Medical benefit coverage criteria for specified complement inhibitor products for multiple indications (aHUS, PNH, gMG, NMOSD) including initial and continuation authorization requirements; applies to UnitedHealthcare commercial plans referenced in the document.
Bkemv (eculizumab-aeeb) and Epijski (epysqli) have been added to the list of applicable complement inhibitor drug products and to the Review at Launch program; some members may not be eligible for coverage under Review at Launch.
Coverage criteria were revised to reference 'a complement C5 inhibitor' (class-based language) instead of naming only Soliris/Ultomiris and to expand combination-therapy prohibitions to include additional complement inhibitors and FcRn blockers where applicable.
HCPCS codes Q5151 and Q5152 were added to the Applicable Codes section.
5named drug products
4indications detailed
12 monthsmax approval length
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aHUS initial: Documentation supporting aHUS diagnosis by ruling out STEC-HUS and TTP (e.g., rule out ADAMTS13 deficiency); laboratory results, signs, and/or symptoms attributed to aHUS (e.g., thrombocytopenia, microangiopathic hemolysis, thrombotic microangiopathy, acute renal failure); patient is treatment naïve to the requested product; dosing per US FDA labeled dosing for aHUS; prescribed by or in consultation with a hematologist or nephrologist; initial authorization will be for no more than 12 months.
Referenced clinical trial entry criteria include platelet count ≤150 x10^9/L, evidence of hemolysis (elevated LDH), and elevated serum creatinine or dialysis requirement; Complete TMA Response defined by normalization of platelet count and LDH plus ≥25% improvement in serum creatinine assessed ≥28 days apart.
aHUS continuation: Patient has previously been treated with the requested product; documentation demonstrating a positive clinical response from baseline (e.g., reduction of plasma exchanges, reduction of dialysis, increased platelet count, reduction of hemolysis); dosing per US FDA labeled dosing for aHUS; prescribed by or in consultation with a hematologist or nephrologist; reauthorization will be for no more than 12 months.
PNH initial: Documentation supporting PNH diagnosis including flow cytometry confirming presence of PNH clones and laboratory results, signs, and/or symptoms attributed to PNH; dosing per US FDA labeled dosing for PNH; patient is not receiving the requested product in combination with another complement C5 inhibitor, a complement C3 inhibitor (e.g., pegcetacoplan), or a complement factor B inhibitor (e.g., iptacopan); for PiaSky (crovalimab) initial authorization only: history of trial and failure, contraindication, or intolerance to a complement C5 inhibitor, Empaveli (pegcetacoplan), and Fabhalta (iptacopan) as specified; prescribed by or in consultation with a hematologist or oncologist; initial authorization will be for no more than 12 months.
PNH continuation: Patient has previously been treated with the requested product; documentation demonstrating a positive clinical response from baseline (e.g., stabilization/increase of hemoglobin, reduction in transfusions, improvement in hemolysis, decrease in LDH, increased reticulocyte count); dosing per US FDA labeled dosing for PNH; patient is not receiving the requested product in combination with another complement C5 inhibitor, a complement C3 inhibitor, or a complement factor B inhibitor; for PiaSky, not in combination with a factor D inhibitor when specified; prescribed by or in consultation with a hematologist or oncologist; reauthorization will be for no more than 12 months.
gMG initial: Submission of medical records confirming: no prior failure of a complement C5 inhibitor; diagnosis of generalized myasthenia gravis; positive anti‑AChR antibody serology; MGFA Clinical Classification II, III, or IV at initiation; MG‑ADL total score ≥ 6 at initiation; history of failure of ≥2 immunosuppressive agents over ≥12 months OR failure of at least one immunosuppressive therapy plus ≥4 courses of plasmapheresis/IVIG over ≥12 months without control; dosing per US FDA labeled dosing for gMG; patient is not receiving the requested product in combination with another complement C5 inhibitor or an FcRn blocker; prescribed by or in consultation with a neurologist; initial authorization will be for no more than 12 months.MG-ADL ≥ 6
Medicare-specific references in CMS section for some prior‑therapy requirements.
gMG continuation: Patient has previously been treated with the requested product; submission of medical records demonstrating ≥2‑point improvement in MG‑ADL from baseline and reduction in signs/symptoms of myasthenia gravis; maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (add‑on, escalation, or rescue therapy considered treatment failure); dosing per US FDA labeled dosing for gMG; patient is not receiving another complement C5 inhibitor or an FcRn blocker for the same indication; prescribed by or in consultation with a neurologist; reauthorization will be for no more than 12 months.
