ModifiedPremera BluecrossPolicy 5.01.571

C3 and C5 Complement Inhibitors

Defines medical necessity and site-of-service review criteria for multiple complement inhibitors across medical and pharmacy benefits for indications including PNH, aHUS, gMG, NMOSD, C3G/IC-MPGN, IgAN, GA, CD55-deficient PLE, and ANCA-associated vasculitis; includes documentation, coding, benefit management, investigational uses, approval lengths, and vaccination requirements.

Policy Summary

PayerPremera Bluecross

PolicyC3 and C5 Complement Inhibitors

Policy CodePolicy 5.01.571

Change TypeMultiple additions and revisions to drug-specific and site-of-service criteria

Effective DateJun 1, 2026

Next Review Date

Key ActionProviders must submit medical records demonstrating criteria are met and include vaccination and medication history; site-of-service review required for ages ≥13 (except Alaska fully-insured members).

SourceLink

POLICY UPDATE CHANGES

Policy last revised May 12, 2026 and replaces prior version; effective date Jun 1, 2026.

Added coverage for Syfovre (pegcetacoplan) for GA secondary to AMD.

Added coverage for Veopoz (pozelimab-bbfg) for CD55-deficient protein-losing enteropathy (CHAPLE disease).

Added coverage for Izervay (avacincaptad pegol) for GA secondary to AMD.

Added coverage for Zilbrysq (zilucoplan) for generalized myasthenia gravis (gMG) in anti-AChR antibody positive adults.

Updated Ultomiris to include coverage criteria for certain individuals with NMOSD.

Added coverage criteria for Fabhalta (iptacopan) for certain individuals with PNH.

Updated confirmed granulocyte clone size to ≥ 15% for Soliris, Ultomiris, and Empaveli for PNH treatment.

Removed Ultomiris SC on-body injector coverage criteria as product will not be available.

Added coverage criteria for Piasky (crovalimab-akkz) for PNH.

Clarified that medications listed are subject to the product's FDA dosage and administration prescribing information.

Clarified non-formulary exception authorizations may be approved up to 12 months.

Added exception to site-of-service requirements for certain individuals receiving treatment for cytokine release syndrome (CRS).

Updated Empaveli, Fabhalta, and Piasky requirement from 'completed at least 3 months of therapy with Soliris' to 'completed at least 3 months of therapy with an eculizumab product.'

Updated generalized myasthenia gravis coverage criteria for multiple products to add additional medications that must not be used concurrently (including Uplizna in 2026 update).

Updated Empaveli, Fabhalta, and Piasky coverage criteria to reflect the eculizumab-product language and other concurrent-use clarifications.

Updated policy to indicate Site of Service Medical Necessity criteria can apply to injection drugs and clarified exception for Alaska.

Updated Bkemv (eculizumab-aeeb) and Epysqli (eculizumab-aagh) and Soliris coverage statuses and concurrent-use lists across 2025–2026 updates.

Numerous drugs and indications were added over time (e.g., Ultomiris, Empaveli, Syfovre, Veopoz, Izervay, Zilbrysq, Bkemv, Epysqli, Piasky, Fabhalta).

Confirmed granulocyte clone size threshold for PNH updated to ≥ 15% for certain products.

Initial approval length for many products updated from 6 months to 12 months.

Eculizumab-product cross-concurrency restrictions expanded and clarified (added multiple named products and inebilizumab).

Site of Service Medical Necessity criteria can apply to injection drugs and was clarified for Alaska members.

Multiple HCPCS codes added, removed, or termed across revision history (e.g., J3590 removed, C9151 termed).

Moved Fabhalta (iptacopan) coverage criteria for C3G and IgAN into this policy from another policy.

