ModifiedPremera BluecrossPolicy 5.01.39

C3 and C5 Complement Inhibitors (site-of-service and medical necessity)

Defines medical necessity, site-of-service review rules, and coverage criteria for multiple C3/C5 complement inhibitor drugs (IV, injectable, and select oral/SC agents) across indications including PNH, aHUS, C3G/IC-MPGN, gMG, GA, and others; intended for providers and applies to Premera Bluecross plans except where noted for Alaska fully insured members.

Policy Summary

PayerPremera Bluecross

PolicyC3 and C5 Complement Inhibitors (site-of-service and medical necessity)

Policy CodePolicy 5.01.39

Change TypeAdded and revised coverage criteria

Effective Date

Next Review Date

Key ActionSubmit prior authorization with required documentation (diagnosis confirmation, relevant labs, vaccination records and specialist consultation as applicable).

SourceLink

POLICY UPDATE CHANGES

Added coverage criteria for Piasky (crovalimab-akkz) for the treatment of certain individuals with paroxysmal nocturnal hemoglobinuria (PNH).

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

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

Updated myasthenia gravis coverage criteria to add Uplizna (inebilizumab-cdon) to the list of medications not to be used concurrently with several complement inhibitors.

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

~20drugs listed or referenced

>=15%PNH clone threshold

>=1.5x ULNLDH threshold

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

<10.5 g/dLHemoglobin switch threshold

>=2 weeksVaccination timing

Coverage Criteria by Indication and Product

Empaveli (pegcetacoplan) — PNH

Empaveli (pegcetacoplan) for PNH — Covered when ALL are met:

Empaveli for PNH initial coverage: The individual is aged 18 years or older

PNH diagnosis: Documented diagnosis of PNH confirmed by granulocyte or monocyte clone size of at least 15%>=15%

Prior anti-C5 therapy requirement when specified: Has completed at least 3 months of therapy with an eculizumab product or Ultomiris and failed to achieve hemoglobin >= 10.5 g/dL when applicable (policy allows this as a prior-therapy condition)Hb >=10.5 g/dL

Short-term (4-week) concomitant therapy allowed when switching; long-term concomitant therapy beyond 4 weeks is considered investigational.

Vaccination: Received vaccinations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae at least 2 weeks prior to initiation>=2 weeks

Fabhalta (iptacopan) — PNH

Fabhalta (iptacopan) for PNH — Covered when ALL are met:

Age: The individual is aged 18 years or older

PNH diagnosis: Documented PNH confirmed by granulocyte or monocyte clone size of at least 15%>=15%

Prior eculizumab-class exposure: Has completed at least 3 months of therapy with an eculizumab product or Ultomiris3 months

Residual anemia while on anti-C5: Experienced residual anemia defined as hemoglobin < 10.5 g/dL AND LDH >= 1.5x ULN while receiving an eculizumab product or Ultomiris

Piasky (crovalimab-akkz) — PNH

Piasky (crovalimab-akkz) for PNH — Covered when ALL are met:

Age: The individual is aged 13 years or older

PNH diagnosis: Documented PNH confirmed by granulocyte or monocyte clone size of at least 15%>=15%

Prior eculizumab-class exposure: Has completed at least 3 months of therapy with an eculizumab product or Ultomiris3 months

Residual anemia: Experienced residual anemia defined as hemoglobin < 10.5 g/dL AND LDH >= 1.5x ULN while receiving an eculizumab product or Ultomiris

Eculizumab and Ravulizumab products — PNH and aHUS

Eculizumab and Ravulizumab products — PNH and aHUS — Covered when ALL are met (indication-specific nodes differ):

Age for PNH: Individual is aged 18 years or older for Soliris/Epysqli/Bkemv (Ultomiris allowed from 1 month of age for PNH)

PNH diagnosis: Documented PNH confirmed by granulocyte or monocyte clone size of at least 15%>=15%

Active hemolysis for treatment-naïve PNH: Treatment-naïve individuals have active hemolysis as measured by LDH >= 1.5x ULNLDH >=1.5x ULN

Vaccination for PNH/aHUS: Received vaccination against Neisseria meningitidis at least 2 weeks prior to first dose

Empaveli (pegcetacoplan) — C3G / IC-MPGN

Empaveli (pegcetacoplan) for C3G / IC-MPGN — Covered when ALL are met:

Age/weight: Individual is aged 12 years or older and weighs more than 30 kg>=12 years; >30 kg

Diagnosis confirmation: Diagnosis of C3G or primary IC-MPGN confirmed by biopsy with evidence of active disease

Proteinuria: Documented urine protein-to-creatinine ratio (UPCR) of >= 1 g/gUPCR >=1 g/g

Renal function: Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m2

Generalized Myasthenia Gravis (gMG)

Generalized Myasthenia Gravis (gMG) — Covered when ALL are met:

Serology: Documented positive serologic test for anti-acetylcholine receptor (anti-AChR) antibodies

Age: For Epijkstra/Bkemv/Soliris: individual aged 6 years or older; for Ultomiris adult age criteria apply as specified>=6 years for some agents; >=18 for Ultomiris

Concomitant baseline therapy: Is currently using the acetylcholinesterase inhibitor pyridostigmine, has tried and failed it, or has contraindication

Immunosuppressive therapy trials: Is currently using 2 or more immunosuppressive therapies (or has tried and failed 2 ISTs) or has contraindications to use of 2 ISTs

gMG — Ultomiris (ravulizumab-cwvz)

Ultomiris (ravulizumab-cwvz) IV for generalized myasthenia gravis (gMG) Anti-AchR positive — covered when ALL are met

gMG Ultomiris initial criteria: The individual is aged 18 years or older AND documented positive anti-AchR antibodies AND currently using pyridostigmine (or tried/failed/has contraindication) AND currently using 2 or more immunosuppressive therapies (or tried/failed 2 ISTs or contraindicated) AND received Neisseria meningitidis vaccination >= 2 weeks prior to first dose AND medication is not used concurrently with an eculizumab product, Imaavy (nipocalimab-aahu), or Rystiggo (rozanolixizumab-noli)