NMOSD initial: Diagnosis of NMOSD by a neurologist with past medical history consistent with NMOSD clinical syndromes (e.g., optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic diencephalic or cerebral syndrome); positive AQP4‑IgG serology; other diagnoses (e.g., multiple sclerosis) ruled out; patient has not failed a prior complement C5 inhibitor for NMOSD; history of failure/contraindication/intolerance to rituximab therapy as applicable for Medicare reviews; history of ≥2 relapses in prior 12 months OR ≥3 relapses in prior 24 months with ≥1 in prior 12 months; dosing per US FDA labeled dosing for NMOSD; prescribed by or in consultation with a neurologist; patient is not receiving concomitant MS disease‑modifying therapies, anti‑IL6 therapy, or B‑cell depletion therapy for the same indication; initial authorization will be for no more than 12 months.Relapse history per criteria
NMOSD continuation: Patient has previously been treated with the requested product; documentation of positive clinical response from baseline demonstrated by reduction in number and/or severity of relapses and maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (add‑on/escalation considered treatment failure); dosing per US FDA labeled dosing for NMOSD; prescribed by or in consultation with a neurologist; patient is not receiving concomitant MS DMTs, anti‑IL6 therapy, or B‑cell depletion therapy for the same indication; reauthorization will be for no more than 12 months.
aHUS (initial therapy)
Covered when ALL of the following are met (example: aHUS, ravulizumab/eculizumab):
aHUS coverage criteria: Patient has a diagnosis of atypical hemolytic uremic syndrome and meets diagnostic/clinical trial‑like criteria such as platelet count ≤150 x10^9/L, evidence of hemolysis (elevated LDH), and serum creatinine above the upper limit of normal or requires dialysis; documentation of prior complement inhibitor exposure as applicable; dosing per US FDA labeled dosing; prescribed by or in consultation with a hematologist or nephrologist.see text
Complete TMA Response definition: normalization of platelet count and LDH plus ≥25% improvement in serum creatinine at two assessments ≥28 days apart; trial‑based entry criteria summarized from Rondeau et al.
PNH (initial or switch therapy)
Covered when ALL of the following are met (example: PNH, complement inhibitors):
PNH coverage criteria: Patient has a diagnosis of paroxysmal nocturnal hemoglobinuria; for treatment‑naïve PNH with active hemolysis, evidence includes LDH ≥1.5×ULN and at least one PNH symptom; for switching therapies document prior eculizumab therapy and persistent anemia or inadequate response when relevant; dosing per US FDA labeled dosing; meningococcal vaccination or appropriate antibiotic prophylaxis documented; prescribed by or in consultation with a hematologist or oncologist.see text
Trials used LDH ≥1.5×ULN for enrollment and defined hemolysis control as LDH ≤1.5×ULN and breakthrough hemolysis as LDH ≥2×ULN with new/worsening hemolysis symptoms; pegcetacoplan demonstrated superiority to eculizumab in patients with persistent anemia on eculizumab.
Generalized myasthenia gravis (gMG)
Covered when ALL of the following are met (example: generalized myasthenia gravis):
gMG coverage criteria: Patient has generalized myasthenia gravis with MG‑ADL score ≥6 and MGFA Class II‑IV; prior failure of at least two immunosuppressive agents over ≥12 months or failure of at least one immunosuppressive therapy plus ≥4 courses of plasmapheresis/IVIG over ≥12 months without control per trial criteria; meningococcal vaccination documented; dosing per US FDA labeled dosing; prescribed by or in consultation with a neurologist.see text
Covered when ALL of the following are met (example: AQP4+ NMOSD):
NMOSD coverage criteria: Patient is adult with AQP4‑IgG positive neuromyelitis optica spectrum disorder with history of relapses (e.g., ≥2 relapses in prior 12 months or ≥3 in prior 24 months with at least one in prior 12 months) and EDSS ≤7; meningococcal vaccination documented; dosing per US FDA labeled dosing; prescribed by or in consultation with a neurologist.see text
Ravulizumab and eculizumab trial entry and primary endpoint criteria summarized (CHAMPION‑NMOSD, PREVENT).