12Drugs with criteria

9Indications with explicit criteria

12HCPCS/Q codes listed

12Approval length (months)

>=15%PNH clone threshold

Coverage Summary

This policy defines medical necessity and site-of-service review criteria for multiple complement inhibitors across both medical and pharmacy benefits. It covers C3 and C5 complement inhibitors for indications including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), neuromyelitis optica spectrum disorder (NMOSD), C3 glomerulopathy/IC‑MPGN, primary IgA nephropathy (IgAN), geographic atrophy (GA) secondary to AMD, CD55‑deficient protein‑losing enteropathy (CHAPLE), and ANCA‑associated vasculitis.

Benefit assignment is drug‑specific: several agents (e.g., Bkemv, Epysqli, Izervay, Soliris, Syfovre, Piasky, Ultomiris, Veopoz, Zilbrysq) are managed under the medical benefit, Fabhalta, Tavneos, and Zilbrysq are listed under the pharmacy benefit, and Empaveli is managed through both medical and pharmacy benefits.

The policy includes a Site‑of‑Service (SOS) Medical Necessity review for IV/injectable administrations for members aged ≥13 (excluding Alaska fully‑insured members), specifying preferred outpatient sites (physician office, infusion center, home infusion) and circumstances when hospital‑based outpatient care is medically necessary.

Initial and reauthorization approval lengths were updated effective June 1, 2026: initial authorization and re‑authorization may be approved for up to 12 months when drug‑specific criteria are met.

Medical‑Necessity Criteria (drug‑specific)

Ultomiris (ravulizumab-cwvz) — aHUS

Ultomiris (ravulizumab-cwvz) and Soliris (eculizumab) — aHUS (atypical hemolytic uremic syndrome).

ALL of the following

Diagnosis of aHUS with documented microangiopathic hemolytic anemia as evidenced by hemoglobin < 8 g/dL, negative Coomb's test, and peripheral blood smear with schistocytes/helmet cells.
Documented thrombocytopenia with platelet count < 140,000/mm3.
Documented acute kidney injury established by renal function studies consistent with aHUS.
Documentation that Shiga toxin E. coli-related HUS (STEC-HUS) has been excluded.
Member received Neisseria meningitidis vaccination >= 2 weeks prior to initiation of first dose.
For Ultomiris specifically: dosing and administration planned per FDA‑approved labeling for aHUS (or equivalent documentation for weight-based dosing).

Ultomiris (ravulizumab-cwvz) — generalized myasthenia gravis (gMG)

Ultomiris (ravulizumab-cwvz) or Soliris (eculizumab) — generalized myasthenia gravis (gMG).

ALL of the following

Member is aged >= 6 years (per product labeling for eculizumab/related agents).
Documented positive serologic test for anti-acetylcholine receptor (anti-AchR) antibodies.
Member is currently using an acetylcholinesterase inhibitor (e.g., pyridostigmine), has tried and failed pyridostigmine, or has a contraindication to its use.
Member has tried and failed (or has contraindications to) two or more immunosuppressive therapies (ISTs) such as glucocorticoids, azathioprine, mycophenolate mofetil, or cyclosporine, or is currently using >=2 ISTs.
Member received Neisseria meningitidis vaccination >= 2 weeks prior to first dose.

Ultomiris (ravulizumab-cwvz) — NMOSD (AQP4+ )

Ultomiris (ravulizumab-cwvz) or Soliris (eculizumab) — neuromyelitis optica spectrum disorder (NMOSD) in AQP4‑IgG positive individuals.

ALL of the following

Member is aged >= 18 years.
Documented diagnosis of NMOSD confirmed by at least one core clinical characteristic (e.g., optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy/diencephalic syndrome with NMOSD‑typical MRI lesions, or symptomatic cerebral syndrome with NMOSD‑typical brain lesions).
Positive test for AQP4‑IgG antibodies.
Alternative diagnoses (e.g., multiple sclerosis) have been excluded.
History of >=2 relapses in the last 12 months OR >=3 relapses in the last 24 months.

Ultomiris (ravulizumab-cwvz) — PNH

Ultomiris (ravulizumab-cwvz) or Soliris (eculizumab) — paroxysmal nocturnal hemoglobinuria (PNH).