Site-of-service review applies for IV Ultomiris

gMG — Zilbrysq (zilucoplan)

Zilbrysq (zilucoplan) SC for generalized myasthenia gravis (gMG) Anti-AchR positive — covered when ALL are met

gMG Zilbrysq initial criteria: Age >= 18 AND documented positive anti-AChR antibodies AND currently using pyridostigmine (or tried/failed/contraindicated) AND currently using 2 or more ISTs (or tried/failed 2 ISTs or contraindicated) AND received Neisseria meningitidis vaccination >= 2 weeks prior to first dose AND has tried and failed at least one of: Epijkstra (eculizumab-aagh) OR Ultomiris (ravulizumab-cwvz) OR Vyvgart (efgartigimod alfa-fcab) OR Vyvgart Hytrulo AND medication is not used concurrently with an eculizumab product, Imaavy, Rystiggo, Uplizna, or Ultomiris

Policy updated to require trial with a preferred brand product first where specified

NMOSD — eculizumab / ravulizumab

NMOSD — eculizumab / ravulizumab — Covered when ALL are met:

NMOSD eculizumab/ravulizumab criteria: Age >= 18 AND documented NMOSD diagnosis confirmed by at least one core clinical characteristic (optic neuritis OR acute myelitis OR area postrema syndrome OR acute brainstem syndrome OR symptomatic narcolepsy/diencephalic syndrome with NMOSD-typical MRI lesions OR symptomatic cerebral syndrome with NMOSD-typical brain lesions) AND positive AQP4-IgG antibodies AND exclusion of alternative diagnoses AND history of >=2 relapses in last 12 months or >=3 relapses in last 24 months AND EDSS <= 7 AND received Neisseria meningitidis vaccination >= 2 weeks prior to initiation AND had inadequate response or intolerance to Epijkstra where specified

Site-of-service review applies to certain IV products

ANCA-associated vasculitis — Tavneos (avacopan)

ANCA-associated vasculitis — Tavneos (avacopan) — Covered when ALL are met:

ANCA-associated vasculitis Tavneos criteria: Age >= 18 AND diagnosis of ANCA-associated vasculitis due to granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) AND documentation of positive PR3 or MPO antibodies AND Tavneos is used in combination with rituximab or cyclophosphamide

Geographic Atrophy — Syfovre and Izervay

Geographic Atrophy (GA) secondary to dry AMD — Syfovre and Izervay — Covered when ALL are met:

Syfovre GA criteria: Age >= 60 AND documented GA secondary to dry AMD AND not GA secondary to other diseases AND no CNV in same eye needing treatment AND BCVA > 24 letters (20/320) AND total GA lesion size per eye 2.5–17.5 mm^2 AND Syfovre not used concurrently with Izervay AND prescribed by or in consultation with an ophthalmologist AND dose <= 15 mg every 25 days per affected eye

Izervay GA criteria: Age >= 50 AND documented GA secondary to dry AMD AND not GA secondary to other diseases AND no CNV or diabetic retinopathy in same eye needing treatment AND Izervay not used concurrently with Syfovre AND BCVA between 20/25 and 20/320 AND total GA lesion size per eye 2.5–17.5 mm^2 AND prescribed by or in consultation with an ophthalmologist

CHAPLE — Veopoz (pozelimab-bbfg)

CD55-deficient protein-losing enteropathy (CHAPLE) — Veopoz (pozelimab-bbfg) — Covered when ALL are met:

CHAPLE Veopoz criteria: Age >= 1 year AND clinical diagnosis of CD55-deficient protein-losing enteropathy (PLE) confirmed by biallelic CD55 loss-of-function mutation detected by genetic testing AND active disease defined by hypoalbuminemia (serum albumin < 3.2 g/dL) plus at least one symptom (abdominal pain, diarrhea, peripheral edema, facial edema) in prior 6 months AND maximum prescribed maintenance dose limited to 800 mg once weeklyserum albumin <3.2 g/dL

Meningococcal vaccination and prophylaxis required prior to first dose; Veopoz is contraindicated in unresolved Neisseria meningitidis infection.

PNH — Empaveli (pegcetacoplan) (Indication summary)

Paroxysmal nocturnal hemoglobinuria (PNH) — Empaveli (pegcetacoplan) — indication summary

Empaveli indication: Empaveli is indicated for adult individuals with PNH; studied in PEGASUS and PRINCE trials including switch settings

Policy allows short-term (4-week) concomitant therapy with an eculizumab product or Ultomiris when switching to reduce hemolysis risk; long-term concomitant therapy beyond 4 weeks is considered investigational for Empaveli, Fabhalta, and Piasky.

Empaveli — Evidence summaries

PNH evidence: PEGASUS showed Empaveli produced greater mean hemoglobin increase versus eculizumab at Week 16 (LS mean difference +3.84 g/dL) and increased transfusion avoidance (85.4% vs 14.5%); durable Hb increase at Week 48

PEGASUS enrolled adults uncontrolled on Soliris and included a 4-week run-in with combined therapy; hemolysis-related discontinuations occurred in a minority

C3G/IC-MPGN evidence: VALIANT Phase 3 supported Empaveli second indication for C3G/IC-MPGN (>=12 years) demonstrating reduction in proteinuria and stabilization of eGFR

Dosing for adults 1080 mg BIW; pediatric dosing weight-based for kidney indications

Fabhalta — Evidence summaries

Fabhalta APPLY-PNH: APPLY-PNH showed iptacopan 200 mg BID achieved higher proportions of hemoglobin increases >=2 g/dL and sustained Hb >=12 g/dL without transfusion versus continuation of anti-C5 therapies at 24 weeks

APPOINT-PNH enrolled complement-inhibitor–naïve patients; monitor for infections and vascular events (MAVEs)