General combination and prior-therapy criteria
Covered when ALL of the following are met for each indication per policy (examples summarized from revisions):
Class-substitution and combination therapy rules: Patient is not receiving the requested product in combination with a different complement C5 inhibitor (e.g., Bkemv, Epysqli, PiaSky, Soliris, Ultomiris) for the same indication; where specified for an indication, patient is also not receiving concomitant FcRn blockers, complement C3 inhibitors, complement factor B inhibitors, disease‑modifying therapies for MS, anti‑IL6 therapy, or B‑cell depletion therapy for the same indication.
Replaced prior product‑specific combination prohibitions with class‑based language; see indication sections for therapies specifically prohibited per indication.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
PNH-specific (summary of revision):
PNH prior therapy/combo: Patient is not receiving the requested product in combination with a different complement C5 inhibitor for treatment of the same indication; PiaSky initial authorization requires history of trial and failure, contraindication, or intolerance to a complement C5 inhibitor class as specified.
Replaced product‑specific language to reference complement C5 inhibitor class (e.g., Bkemv, Epysqli, PiaSky, Soliris, Ultomiris).
Generalized Myasthenia Gravis (gMG)
Generalized myasthenia gravis (AChR antibody positive) specific (summary of revision):
gMG prior therapy: Patient has not failed a previous course of a complement C5 inhibitor therapy (e.g., Bkemv, Epysqli, Soliris, Ultomiris, or Zilbrysq) and is not receiving the requested product in combination with another complement C5 inhibitor or an FcRn blocker for treatment of the same indication.
Expanded prior‑failure and combination therapy language to include additional agents and classes.
Neuromyelitis Optica Spectrum Disorder (NMOSD)
Neuromyelitis optica spectrum disorder (NMOSD) specific (summary of revision):
NMOSD prior therapy/combo: Patient has not failed a previous course of a complement C5 inhibitor therapy for NMOSD (e.g., Bkemv, Epquelize, Soliris, Ultomiris) and is not receiving the requested product in combination with disease‑modifying therapies FDA‑approved for multiple sclerosis or other prohibited concomitant therapies for the same indication.
Replaced product‑specific references with class‑based language and generalized combination therapy prohibition to MS DMTs and other specified agents.
Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), Soliris (eculizumab), and Ultomiris (ravulizumab) are considered unproven and not medically necessary for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS).
Eculizumab is not indicated for treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC‑HUS); available studies are limited and further evidence is needed to establish safety and effectiveness in this indication.
Eculizumab products and related complement inhibitors listed in this policy (including brand, biosimilar, and class members) are not indicated for treatment of STEC‑HUS and therefore use of these agents for STEC‑HUS is considered unproven.
Requests for a listed complement inhibitor will be denied when the product is prescribed in combination with another complement C5 inhibitor for the same indication. The policy also prohibits combination use with specified alternative complement pathway inhibitors (e.g., complement C3 or factor B inhibitors) and with FcRn blockers where noted; such combinations are considered not medically necessary.
Treatment of STEC‑HUS with eculizumab or other listed complement inhibitors is considered unproven and, in the absence of stronger supporting evidence, would be considered not medically necessary.
Use of eculizumab for STEC‑HUS is explicitly considered unproven and not medically necessary and may be denied when submitted for this indication.
Laboratory threshold used for PNH Study 301 enrollment (not a billing code)
Applicable HCPCS Codes AddedHCPCS
Q5151
HCPCS code added (document lists Q5151)
Q5152
HCPCS code added (document lists Q5152)
MG-ADL score
MG-ADL thresholdMyasthenia Gravis Activities of Daily Living (MG-ADL) total score ≥ 6 at initiation of therapy
MGFA class requirementMGFA Clinical Classification II, III, or IV at initiation
Prior C5 inhibitor failure prohibitionPatient has not failed a previous course of a complement C5 inhibitor therapy prior to initiation
NMOSD relapse history
Primary relapse threshold (12 months)History of ≥ 2 relapses during the previous 12 months prior to initiating therapy
Alternate relapse threshold (24 months)
Prior Authorization, Documentation, and Step Therapy
Prior Authorization
Prior Authorization Required
Prior authorization is required for the listed complement inhibitor products. Initial and reauthorization approvals are limited to a maximum of 12 months and require submission of supporting clinical documentation demonstrating the indication-specific eligibility and benefit from therapy.