ALL of the following

Documented diagnosis of PNH based on flow cytometry demonstrating deficient GPI-anchored proteins (e.g., CD55, CD59) on red blood cells or granulocytes consistent with PNH clone.
Clinical evidence of hemolysis (e.g., elevated LDH, hemoglobinuria, anemia) OR history of transfusion dependence or thrombotic events attributable to PNH.
Member received Neisseria meningitidis vaccination >= 2 weeks prior to initiation of first dose.
For switching from another C5 inhibitor (e.g., eculizumab to ravulizumab), documentation of prior response, reason for switch (e.g., dosing interval, tolerability), and treatment dates/dosing provided; switch consistent with labeling or accepted clinical practice.

Coding

HCPCS codes - medical benefit injectable/infusionHCPCSCovered

J1304	Injection, eculizumab, 10 mg
J3358	Injection, ravulizumab-cwvz, 10 mg
J3490	Unclassified drugs (historic or non-specific code)
J3590	Unclassified biologics

HCPCS / other coding changes noted in revision historymixed

C9399	Unclassified drugs or biologicals, miscellaneous
Q5105	New specific HCPCS/Q-code placeholder (example)

Billing Rule

HCPCS coding updates

Use current, specific HCPCS/J/Q codes when billing for complement inhibitor therapies. Do not bill historical non-specific codes (for example, J3490 or other unclassified codes) when a specific HCPCS or Q-code exists for the product. Ensure authorization requests and claim submissions use the updated codes and include supporting documentation noting medical necessity and site-of-service determinations.

Provider action — Investigational/Not covered uses: Do not submit prior authorization requests using HCPCS codes for indications that are investigational or not covered; such requests will be denied. Include diagnosis codes and supporting clinical rationale if the request is for a covered indication.
Provider action — Non-formulary exception duration: When a non-formulary exception is granted for a medical-benefit injectable, document the approved exception duration in the authorization and bill using the specific HCPCS code for the drug and the dates of service within the approved timeframe.
Provider action — Concurrent therapy exclusions: Do not bill for concurrent use of two complement inhibitors (e.g., eculizumab and ravulizumab) for the same treatment period; concurrent therapy is excluded and will not be authorized or paid.
Provider action — Site-of-service exception for cytokine release syndrome: For CRS grade 3–4 requiring hospital-based outpatient setting (per policy criteria), document CRS grade and supportive measures (vasopressors, oxygen/positive pressure) in the authorization; bill using the medically appropriate HCPCS codes and facility modifiers as required.

Provider Actions and Requirements

Prior Authorization

Medical necessity and site‑of‑service review required

Medical records must be submitted to support medical necessity for medical‑benefit reviews. Site‑of‑service medical necessity review applies for administration of listed IV/injectable drugs for individuals aged 13 and older except Alaska fully‑insured members (Alaska exception).

Applicable to IV/injectable drugs listed in this policy.
Site‑of‑service review applies for ages ≥13; Alaska fully‑insured members are excluded from SOS criteria.

Documentation Required

Required documentation for reviews

Submit office visit notes and supporting clinical records to demonstrate criteria are met. Documentation should include diagnosis, relevant history, physical exam, vaccination history, and medication history.

Background and Evidence

Complement inhibitors target a range of diseases driven by pathologic complement activation: PNH (intravascular and extravascular hemolysis), aHUS (complement‑mediated thrombotic microangiopathy), gMG (neuromuscular junction damage), NMOSD (AQP4‑IgG mediated astrocytopathy), GA secondary to AMD (complement‑driven lesion growth), C3G/IC‑MPGN and IgAN (complement‑mediated glomerular disease), CHAPLE (CD55 deficiency), and ANCA‑associated vasculitis.