Safety signals: Serious adverse events were infrequent (~3%); three major adverse vascular events occurred in APPLY-PNH; monitor for infections and vascular events

Izervay — Evidence summaries

Efficacy: GATHER1 and GATHER2 demonstrated reduced GA lesion growth versus placebo through 12–24 months (e.g., least square mean square-root change 0.292 mm vs 0.402 mm at 12 months in GATHER1; reduced annual growth rate in GATHER2)

No meaningful BCVA benefit demonstrated; monitor lesion growth outcomes

Safety: Common ocular adverse events include conjunctival hemorrhage, hyperemia, punctate keratitis, and increased IOP; contraindicated in ocular/periocular infections and active intraocular inflammation

Syfovre — Evidence summaries

Efficacy: DERBY and OAKS trials showed Syfovre reduced GA lesion growth through 24 months with variable significance (OAKS significant at 12 months; DERBY did not meet significance at month 12); combined data show benefit over 2 years

Treatment benefit observed as early as 6 months and increased over 2 years in combined data

Safety: Increased rates of new-onset exudative AMD and other ocular adverse events; injection-related risks include endophthalmitis and intraocular inflammation

Reported injection-level rates: endophthalmitis 0.047% per injection, intraocular inflammation 0.22% per injection

Tavneos — Evidence summaries

Efficacy: Phase II (CLEAR, CLASSIC) and III (ADVOCATE) trials showed avacopan 30 mg BID was noninferior to prednisone taper for remission at Week 26 and superior for sustained remission at Week 52 when used with cyclophosphamide or rituximab

Improved glucocorticoid-sparing outcomes and HRQoL noted

Soliris / Ultomiris — Evidence summaries

Indications and safety: Soliris and Ultomiris are indicated for PNH and aHUS among other indications; both carry boxed warnings for life-threatening and fatal meningococcal infections and are available through REMS

Ultomiris has longer half-life and less frequent dosing and was non-inferior to Soliris in PNH studies

gMG evidence (Ultomiris): Ultomiris demonstrated statistically significant improvement in MG-ADL and QMG scores at Week 26 versus placebo in gMG patients

Most participants were on concomitant ISTs and corticosteroids

Ultomiris (ravulizumab-cwvz) coverage

Ultomiris indications and safety: Indicated for PNH (adult and pediatric >=1 month), aHUS (adult and pediatric >=1 month), and adult gMG who are anti-AChR antibody-positive; includes boxed warning for meningococcal infections and is available only through REMS

Longer dosing interval versus Soliris (every 8 weeks vs every 2 weeks)

Veopoz (pozelimab-bbfg) coverage

Veopoz indication and preconditions: Indicated for CD55-deficient PLE (CHAPLE) in patients >=1 year with confirmed biallelic CD55 loss-of-function mutation and active disease defined by hypoalbuminemia (<3.2 g/dL) plus symptoms; meningococcal vaccination and prophylaxis required prior to first dose; contraindicated in unresolved Neisseria meningitidis infectionserum albumin <3.2 g/dL

Efficacy from single-arm study with normalization of albumin and IgG by 12 weeks

Zilbrysq (zilucoplan) coverage

Zilbrysq indication and safety: Indicated for adult anti-AChR antibody-positive gMG; subcutaneous self-administered daily dosing; boxed warning for meningococcal infections and available only through REMS; trials showed significant improvement in MG-ADL and QMG scores

Policy updated to require trial with a preferred brand product first where specified

Piasky (crovalimab-akkz) coverage

Piasky indication and safety: Studied for PNH in adults; demonstrated hemolysis control and noninferiority to eculizumab in COMMODORE-2; risk of transient immune complex reactions when switching from prior complement inhibitors; no meningococcal infections reported in trials

Pediatric evidence limited

Policy-level coverage constraints and sequencing

Policy-level coverage constraints and therapy sequencing requirements recorded in history:

eculizumab product prior therapy for certain drugs: Certain drugs (Empaveli, Fabhalta, Piasky historically) require completion of at least 3 months of therapy with an eculizumab product before coverage where specified3 months

Policy language updated from 'Soliris' to 'an eculizumab product' in history entries

concurrent use prohibitions for myasthenia gravis: Eculizumab products and specified agents (Imaavy, Rystiggo, Vyvgart, Vyvgart Hytrulo, Ultomiris, Zilbrysq, and Uplizna added in 2026) must not be used concurrently per updated MG coverage criterianone

Concurrent use prohibitions expanded in 2025–2026 updates

site of service exception: Site of Service Medical Necessity criteria exceptions exist for Alaska fully-insured members and for certain cytokine release syndrome treatments; check member-specific rules

Site-of-service medical necessity review under this policy applies to medical-benefit IV and injectable complement inhibitors and related agents, and does not apply to Alaska fully‑insured members; for those members follow the separate infusion and injection drug medical necessity criteria or contact Customer Service for guidance. For individuals aged 13 years and older the site where the drug is administered (hospital outpatient infusion department, infusion center, physician office, or home) will be reviewed for medical necessity. Preferred medically necessary sites include the physician's office, an outpatient infusion center, or home infusion; hospital-based outpatient infusion is limited to specific circumstances (e.g., initial course or re‑initiation after ≥6 months, no closer outpatient/home infusion option, or high‑risk clinical conditions) as detailed in the policy.

Uses of the listed agents that are not consistent with their FDA‑approved indications and dosing are considered investigational under this policy. Coverage determinations must reflect each product's FDA prescribing information, and off‑label requests will be evaluated as investigational unless a covered indication and criteria are met.

Concurrent administration of multiple complementary complement‑targeting therapies is restricted. Specifically, the policy excludes concurrent use of the medications in this policy with eculizumab products, Imaavy (nipocalimab‑aahu), Rystiggo, and other listed complement‑targeting agents. Additionally, short‑term concomitant therapy (up to 4 weeks) is allowed only when switching from an eculizumab product or Ultomiris to certain agents to reduce hemolysis risk; long‑term (>4 weeks) concomitant therapy with an eculizumab product or Ultomiris when using Empaveli, Fabhalta, or Piasky is considered investigational.

