tried and had an inadequate response to TWO of: iptacopan (Fabhalta), pegcetacoplan (Empaveli), ravulizumab (Ultomiris) OR has an intolerance, FDA labeled contraindication, or hypersensitivity to ALL of: iptacopan, pegcetacoplan, AND ravulizumab) [medical record documentation required].

Initial Criteria for Approval - Eculizumab products (PNH, aHUS, gMG, NMOSD) detailed blocks

Eculizumab-specific initial approval criteria across indications

PNH - eculizumab-specific: If request is for an eculizumab product AND ONE of: patient has tried and had inadequate response to ALL of iptacopan (Fabhalta), pegcetacoplan (Empaveli), AND ravulizumab (Ultomiris); OR patient has intolerance/contraindication/hypersensitivity to ALL of those agents [medical record documentation required].

Either prior failure to all listed agents or intolerance

aHUS - age and diagnostic exclusions

Age by agent: If request is for an eculizumab product, patient is 2 months of age or older; OR if request is for ravulizumab, patient is 1 month of age or older.
Differential diagnosis: A differential diagnosis of complement-mediated HUS has been demonstrated (screening for STEC-HUS, pneumococcal causes, ADAMTS13 <10% to exclude TTP, defective cobalamin metabolism) [medical record documentation required].
ADAMTS13 activity: Patient has ADAMTS13 activity level greater than 5% [medical record documentation required].ADAMTS13 > 5%
Exclude STEC-HUS: Patient does NOT have Shiga toxin E.coli related hemolytic uremic syndrome (STEC-HUS) [medical record documentation required].
Agent-specific allowance: One of: request is for ravulizumab; OR request is for an eculizumab product AND patient has tried and had inadequate response to ravulizumab OR cannot tolerate ravulizumab.

gMG - eligibility and requirements

Diagnosis and age: Patient has diagnosis of generalized myasthenia gravis (gMG) AND request is for an eculizumab product or ravulizumab; patient is 18 years or older OR if request for eculizumab product patient is 6 years or older [medical record documentation required].
Serology: Positive serological test for anti-acetylcholine receptor (AChR) antibodies [medical record documentation required].
Disease severity: MGFA clinical classification class II to IVb or comparable standardized rating scale [medical record documentation required].
ADL impairment: Impaired activities of daily living defined by MG-ADL total score of 6 or higher or comparable standardized scale [medical record documentation required].MG-ADL >= 6

NMOSD - eligibility and requirements

Core clinical characteristic: Diagnosis confirmed by presence of at least ONE core clinical characteristic (optic neuritis; acute myelitis; area postrema syndrome; acute brainstem syndrome; symptomatic narcolepsy/diencephalic syndrome with typical MRI lesions; symptomatic cerebral syndrome with NMOSD-typical brain lesions) [medical record documentation required].
Recent attack: Patient has had at least ONE attack or relapse in the last 12 months prior to treatment with an immunotherapy or complement inhibitor for NMOSD [medical record documentation required].
Exclude alternative diagnoses: Patient does NOT have any other alternative diagnoses that explain current symptoms (e.g., multiple sclerosis) [medical record documentation required].
Agent-specific prior therapy for eculizumab: One of: request is for ravulizumab; OR request is for an eculizumab product AND patient has tried and had inadequate response to ALL of inebilizumab, ravulizumab, AND satralizumab OR intolerance/contraindication/hypersensitivity to ALL of those agents [medical record documentation required].

Non-preferred eculizumab product (Soliris or other non-preferred biosimilar) requirements: If request is for Soliris (eculizumab) or a non-preferred eculizumab biosimilar (e.g., eculizumab-aeeb [Bkemv]), ONE of: patient has tried and had inadequate response to preferred biosimilar eculizumab-aagh (Epysqli); OR intolerance/contraindication/hypersensitivity to Epysqli not expected to occur with requested product; OR documented serious adverse event to Epysqli not anticipated with requested product AND prescriber completed and submitted FDA MedWatch Adverse Event Reporting Form [medical record documentation required].