Mechanistically, agents act at different points in the cascade: C3 inhibitors (e.g., pegcetacoplan/Syfovre, Empaveli) bind C3/C3b and reduce opsonization and both intra‑ and extravascular hemolysis or downstream complement activation, while C5 inhibitors (e.g., eculizumab/Soliris, ravulizumab/Ultomiris, avacincaptad/Izervay, crovalimab/Piasky, zilucoplan/Zilbrysq) block C5 cleavage and prevent formation of the terminal membrane attack complex, limiting intravascular hemolysis or MAC‑mediated tissue injury; C5a receptor blockade (e.g., avacopan/Tavneos) inhibits C5a‑mediated neutrophil activation in vasculitis.

Benefit management and safety considerations include product‑specific benefit assignments (medical vs pharmacy), REMS/meningococcal vaccination or prophylaxis requirements for agents with meningococcal risk, restrictions on concurrent use of overlapping complement or related immunotherapies for certain indications (e.g., gMG), drug‑specific eligibility thresholds (e.g., PNH clone size, LDH or hemoglobin cutoffs, UPCR and eGFR for nephrology indications), and site‑of‑service rules with an added exception for cytokine release syndrome.

Study / source	Key findings
PEGASUS (Empaveli vs Soliris)	Empaveli increased hemoglobin by +2.37 g/dL vs -1.47 g/dL for Soliris at week 16 (difference 3.84 g/dL, p<0.0001); transfusion avoidance 85.4% vs 14.5% (significant); Hb normalization without transfusion 34.1% vs 0%; durability through week 48 (Hb +2.7 g/dL).
VALIANT (Empaveli in C3G/IC-MPGN)	At Week 26, Empaveli achieved a 68% reduction in proteinuria versus placebo (geometric mean UPCR ratio 0.33 vs 1.03; P<0.0001) and stabilized eGFR (difference +6.31 mL/min/1.73 m2, nominal P=0.03).
APPLY‑PNH (Fabhalta)	At 24 weeks, Fabhalta showed higher proportions achieving ≥2 g/dL hemoglobin increases without transfusion and sustained hemoglobin ≥12 g/dL without transfusion versus continued anti‑C5 therapy; met co‑primary endpoints.
GATHER (Izervay) - GATHER1 / GATHER2	Izervay reduced GA growth rate at 12 months (GATHER1) and sustained benefit through 2 years (GATHER2); GATHER2 showed GA growth rate 1.75 mm2/yr vs 2.12 mm2/yr for control; small absolute increase in choroidal neovascularization (~11.6% vs 9%).
DERBY / OAKS (Syfovre)	Syfovre reduced GA lesion growth versus sham: OAKS showed 21% reduction (monthly) at 12 months (p=0.0004); DERBY did not reach statistical significance at month 12 (approx 12% reduction, p=0.0609); increased new‑onset exudative AMD observed (higher rates vs sham).
ADVOCATE (Tavneos)	Avacopan (Tavneos) was noninferior to prednisone taper for remission at week 26 and superior for sustained remission at week 52 in ANCA‑associated vasculitis; improved steroid‑related outcomes and HRQoL measures.
NMOSD Study 1 (Soliris)	Soliris significantly prolonged time to first adjudicated relapse in AQP4+ NMOSD (relative risk reduction 94%; hazard ratio 0.058; p<0.0001) and reduced annualized relapse rate and hospitalizations versus placebo.
Key clinical trial citations / other pivotal evidence	Multiple pivotal trials and prescribing information support indications (e.g., Hillmen NEJM 2006 for eculizumab; Hill et al. 2021 pegcetacoplan vs eculizumab; avacopan ADVOCATE 2021; phase III PNH and GA trials cited in prescribing information).

Revision History

2026-06-01policy_effective_dateLatest

Policy effective date (interim review approved May 12, 2026); initial authorization length for many products updated from 6 months to 12 months; Fabhalta coverage moved into this policy.

2026-05-12policy_revisionLatest

Policy last revised May 12, 2026 (interim review approved) and replaces prior version; revision included moving Fabhalta coverage into this policy and updating initial approval lengths to 12 months.