Soliris (eculizumab) is not indicated for Shiga toxin E. coli‑related hemolytic uremic syndrome (STEC‑HUS). Soliris also carries a boxed warning for life‑threatening and fatal meningococcal infections and is available only through a REMS program; REMS requirements and meningococcal vaccination documentation are required per product labeling.

Veopoz (pozelimab‑bbfg) is contraindicated in individuals with an unresolved Neisseria meningitidis infection. Per the product labeling, meningococcal vaccination and prophylactic measures should be completed prior to the first dose; lack of vaccination or unresolved infection may preclude coverage.

The policy retains an explicit investigational stance for any use of the listed drugs that is not an FDA‑labeled, covered indication in this document. Requests for non‑labeled uses will be evaluated as investigational unless supported by a covered criterion.

Hospital‑based outpatient infusion or injection services are considered not medically necessary when the site‑of‑service criteria in this policy are not met. Hospital outpatient administration is generally reserved for the initial treatment course, re‑initiation after ≥6 months, when no nearer outpatient/home infusion resources exist, or when the patient has listed high‑risk clinical conditions that increase infusion risk.

When switching from an eculizumab product or Ultomiris to Empaveli, Fabhalta, or Piasky, the policy allows short‑term concomitant therapy of up to 4 weeks to reduce hemolysis risk during the transition; however, long‑term concomitant therapy beyond 4 weeks is considered investigational and therefore not medically necessary under this policy.

Coverage criteria clarify that listed complement inhibitors must not be used concurrently with specified immunotherapies in certain indications (notably generalized myasthenia gravis). The myasthenia gravis criteria were updated to expand the list of agents that cannot be used concurrently (including eculizumab products, Ultomiris, Imaavy, Rystiggo, Vyvgart products, Zilbrysq, and Uplizna where noted); adherence to these concurrency restrictions is required for approval.

Historical policy language that previously described some non‑covered or investigational situations (for example, prior wording about long‑term concomitant therapy with Soliris/Ultomiris when switching to Empaveli) has been retained in the policy history for reference but the operative coverage language reflects current revisions and class‑level wording (e.g., requirement for prior use of an eculizumab product rather than a specific brand).

Initial Therapy — Authorization and Sequencing

Continuation, Reauthorization, and Switching

Step Therapy and Prior Trial Requirements

Requirement	Applies to / Example agents
Prior trial with and inadequate response or intolerance to specified agents as listed in the indication-specific criteria (i.e., prior use and failure/intolerance required where the criteria state).
Examples: eculizumab products (Epysqli, Soliris, Bkemv) required as prior therapy before some alternative C5/C3 agents per individual indication language; Zilbrysq requires prior failure of at least one listed gMG agent (see Zilbrysq criteria).

Step requirement	Drugs / context
Must have tried and failed (or have intolerance to) specified alternative complement-targeting therapies prior to coverage when indicated by the drug-specific criteria.
Example: For Zilbrysq (gMG) the member must have tried and failed at least one of Epysqli (eculizumab-aagh), Ultomiris (ravulizumab-cwvz), Vyvgart (efgartigimod alfa-fcab), or Vyvgart Hytrulo before Zilbrysq will be covered.

Consideration	Policy detail / relevance
Prior anti-C5 therapy or documented inadequate response may be relevant to authorization decisions for C3-targeting agents in PNH based on trial populations.
Trials that supported C3-targeting agents (e.g., Empaveli PEGASUS, Fabhalta APPLY-PNH) enrolled individuals with prior anti-C5 exposure or residual anemia despite stable anti-C5 therapy; prior anti-C5 use or failure can justify switching to C3-targeting agents per policy.

Requirement	Details / Notes
Require trial of a preferred brand product first for Zilbrysq (updated in 2025).
Policy updated to require trial with a preferred brand product first for Zilbrysq; additionally, where an eculizumab-product trial is required prior to alternatives, completion of at least 3 months of therapy with an eculizumab product is specified (policy language changed from 'Soliris' to 'an eculizumab product').

Class-level requirement	Policy language / duration
Prior trial of an eculizumab product is required before coverage of certain other complement inhibitors where specified.
Policy language was updated from specifying Soliris to requiring completion of at least 3 months of therapy with an eculizumab product (class-level wording) before some alternative agents will be authorized; applies in indications where the step is listed (e.g., some PNH/aHUS/gMG criteria).

Provider Requirements and Documentation

Prior Authorization

Prior Authorization Required and Coding

Prior authorization is required for all drugs listed in this policy. Providers must submit appropriate HCPCS/J‑codes (see coding table) on the authorization request. Site‑of‑service (SOS) review applies for IV and injectable drugs for members aged 13 and older (SOS review does not apply to Alaska fully‑insured members). Failure to meet SOS criteria may render the chosen site not medically necessary and result in denial of payment.

HCPCS/J‑codes required on PA request (see policy coding).
SOS review applies to listed IV/injectable complement inhibitors for members ≥13 (Alaska fully‑insured members exempt).

Note

Confirm FDA Indication and Dosing

Coverage determinations must reflect the drug’s FDA‑indicated populations and dosing. Prescribers should confirm the product’s FDA indication, age limits, weight‑based dosing (when applicable), and administration schedule and document adherence to the product’s FDA dosing and administration in the medical record.

Confirm FDA indication, age and weight criteria, and follow product PI for dosing/administration.