Common requirements: Patient will NOT be using the requested agent in combination with another agent used to treat the requested indication (Combination Agents table) AND prescriber is a specialist or has consulted a specialist AND requested quantity does NOT exceed maximum units allowed for duration of approval AND for inpatient/outpatient hospital administration Site of Care Criteria applies.

gMG continuation: For gMG: request is for an eculizumab product or ravulizumab AND patient has demonstrated positive clinical response (e.g., improved MG-ADL, QMG, or comparable scale) [medical record documentation required].MG-ADL >= 6

NMOSD continuation: For NMOSD: request is for an eculizumab product or ravulizumab AND patient has had a positive clinical response while using the requested agent, demonstrated by disease stabilization or improvement (e.g., reduced relapses, improvement/stabilization of vision or paralysis) [medical record documentation required].

Non-preferred eculizumab continuation: If request is for Soliris or a non-preferred eculizumab biosimilar, ONE of: tried and had inadequate response to preferred biosimilar Epysqli; OR intolerance/contraindication/hypersensitivity to Epysqli not expected with requested product; OR documented serious adverse event to Epysqli not anticipated with requested product AND prescriber submitted FDA MedWatch form [medical record documentation required].

Common continuation requirements: Patient will NOT be using the requested agent in combination with another agent used to treat the indication; prescriber is a specialist or consulted one; requested quantity does NOT exceed maximum units allowed for duration of approval; Site of Care Criteria applies for inpatient/outpatient hospital infusion or injection requests [medical record documentation required].

Home/office setting:

If Site of Care criteria above are not met, injection/infusion will be administered in a home-based infusion or physician office setting with or without supervision by a certified healthcare professional.

Billing Rule

Quantity limits / maximum units

Requested quantity must not exceed the product- and indication-specific maximum units allowed for the duration of approval; see policy tables for exact limits and examples below.

J1307 (crovalimab-akkz, PiaSky)
J1299 (eculizumab, Soliris)
Q5152 (eculizumab-aeeb, Bkemv)
Q5151 (eculizumab-aagh, Epysqli)
J1303 (ravulizumab-cwvz, Ultomiris)
Examples: crovalimab initial 898 / continuation 1,326; eculizumab (PNH) initial 6,600 / continuation 11,700; ravulizumab initial 1,590 / continuation 2,310

Documentation Required

Site of care justification

For outpatient hospital administration, include documentation that the request meets Site of Care Medical Necessity Criteria (one or more of: history of severe adverse event, conditions increasing risk for severe adverse event, uncontrolled mild adverse events despite pre-medication, inability to adhere to regimen, new to therapy or re-initiation, or requirement for a change in product formulation).

Denial Risk

Combination therapy exclusion

Requests will be denied if the patient will use the requested agent in combination with another agent used to treat the same indication; refer to the policy’s Combination Agents table for prohibited combinations.

01/2026material_change_prior_therapy

For eculizumab products in PNH, added requirement to trial iptacopan (Fabhalta) in addition to pegcetacoplan (Empaveli) and ravulizumab (Ultomiris) prior to approval.

01/2026material_change_diagnostic

For aHUS added requirement for differential diagnosis demonstrating complement-mediated HUS (STEC screening, pneumococcal cultures, ADAMTS13, cobalamin metabolism) and ADAMTS13 activity > 5%.

01/2026material_change_NMOSD

For NMOSD added requirement of at least one attack/relapse in the prior 12 months and exclusion of alternative diagnoses.

01/2026material_change_biosimilar_policy

Added preferred eculizumab biosimilar (eculizumab-aagh, Epysqli) trial requirement before non-preferred eculizumab products (e.g., Soliris, Bkemv) with exception pathways including required FDA MedWatch submission for serious adverse events.

01/2026material_change_prescriber_requirement

Added requirement that prescriber be a specialist or have consulted a specialist for initial and continuation approvals.

Medication exacerbation assessment: Prescriber has assessed and discontinued medications known to exacerbate MG OR provided clinical rationale that discontinuation is not clinically appropriate [medical record documentation required].

Prior/concomitant therapy requirements: One of: tried and inadequate response to at least ONE conventional agent for >=12 months; OR intolerance/contraindication to ALL conventional agents; OR required chronic IVIG at least every 3 months over 12 months without control; OR required chronic plasmapheresis/plasma exchange at least every 3 months over 12 months without control [medical record documentation required].

Eculizumab adult-only escalation: If request is for an eculizumab product and patient is 18 years or older, one of: request is for ravulizumab OR patient has tried and had inadequate response to ALL of ravulizumab, rozanolixizumab, AND efgartigimod; OR intolerance/contraindication/hypersensitivity to ALL of those agents [medical record documentation required].