Applies to Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), PiaSky (crovalimab), Soliris (eculizumab), and Ultomiris (ravulizumab).
Some newly launched products (Bkemv and Epysql i) may be subject to the payer's Review at Launch program; eligibility for coverage may be restricted—see Review at Launch policy.
Documentation Required
Indication- and Trial-Aligned Documentation Required
Prior authorization requests must include indication-aligned, trial-specific documentation at initiation and for continuation requests. Provide clear evidence that the patient meets diagnosis and trial-entry criteria relevant to the requested indication.
Background and Clinical Context
Complement C5 inhibitors (including eculizumab products, ravulizumab, and crovalimab) are indicated for complement‑mediated disorders such as atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (anti‑AChR positive), and neuromyelitis optica spectrum disorder (AQP4‑IgG positive). These agents act by inhibiting terminal complement activity and have demonstrated benefit in clinical trials for these conditions; prescribers should follow indication‑specific diagnostic and monitoring requirements when requesting coverage.
Definitions and Clinical Endpoints
Complete TMA Response
Platelet and LDH normalizationNormalization of platelet count and lactate dehydrogenase (LDH)
Serum creatinine improvement≥ 25% improvement in serum creatinine from baseline
Repeat assessment timingCriteria must be met at two separate assessments obtained at least 28 days (4 weeks) apart
AQP4-IgG positive NMOSD
DefinitionNeuromyelitis optica spectrum disorder (NMOSD) with positive anti‑aquaporin‑4 immunoglobulin G (AQP4‑IgG) serology
Diagnostic requirementDiagnosis by a neurologist with MS and other alternative diagnoses ruled out
Policy Revision History and Material Changes
2025-09-01operational_updateLatest
Bkemv (eculizumab-aeeb) and Epysqli (eculizumab-aagh) were added to the list of applicable complement inhibitor drug products and included in the Review at Launch program; some members may not be eligible for coverage under Review at Launch.
2025-09-01coverage_criteria_revisionLatest
Coverage criteria were revised to generalize product-specific language to class-based references (e.g., 'a complement C5 inhibitor') and to expand combination-therapy prohibitions to include additional complement inhibitors and FcRn blockers where applicable.
History of ≥ 3 relapses during the previous 24 months with at least one relapse occurring within the past 12 months
AQP4-IgG requirementPositive serologic test for anti-aquaporin-4 immunoglobulin G (AQP4-IgG)/NMO-IgG antibodies required for diagnosis
Laboratory and clinical thresholds
PNH enrollment LDHLDH ≥ 1.5 × ULN used as an enrollment criterion in PNH trials (hemolysis threshold)
Hemolysis control definitionLDH ≤ 1.5 × ULN used to define hemolysis control in trials
Breakthrough hemolysis definitionBreakthrough hemolysis defined as new/worsening hemolysis with LDH ≥ 2 × ULN after prior reduction to ≤ 1.5 × ULN on treatment
aHUS Complete TMA entry labsPlatelet count ≤ 150 × 10^9/L and evidence of hemolysis (elevated LDH) and serum creatinine above upper limit of normal or dialysis requirement in aHUS trials
For PNH: flow cytometry confirming PNH clones; documentation of PNH signs/symptoms (e.g., anemia, hemoglobinuria, thrombosis, renal disease) and prior therapy history.
For aHUS: documentation ruling out STEC-HUS and TTP (e.g., ADAMTS13 testing) plus laboratory and clinical signs consistent with aHUS.
For gMG: medical records confirming diagnosis, positive anti-AChR serology, MGFA clinical classification (Class II–IV), MG-ADL score ≥ 6 at initiation, and documentation of prior complement C5 inhibitor exposure or absence of prior failure as required.
Include baseline labs (e.g., LDH with threshold where applicable such as LDH ≥ 1.5x ULN when referenced by trial criteria), transfusion history, dialysis/exchange requirements, FACIT‑Fatigue or hemoglobin change data when relevant to demonstrate benefit.