Coding, Thresholds, and Numeric Criteria

Drugs subject to site-of-service reviewmixed

Bkemv	eculizumab-aeeb IV (brand name listed)
Epysqli	eculizumab-aagh IV (brand name listed)
Soliris	eculizumab IV
Ultomiris	ravulizumab-cwvz IV

Covered HCPCS/J and biosimilar codesHCPCS

J1299	Injection, eculizumab (Soliris), 2 mg (new code effective 04/01/25)
J1300	Injection, eculizumab (Soliris), 10 mg (code terminated 04/01/25)
J1303	Injection, ravulizumab-cwvz (Ultomiris), 10 mg
J1307	Injection, crovalimab-akkz (Piasky), 10 mg
J2781	Injection, pegcetacoplan, intravitreal, 1 mg
J2782	Injection, avacincaptad pegol (Izervay), 0.1 mg
J3490	Unclassified drugs (Use to report: Empaveli)
J9376	Injection, pozelimab-bbfg (Veopoz), 1 mg
Q5151	Injection, eculizumab-aagh (Epysqli), biosimilar, 2 mg (new code effective 04/01/25)
Q5152	Injection, eculizumab-aeeb (Bkemv), biosimilar, 2 mg (new code effective 04/01/25)

No explicit codes provided in this document sectionmixed

NDCs and HCPCS not listed in this section

No explicit CPT/HCPCS/NDC codes present in these chunks

Covered HCPCS/J codes referenced in history and coding updatesHCPCS

J1303	HCPCS code added (document reference)
J1299	HCPCS code added (document reference)
J1300	HCPCS code (termed J1300)
J1307	HCPCS code added January 2025
J2781	HCPCS code added for Veopoz
J2782	HCPCS code added April 2024
J9376	HCPCS code added April 2024
C9162	HCPCS code added January 2024 (termed later)
Q5151	HCPCS code for Epijkstra/Epysqli
Q5152	HCPCS code for Bkemv

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inv-39: LDH for active hemolysis

LDH thresholdLactic acid dehydrogenase (LDH) ≥ 1.5 × upper limit of normal

ContextUsed to define active hemolysis in treatment‑naïve PNH and for residual hemolysis when assessing switches from anti‑C5 therapy

Supporting requirementDocument LDH result with laboratory reference range to confirm ≥1.5× ULN

inv-40: PNH clone size

Diagnostic clone sizeGranulocyte or monocyte PNH clone ≥ 15%

Use caseRequired to confirm PNH diagnosis for coverage of listed complement inhibitors

Site-of-Service Rules and Preferred Settings

Note

Use office, infusion center, or home infusion as preferred administration sites

Prefer office, infusion center, or home infusion for administration when clinically appropriate; hospital‑based outpatient infusions are generally not medically necessary unless policy exceptions apply (initial course, re‑initiation after ≥6 months, no closer outpatient/home infusion, or high‑risk clinical conditions).

Preferred medically necessary sites: physician's office, infusion center, or home infusion.
Hospital outpatient setting allowed only under the policy's specified exceptions.

Note

Include SOS details for IV products subject to site‑of‑service review

For certain IV products (for example, eculizumab products and Ultomiris), include site‑of‑service information because these agents are subject to SOS review; the policy applies SOS review to individuals aged 13 years and older.

Indicate planned administration site on the PA (infusion center, hospital outpatient, or office).
SOS review applies for those aged ≥13 years per policy.

Biosimilar and Product Preference Notes

Billing Rule

Specify Soliris/eculizumab product and expect SOS review

When submitting PA for Soliris (eculizumab) or its biosimilars, indicate the specific eculizumab product (Soliris, Epysqli, Bkemv) and anticipate site‑of‑service review for IV administration.

List the exact eculizumab product name and associated HCPCS/Q code if available.
Site‑of‑service review applies for IV eculizumab products.

Billing Rule

Use listed HCPCS/Q and J codes for eculizumab and biosimilars on PA and claims

Use the designated HCPCS Q‑codes for eculizumab biosimilars and the applicable J‑codes for eculizumab/ravulizumab on PA and billing submissions (policy lists Q5151/Q5152 and J1299/J1303 among others).

Report biosimilar Q‑codes (e.g., Q5151, Q5152) or J‑codes per the policy coding table.

Key Definitions and Clinical Thresholds

inv-71: Active hemolysis definition (LDH threshold)

Active hemolysis definitionActive hemolysis = LDH ≥ 1.5 × upper limit of normal

ApplicationDefines treatment‑naïve eligibility for anti‑C5 agents and assists assessment of residual hemolysis when switching therapies

Required documentationReport LDH value with laboratory ULN and date drawn

inv-72: PNH diagnostic threshold (clone size)

PNH diagnostic thresholdPNH diagnosis requires granulocyte or monocyte clone size ≥ 15%

Role in coverageUsed to confirm diagnosis prior to authorizing complement inhibitor therapy

Background and Clinical Context

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, complement‑mediated hemolytic disorder caused by somatic mutations resulting in deficient complement‑regulatory proteins on blood cells. Complement inhibitors targeting C3 or C5 reduce intravascular and extravascular hemolysis and lower transfusion requirements. This policy defines coverage criteria across multiple complement‑targeting agents for PNH and related complement‑mediated diseases and aligns authorization considerations with FDA indications, vaccination/REMS requirements, diagnostic thresholds (e.g., confirmed granulocyte or monocyte clone ≥ 15%), and trial evidence summarized in the product prescribing information and key trials (e.g., PEGASUS for pegcetacoplan).

Policy Revision History and Material Changes

2026-03-01coverage_criteria_updateLatest

Updated coverage criteria for Bkemv, Epijska (eculizumab-aagh), Soliris, Ultomiris, and Zilbrysq for generalized myasthenia gravis and added Uplizna to medications not to be used concurrently; clarified concurrent-use lists and eculizumab-product prior-therapy language to require completion of at least 3 months with an eculizumab product.

2025-11-01coverage_criteria_update

Added criteria for Empaveli for treatment of C3 glomerulopathy (C3G) and primary IC-MPGN for patients aged ≥12 years to reduce proteinuria.

Policy Summary

PayerPremera Bluecross

PolicyC3 and C5 Complement Inhibitors (site-of-service and medical necessity)

Policy CodePolicy 5.01.39

Change TypeAdded and revised coverage criteria

Effective Date

Next Review Date

Key ActionSubmit prior authorization with required documentation (diagnosis confirmation, relevant labs, vaccination records and specialist consultation as applicable).