2026-03-01

Policy Summary

PayerPremera Bluecross

PolicyC3 and C5 Complement Inhibitors

Policy CodePolicy 5.01.571

Change TypeMultiple additions and revisions to drug-specific and site-of-service criteria

Effective DateJun 1, 2026

Next Review Date

SourceLink

On This Page

If request is for continuation, member demonstrates clinical benefit or disease control on therapy and no contraindications to continued use.

Medication is NOT being used concurrently with another eculizumab product, nipocalimab (Imaavy), rozanolixizumab (Rystiggo), ravulizumab (Ultomiris) when duplicative, inebilizumab (Uplizna), efgartigimod (Vyvgart/Vyvgart Hytrulo), or zilucoplan (Zilbrysq).

Has had an inadequate response or intolerance to Epysqli (if applicable) when relevant to product switch/choice.

Expanded Disability Status Scale (EDSS) score <= 7.

Member received Neisseria meningitidis vaccination >= 2 weeks prior to initiation of first dose.

Dosing and administration consistent with FDA‑approved labeling for PNH (weight-based schedules) and planned monitoring documented.

Provider action — Non-formulary exception and authorization durations: Authorizations must reflect the approved duration for non-formulary exceptions and any re-initiation rules (e.g., hospital-based outpatient setting considered medically necessary for first 90 days when applicable). Claims submitted outside the authorized dates or beyond the approved duration will be denied.

Office visit notes with diagnosis and clinical evaluation.
Vaccination history (e.g., meningococcal or other vaccines as required).
Medication history including prior therapies and dates.

Documentation Required

Vaccination requirement and meningococcal prophylaxis — timing and vaccines required

Vaccination documentation and timing must be provided. For complement inhibitors with meningococcal infection risk, vaccination against Neisseria meningitidis must be given at least 2 weeks before the first dose or documented contraindication/prophylaxis per product labeling. Empaveli and Fabhalta require additional vaccination documentation (Streptococcus pneumoniae and Haemophilus influenzae) at least 2 weeks prior when specified.

Neisseria meningitidis vaccination ≥2 weeks prior to first dose for C5/C3 inhibitors noted in criteria.
Empaveli and Fabhalta: document vaccinations against S. pneumoniae, N. meningitidis, and H. influenzae ≥2 weeks prior.
If vaccination is contraindicated, provide documentation/reasoning per policy and product labeling.

Step Therapy

Prior therapy requirements and concurrent therapy exclusions

Prior therapy and concomitant therapy rules must be documented. Many indications require prior trials or intolerance to specified agents: e.g., for gMG document pyridostigmine use or failure and trial of ≥2 immunosuppressive therapies (or contraindication). For certain PNH switches (Empaveli, Fabhalta, Piasky), document completion of ≥3 months of therapy with an eculizumab product or Ultomiris before switching; short‑term (≤4 weeks) overlap when switching is allowed. Do not use specified agents concurrently — the policy names multiple drugs that must not be used together.

gMG: document pyridostigmine trial/use/failure and trial of ≥2 ISTs or contraindication.
PNH switches: completed ≥3 months on an eculizumab product or Ultomiris before Empaveli/Fabhalta/Piasky; allow short‑term concomitant therapy ≤4 weeks when switching.
Concurrent‑use exclusions: medication must not be used concurrently with other listed eculizumab products and named agents (policy lists specific products).

Denial Risk

Investigational / not‑covered uses — risk of denial if criteria not met

Uses that do not meet the drug‑specific medically necessary criteria in this policy are considered investigational and may be denied. Providers should ensure requested use aligns with the listed drug‑specific criteria and submit supporting documentation; investigational long‑term concomitant therapy (beyond specified short‑term switching allowances) is also treated as investigational.

All other uses not in the drug‑specific criteria are investigational and may be denied.
Long‑term (>4 weeks) concomitant therapy with an eculizumab product or Ultomiris when switching to specified agents is investigational.

Billing Rule

Duration of authorization and non‑formulary exception handling

Initial authorizations and reauthorizations may be approved for up to 12 months when drug‑specific criteria are met and chart notes show continued clinical benefit. Non‑formulary exception authorizations may be handled per policy and have been clarified in recent updates (non‑formulary exception authorizations historically could be approved up to 12 months).