Documentation Required
REMS Enrollment and Meningococcal Vaccination
Enrollment in the applicable REMS program and meningococcal vaccination documentation are required. Provide proof of prescriber REMS enrollment and vaccination status before or at therapy initiation, or documentation of appropriate prophylactic antibiotic use if vaccination is delayed.
REMS enrollment required for Bkemv, Epysqli, PiaSky, Soliris, and Ultomiris — include REMS prescriber enrollment ID or supporting documentation.
Document completion or update of meningococcal vaccination at least 2 weeks prior to the first dose when feasible; if treatment cannot be delayed, document counseling and any prophylactic antibiotic plan and monitoring for meningococcal infection.
Monitor and document vigilance for invasive Neisseria meningitidis infection signs; note that vaccination does not eliminate risk and infections must be evaluated promptly.
Step Therapy
Step Therapy / Prior Failure Requirements
Step-therapy and prior-failure requirements apply for certain products and indications. Authorization may require evidence of trial and failure, contraindication, or intolerance to a prior complement C5 inhibitor or other specified agents before approving an alternative complement inhibitor.
For PiaSky (crovalimab) initial authorization in PNH: require trial and failure, contraindication, or intolerance to a complement C5 inhibitor (Bkemv, Epysqli, Soliris, or Ultomiris) — Medicare reviews may follow CMS-specific rules.
For gMG and NMOSD where the policy specifies prior C5 exposure: document prior course and outcome (failure/intolerance) of a complement C5 inhibitor where the revised criteria require it.
Requests for combination use of more than one complement C5 inhibitor, or concurrent use with an FcRn blocker for the same indication, may be denied — include documentation if combination therapy is clinically justified.
Note
Alternative Therapy Consideration for PNH
When alternative therapies have evidence of benefit in specific clinical scenarios, submit supporting clinical rationale and objective data. For PNH patients remaining anemic on C5 inhibitor therapy, evidence for switching to or using a complement C3 inhibitor (e.g., pegcetacoplan) should be provided if proposing an alternative to a C5 inhibitor.
Include hemoglobin trends, transfusion history, FACIT‑Fatigue changes, and other trial-relevant outcomes demonstrating insufficient response to current C5 inhibitor therapy.
If requesting an alternative agent (e.g., Empaveli/pegcetacoplan) document prior therapy, rationale for switching, and expected benefit based on clinical trial evidence.
Typical clinical history
Past medical history consistent with NMOSD-related events (e.g., optic neuritis, acute myelitis, area postrema syndrome, brainstem or diencephalic/cerebral syndromes)
Complete TMA Response
Platelet and LDH normalizationNormalization of platelet count and lactate dehydrogenase (LDH)
Serum creatinine improvement≥ 25% improvement in serum creatinine from baseline
Assessment intervalMust be documented at two assessments at least 28 days apart
Breakthrough hemolysis
Clinical worsening plus LDH thresholdBreakthrough hemolysis: new or worsening signs/symptoms of intravascular hemolysis with LDH ≥ 2 × ULN after prior reduction of LDH to ≤ 1.5 × ULN on treatment
Context in trialsUsed as a secondary efficacy endpoint in PNH trials (e.g., crovalimab vs eculizumab) to capture on‑treatment hemolytic episodes
Associated clinical measuresMay coincide with transfusion requirement or hemoglobin decline though definition centers on LDH increase plus clinical worsening
REMS
DefinitionRisk Evaluation and Mitigation Strategy (REMS): a restricted program under which certain complement inhibitors are available and prescribers must enroll and comply with program requirements
Products includedBkemv, Epysqli, PiaSky, Soliris, and Ultomiris are available only through a restricted REMS program
Prescriber obligationsPrescribers must enroll in the REMS program and comply with REMS enrollment and program requirements; document REMS enrollment
Meningococcal vaccination requirement
Vaccination timingComplete or update meningococcal vaccination at least 2 weeks prior to the first dose of certain complement inhibitors (e.g., PiaSky, Soliris, Ultomiris) unless risks of delaying therapy outweigh infection risk
If urgent therapy neededIf urgent therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and consider antibiotic prophylaxis per trial practices
Monitoring after vaccinationPatients remain at increased risk for invasive Neisseria meningitidis even after vaccination; monitor for early signs and evaluate immediately if infection suspected
2025-09-01coding_updateLatest
HCPCS codes Q5151 and Q5152 were added to the Applicable Codes section.