SourceLink

On This Page

Hb <10.5 g/dL; LDH >=1.5x ULN

Vaccination: Received vaccinations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae at least 2 weeks prior to initiation>=2 weeks

Short-term (4-week) concomitant therapy allowed when switching; long-term concomitant therapy beyond 4 weeks is investigational.

Hb <10.5 g/dL; LDH >=1.5x ULN

Short-term (4-week) concomitant therapy allowed when switching; long-term concomitant therapy beyond 4 weeks is investigational.

Vaccination: Received vaccinations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae at least 2 weeks prior to initiation>=2 weeks

Soliris/Ultomiris carry REMS and boxed warnings for meningococcal infection

aHUS baseline criteria: For aHUS: microangiopathic hemolytic anemia (Hb <8 g/dL with negative Coombs and schistocytes), thrombocytopenia (platelets <140,000/mm3), and acute kidney injury on renal studiesHb <8 g/dL; platelets <140,000/mm3

Also exclude STEC-HUS

Step requirement for some agents: Has had an inadequate response or intolerance to Epijkstra/Epysqli (as specified) when required for certain uses

ACEi/ARB trial or intolerance: Either has tried an ACE inhibitor or ARB with persistent UPCR >= 1 g/g OR has intolerance to ACEi/ARBUPCR >=1 g/g

Biopsy fibrosis limit: Does not have >50% global glomerulosclerosis or interstitial fibrosis on baseline biopsy<=50%

Vaccination: Received vaccinations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae at least 2 weeks prior to initiation>=2 weeks

Prescriber: Medication prescribed by or in consultation with a nephrologist

Dose limited to 1,080 mg twice weekly

Vaccination: Received Neisseria meningitidis vaccination at least 2 weeks prior to initiation>=2 weeks

Concurrent medication restrictions: Medication is not being used concurrently with specified other biologics/agents listed in policy (e.g., Imaavy, Rystiggo, Vyvgart products, Ultomiris, Uplizna, Zilbrysq where applicable)

Prior inadequate response: Has had an inadequate response or intolerance to Epijkstra (eculizumab) for some eculizumab alternatives where specified

Zilbrysq requires prior failure of listed agents

Refer to state-specific exception (Alaska HB 226) and CRS exceptions in history

Non‑formulary exceptions do not waive FDA dosing requirements.

Prior Authorization

Prior Authorization and Exception Length

Initial authorizations follow drug‑specific limits: non‑formulary exception reviews may be approved up to 12 months; most other listed products (Bkemv, Empaveli, Epysqli, Piasky, Syfovre, Soliris, Tavneos, Ultomiris, Veopoz) may be approved up to 6 months for initial review. Re‑authorizations for most drugs (including Bkemv, Empaveli, Epysqli, Fabhalta, Izervay, Piasky, Soliris, Syfovre, Tavneos, Ultomiris, Veopoz, and Zilbrysq) may be approved up to 12 months if criteria are met and the chart documents continued clinical benefit.

Non‑formulary exception reviews — up to 12 months.
Initial approvals for listed products — typically up to 6 months (see drug list).
Re‑authorization — up to 12 months when continued benefit documented.

Denial Risk

Concurrent Therapy Exclusion and Switching Guidance

Concurrent use exclusions: several products must not be used concurrently with certain other complement agents. Examples include eculizumab products, Imaavy (nipocalimab), Rystiggo (rozanolixizumab), Vyvgart (efgartigimod) products, Ultomiris, and Zilbrysq — check the specific drug criteria. Short‑term (up to 4 weeks) concomitant therapy is allowed only when switching from an eculizumab product or Ultomiris to reduce hemolysis risk; long‑term concomitant use beyond specified short intervals is considered investigational.

Long‑term concurrent therapy with another listed complement inhibitor is generally excluded.
Allow short‑term (≤4 weeks) overlap when switching from eculizumab product or Ultomiris to certain agents.

Documentation Required

REMS / Boxed Warning Considerations

Several products carry REMS requirements and boxed warnings about meningococcal infection risk (for example, Soliris, Ultomiris, Zilbrysq). Providers must document meningococcal vaccination prior to initiation (or documented appropriate prophylaxis when vaccination is not feasible) and counsel patients about the infection risk per the REMS. Soliris and Ultomiris are available only through restricted REMS programs.

Document meningococcal vaccination at least 2 weeks prior to first dose when required by the product labeling.
If vaccination cannot be completed prior to therapy, document antibacterial prophylaxis per product guidance and REMS.
Ensure REMS enrollment and documentation when required (Soliris, Ultomiris, Zilbrysq).

Documentation Required

Veopoz Vaccination, Contraindication, and Documentation

Veopoz is contraindicated in individuals with unresolved Neisseria meningitidis infection. Prior to Veopoz initiation, providers must document genotype confirmation of biallelic CD55 loss‑of‑function mutation and baseline hypoalbuminemia (serum albumin <3.2 g/dL) with supporting signs/symptoms. All individuals should receive meningococcal vaccination and antibacterial prophylaxis as recommended prior to first dose.

Contraindication: unresolved Neisseria meningitidis infection.
Required documentation: confirmed biallelic CD55 mutation and baseline hypoalbuminemia (<3.2 g/dL) with clinical signs of active PLE.
Document meningococcal vaccination and prophylactic antibacterials prior to initiation.

Documentation Required

Required Clinical Documentation

Providers must submit comprehensive clinical documentation with the PA request. Medical records should demonstrate that all drug‑specific medical necessity criteria are met.

Office visit notes with diagnosis, relevant history, physical exam.
Vaccination history (meningococcal, pneumococcal, H. influenzae when required).
Medication history including prior complement inhibitors, dates, doses, and reason for discontinuation or inadequate response.
Relevant laboratory data (e.g., Hb, LDH, UPCR, eGFR, platelet count), biopsy reports (when applicable), and genotype testing (for Veopoz).
Chart notes demonstrating positive clinical response for reauthorization requests.