Initial authorization: up to 12 months.
Reauthorization: up to 12 months if criteria met and positive clinical response documented.
Non‑formulary exceptions: review and duration handled per policy; historically could be approved up to 12 months and language has been clarified.

Billing Rule

Benefit management assignment — which drugs are medical vs pharmacy

Benefit management assignment varies by product. Medical benefit management applies to Bkemv, Epysqli, Izervay, Soliris, Syfovre, Piasky, Ultomiris, Veopoz, and Zilbrysq; pharmacy benefit to Fabhalta, Tavneos, and Zilbrysq (per prior listings); Empaveli may be managed under both medical and pharmacy benefits. Providers must bill through the appropriate benefit based on the product.

Medical benefit: Bkemv, Epysqli, Izervay, Soliris, Syfovre, Piasky, Ultomiris, Veopoz, Zilbrysq.
Pharmacy benefit: Fabhalta, Tavneos, Zilbrysq.
Both medical and pharmacy: Empaveli.

Note

Refer to product FDA dosing and REMS for dosing/administration and safety requirements

Follow product FDA dosing and administration and REMS requirements where applicable. The policy states that medications are subject to FDA prescribing information; for products with REMS (e.g., Soliris, Ultomiris, Zilbrysq) follow REMS counseling, vaccination, and restricted‑program requirements and include documentation in the record.

Adhere to FDA labeling for dose, administration, contraindications, and required vaccinations.
Comply with REMS requirements and restricted distribution programs where applicable and document REMS counseling and vaccine/prophylaxis as required.

Prior Authorization

Site‑of‑service exception for cytokine release syndrome (CRS) — CRS criteria and SOS link

An exception to site‑of‑service requirements exists for certain individuals receiving treatment for cytokine release syndrome (CRS). Hospital‑based outpatient may be medically necessary for CRS when ALL CRS criteria are met: temperature ≥38 °C, hypotension requiring ≥1 vasopressor, and hypoxia requiring high‑flow oxygen or positive pressure ventilation. Refer to the policy's Site‑of‑Service criteria for details and the Site‑of‑Service criteria link.

CRS exception requires all of: fever ≥38 °C; hypotension needing ≥1 vasopressor; hypoxia requiring high‑flow oxygen device or positive‑pressure ventilation.
When CRS criteria are met, hospital‑based outpatient site may be considered medically necessary despite standard SOS rules.
See Site‑of‑Service Medical Necessity section for full criteria and exceptions; Alaska fully‑insured members remain excluded from SOS rules.

March 1, 2026 annual review approved February 9, 2026: updated gMG concurrent-use exclusions adding Uplizna and clarified other concurrent-use lists.

2025-10-03policy_revision

October 3, 2025 effective updates clarified that Site of Service Medical Necessity criteria can apply to injection drugs and updated age and coding/HCPCS changes across 2024–2025.

2025-07-01policy_revision

2025 updates (effective various dates) added exception to SOS requirements for cytokine release syndrome (CRS); non-formulary exception authorizations clarified up to 12 months; added Bkemv and Epysqli; changed Empaveli/Fabhalta/Piasky requirement from 'Soliris' to 'an eculizumab product' and clarified concurrent-use exclusions.

2024-08-02policy_revision

August 2, 2024 effective changes: updated granulocyte clone size threshold for PNH to ≥15% for Soliris, Ultomiris, and Empaveli; removed Ultomiris SC on-body injector; added Piasky coverage criteria.

2023-04-01policy_revision

2023 updates added coverage for Syfovre (pegcetacoplan) for GA, Veopoz (pozelimab) for CHAPLE disease, Izervay (avacincaptad pegol) for GA, and Zilbrysq (zilucoplan) for gMG.

2017-06-02policy_creation

Original policy effective June 2, 2017 (new policy approved Feb 14, 2017); revision history documents additions and updates from 2017 onward.