Note

Supporting Clinical Trial Data

Supportive clinical trial evidence should be included or referenced during review when relevant (examples: Empaveli PEGASUS and VALIANT trials for PNH and C3G/IC‑MPGN; Fabhalta APPLY‑PNH/APPOINT‑PNH trials; Ultomiris non‑inferiority trials and ALXN1210‑MG‑306 for gMG). Summaries of baseline characteristics, prior therapies, primary endpoints, and key efficacy/safety outcomes may aid medical necessity determinations.

Empaveli: PEGASUS (PNH) and VALIANT (C3G/IC‑MPGN) trial findings.
Fabhalta: APPLY‑PNH and APPOINT‑PNH trial results (prior anti‑C5 context).
Ultomiris: Phase 3 non‑inferiority studies vs eculizumab and ALXN1210‑MG‑306 for gMG.

Documentation Required

Ultomiris gMG Documentation Requirements

Ultomiris (ravulizumab) gMG documentation: for initial and continuation requests document anti‑AChR seropositivity, prior/concurrent use of acetylcholinesterase inhibitor (or documented contraindication), trial and failure or contraindication to at least two immunosuppressive therapies (or current use of ≥2 ISTs), vaccination against Neisseria meningitidis at least 2 weeks prior to initiation, and absence of concurrent excluded agents. Include baseline MG‑ADL and QMG scores when available and documentation of clinical response for reauthorization.

Document anti‑AChR antibody positive status.
Document prior/concurrent pyridostigmine use or contraindication.
Document trial/failure of ≥2 ISTs or contraindication to ≥2 ISTs.
Document meningococcal vaccination ≥2 weeks prior to first dose and that therapy is not being used concurrently with excluded agents.
Include baseline and follow‑up MG‑ADL/QMG scores.

Step Therapy

Step Requirements and Required Prior Therapies

Step therapy and prior‑therapy requirements: where specified, providers must document prior use and inadequate response or intolerance to listed agents. For some products (e.g., Fabhalta, Empaveli, Piasky, Zilbrysq), policy requires prior trial(s) with an eculizumab product or Ultomiris for a specified duration before coverage of the new agent.

Updated language: prior therapy requirement is completion of at least 3 months of therapy with an eculizumab product (rather than a specific brand) for certain drugs.
Zilbrysq (gMG) requires trial of a preferred brand product first and failure of listed alternatives (e.g., eculizumab, Ultomiris, Vyvgart products) before use.
Eculizumab trial requirement: prior use duration expressed as class‑based language (e.g., ≥3 months or other specified duration in drug criteria).

DocumentationProvide flow cytometry report showing clone size on granulocytes or monocytes

inv-41: UPCR for C3G/IC-MPGN

UPCR thresholdUrine protein-to-creatinine ratio (UPCR) ≥ 1 g/g

IndicationRequired for Empaveli coverage in C3G or primary IC‑MPGN to document proteinuria

PrerequisiteEnsure UPCR measured on an appropriate specimen (spot urine) and documented in chart

inv-42: eGFR limit for C3G/IC-MPGN

eGFR cutoffEstimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2

IndicationRequired renal function threshold for Empaveli coverage in C3G/IC‑MPGN

DocumentationReport most recent eGFR or creatinine-based calculation in medical record

inv-43: GA lesion size per eye

Lesion size per eyeTotal geographic atrophy (GA) lesion size per eye between 2.5 mm² and 17.5 mm²

Concurrent useSyfovre must not be used concurrently with Izervay per policy

Prescriber requirementPrescribed by or in consultation with an ophthalmologist

inv-44: Syfovre age

Minimum ageSyfovre indicated for individuals aged ≥ 60 years

IndicationFor treatment of geographic atrophy (GA) secondary to dry AMD

Visual acuity requirementBCVA >24 letters (approx. >20/320) as specified in criteria

inv-45: Izervay age

Minimum ageIzervay indicated for individuals aged ≥ 50 years

IndicationFor treatment of geographic atrophy (GA) secondary to dry AMD

Contraindication noteContraindicated in ocular/periocular infections and active intraocular inflammation

inv-46: confirmed granulocyte clone size

Confirmed granulocyte clone sizeDefined as granulocyte clone ≥ 15% for PNH confirmation

Policy updateConfirmed granulocyte clone size updated to ≥15% for Soliris, Ultomiris, and Empaveli coverage criteria

Acceptable assaysReport from validated flow cytometry testing required in documentation

inv-47: serum albumin for active CD55-deficient PLE

Serum albumin thresholdActive CD55‑deficient PLE defined by serum albumin < 3.2 g/dL plus symptoms

Clinical contextUsed to define active disease for Veopoz (pozelimab) initiation in CHAPLE disease

DocumentationProvide baseline serum albumin and symptom history (abdominal pain, diarrhea, peripheral or facial edema) within prior 6 months

Note

Match route and setting to product labeling (SC/oral vs IV vs intravitreal)

Recognize that routes and permitted settings differ by product — e.g., Empaveli SC and Fabhalta oral can be given outpatient/home, while Soliris and Ultomiris are IV and typically require infusion center or hospital/office settings consistent with SOS rules.

Confirm route of administration in the PA (SC, oral, IV, intravitreal) and requested site consistent with product labeling.
Home administration is appropriate for agents labeled for SC or oral self‑administration when clinical and vendor arrangements support it.

Note

Document SOS exception rationale (e.g., Alaska, CRS) when requesting non‑preferred site

Be aware the SOS criteria include exceptions (e.g., Alaska fully‑insured members and CRS exceptions); if requesting an exception, document the specific rationale and refer to the policy history or contact Customer Service as needed.

Document clinical justification when requesting hospital outpatient site under policy exceptions.
Alaska fully‑insured members follow infusion/injection medical necessity criteria instead of SOS rules.

Note

Check SOS application notes and coding history before submission

Refer to the site‑of‑service application notes in the policy and historical clarifications when planning administration location; coding and SOS applicability have been updated in recent history entries and may affect authorization.

Check policy history for coding and SOS applicability updates before submission.
Ensure PA reflects current SOS rules and HCPCS code updates.

Ensure billing aligns with the codes listed in the policy to avoid coding denials.

Billing Rule

Account for biosimilar/product preference updates (preferred → non‑preferred)

Note product preference/status updates in the policy (e.g., Bkemv and Soliris were updated from preferred to non‑preferred) and account for formulary status when requesting PA or exceptions.

If requesting a non‑preferred product, include rationale for use and consider a non‑formulary exception per policy.
Check history entries for recent preference/status changes that may affect authorization.

Documentation expectation

Provide flow cytometry report demonstrating clone percentage

inv-73: Infusion services — definition

DefinitionInfusion services: delivery of a drug directly into the bloodstream through a vein (typically arm/hand)

Typical settingsProvided in physician office, infusion center (infusion suite), home infusion, or hospital-based outpatient infusion department depending on medical necessity and site-of-service rules

DistinctionInfusion center (aka infusion suite) is independent of a hospital per policy definitions

inv-74: Infusion center — definition/alias

Alias/definitionInfusion center (aka infusion suite): a location where infusion services are provided, independent of a hospital

Role in site-of-care reviewInfusion center is a preferred medically necessary site when site-of-service criteria are met

ContrastHospital‑based outpatient infusion is not medically necessary when site-of-service criteria are not met (exceptions apply)

inv-75: C3 inhibitor — definition and examples

DefinitionC3 inhibitor: agent that binds/inhibits complement protein C3 to regulate downstream complement activation

ExamplesPegcetacoplan (Empaveli for PNH; Syfovre intravitreal for GA)

Indications notedUsed for PNH and geographic atrophy (GA) depending on formulation and approval

inv-76: C5 inhibitor — definition and examples

DefinitionC5 inhibitor: agent that inhibits complement protein C5 to prevent formation of C5a and membrane attack complex (MAC)

ExamplesEculizumab (Soliris, Epysqli, Bkemv), Ravulizumab (Ultomiris), and avacincaptad pegol (Izervay) as a C5‑targeting intravitreal agent

Clinical usesUsed across indications including PNH, aHUS, gMG (selected agents), NMOSD, and GA (intravitreal C5 inhibitor)

inv-77: C5a receptor inhibitor — definition and example (Tavneos)

DefinitionC5a receptor inhibitor: agent that blocks the C5a receptor to reduce neutrophil‑mediated inflammation

ExampleAvacopan (Tavneos) — selective C5a receptor inhibitor used in ANCA‑associated vasculitis

Clinical noteAdministered in combination with standard induction (rituximab or cyclophosphamide) per criteria

inv-78: CHAPLE disease — definition

DefinitionCHAPLE disease: CD55‑deficient protein‑losing enteropathy due to biallelic CD55 loss‑of‑function mutations causing complement overactivation and protein loss

Clinical featuresLeads to hypoalbuminemia, protein‑losing enteropathy symptoms (abdominal pain, diarrhea), peripheral/facial edema

Treatment noteVeopoz (pozelimab) indicated for CHAPLE disease in individuals ≥1 year with genetic confirmation

inv-79: gMG definition

DefinitiongMG (generalized myasthenia gravis): autoimmune neuromuscular disease often associated with anti‑AChR antibodies causing fluctuating skeletal muscle weakness

Clinical relevanceSeveral complement inhibitors are approved for anti‑AChR antibody–positive adult patients when specified criteria are met

Typical requirementsDocumentation of positive anti‑AChR serology, baseline functional scores, and prior IST trials per policy

inv-80: 'eculizumab product' collective term definition

Policy useTerm used to specify prior‑therapy requirements (e.g., completion of ≥3 months of therapy with an eculizumab product) for certain alternative agents

DocumentationRecord product name and treatment duration when documenting prior eculizumab exposure

coverage_criteria_update

Required a trial with a preferred brand product first for Zilbrysq myasthenia gravis coverage and updated coding and product preference changes to reflect eculizumab products as preferred/non-preferred (effective Jan 2, 2026 for some changes).

2025-04-01coding_and_criteria_update

Interim review approved March 11, 2025: updated Izervay criteria removing duration limit, added HCPCS code J1299 (termed J1300), and clarified that Site of Service criteria can apply to injection drugs.

2024-03-01coverage_and_coding_update

Annual review approved Feb 14, 2023 and subsequent 2024 updates: added coverage for Ultomiris SC on-body injector for maintenance PNH/aHUS and added Syfovre for geographic atrophy earlier in 2023; coding updates added through 2024 are recorded in history.

2023-10-01coverage_addition

Added coverage for Veopoz (pozelimab-bbfg) for treatment of CD55-deficient protein-losing enteropathy (CHAPLE) and added HCPCS code J2781.

Denial Risk

Check updated concurrent‑use prohibitions before approving therapy

When assessing concurrent‑use lists, verify the member is not on any prohibited concurrent medications; the policy history clarifies concurrent‑use prohibitions added in recent updates and lists specific agents not to be used together.

Confirm absence of prohibited concurrent biologics (Imaavy, Rystiggo, Vyvgart products, Ultomiris, Zilbrysq, etc.) before approving therapy for gMG and other indications.
Document any prior authorization denials or clinical reasons that explain concurrent therapy if present.

Documentation Required

Confirm and document granulocyte clone size ≥15% for PNH coverage

For PNH coverage, confirm granulocyte clone size has been updated in policy history to a threshold of ≥15% when providing diagnostic documentation for eculizumab, ultomiris, and Empaveli approvals.

Provide test results showing granulocyte or monocyte clone size ≥15% as required by policy.
Reference the updated threshold when documenting diagnostic confirmation for PNH.