ModifiedmhnPolicy CP.PHAR.524

Clinical Policy: Pegcetacoplan (Empaveli, Syfovre)

Defines medical necessity, prior authorization, dosing, and coverage criteria for pegcetacoplan (Empaveli and Syfovre) for PNH, C3G/IC‑MPGN, and geographic atrophy across commercial, HIM, and Medicaid lines of business.

Policy Summary

Payermhn

PolicyClinical Policy: Pegcetacoplan (Empaveli, Syfovre)

Policy CodePolicy CP.PHAR.524

Change TypeMaterial updates: new C3G indicationrevised contraindicationsdosing frequency clarified for GA

Effective DateMay 14, 2021

Next Review Date

Key ActionObtain prior authorization with documentation of diagnosis, prescriber specialty, age, relevant labs or imaging, and exclusion of concurrent prohibited therapies.

SourceLink

POLICY UPDATE CHANGES

Added criteria for new FDA-approved indication of C3G/primary IC-MPGN for Empaveli.

Revised Empaveli contraindications and added newer therapies Empaveli should not be prescribed concurrently with for PNH (e.g., Epysqli, PiaSky, Fabhalta, Voydeya, Bkemv).

Revised continued approval duration for PNH from 6 to 12 months and added improvement of extravascular hemolysis as an example of positive response.

For GA (Syfovre), maximum dosing frequency revised from every month to every 25 days and CNV exclusion clarified to apply only to the eye(s) affected by GA.

Added HCPCS code J2781 and removed inactive HCPCS code C9151.

3indications covered

12 monthstypical reapproval

6 months

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Coverage and Medical Necessity Criteria

Prior Authorization

Prior Authorization Required

Prior authorization required. Providers must obtain prior authorization before dispensing Empaveli (pegcetacoplan) or Syfovre for the indications in this policy.

Prior authorization required for Empaveli (PNH, C3G/primary IC‑MPGN) and Syfovre (Geographic Atrophy).
Provider must document dosing, weight-based calculations (where applicable), and relevant laboratory/imaging results at the time of the prior authorization request (e.g., LDH, hemoglobin, UPCR, eGFR, fundus autofluorescence imaging, BCVA).
Providers switching patients from Soliris/Bkemv/Epysqli to Empaveli must submit attestation documenting whether concurrent Soliris/Bkemv/Epysqli therapy is present and, if transitioning, the 4‑week cross‑titration plan.
For claims submission, reference the most current professional coding guidance; inclusion of codes in this policy is informational and does not guarantee payment.

Billing Rule

Coding and Coverage Caution

Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up‑to‑date sources of professional coding guidance prior to claim submission.

HCPCS J2781 — Injection, pegcetacoplan, intravitreal, 1 mg (informational).
HCPCS J7799 — Not otherwise classified drugs, other than inhalation drugs, administered through DME (informational).

Documentation Required

Required Dosing and Coding Documentation

When requesting authorization or preparing claims, include specific dosing details and supporting clinical data to avoid delays or denials.

Document actual dose, frequency, route (SC for Empaveli; intravitreal for Syfovre), and total weekly/monthly dose.
Attach laboratory values and imaging: LDH and hemoglobin for PNH; UPCR and eGFR and kidney biopsy report for C3G/IC‑MPGN; fundus autofluorescence images and BCVA for GA.
For pediatric dosing, document current weight and calculation used to select regimen.
If requesting doses above standard regimen, provide clinical rationale and relevant labs (e.g., LDH >2x ULN).

Step Therapy

Therapy Sequencing Notes

Therapy sequencing and concurrent‑therapy prohibitions are enforced per indication and updated as new therapies receive approval.

Empaveli should not be prescribed concurrently with Syfovre.
For PNH, Empaveli should not be prescribed concurrently with other FDA‑approved PNH complement inhibitors (examples include Soliris, Ultomiris, Fabhalta, Voydeya, Bkemv, Epysqli, PiaSky).
Cross‑titration: when switching from Soliris/Bkemv/Epysqli to Empaveli, continue the prior therapy for 4 weeks after initiating Empaveli then discontinue the prior therapy; provider attestation required.
When switching from Ultomiris, Empaveli should be initiated no more than 4 weeks after the last Ultomiris dose.

Denial Risk

Coverage Caveats

Uses not on‑label and not supported by evidence or relevant off‑label use policies are considered not authorized.

Non‑FDA approved indications not addressed in this policy require documentation per off‑label use policies: CP.CPA.09 (commercial), HIM.PA.154 (health insurance marketplace), CP.PMN.53 (Medicaid).
Inclusion or exclusion of codes in this policy does not by itself guarantee coverage; coding alone does not determine coverage.

Initial Therapy — Rules and Switching

Initial therapy rules

Initial therapy coverage criteria are indication‑specific and must all be met.

Initial therapy rules: Refer to the per‑indication initial criteria for PNH, C3G/primary IC‑MPGN, and GA; all listed conditions for the relevant indication must be satisfied for initial approval.

Initial therapy and switching

Initial dosing and switching rules

Switching from Soliris/Bkemv/Epysqli: Initiate Empaveli while continuing Soliris, Bkemv, or Epysqli at the current dose; after 4 weeks discontinue the prior agent and continue Empaveli monotherapy.

Provider attestation of concomitant therapy presence/absence may be required.

Switching from Ultomiris:

Continuation Therapy and Reapproval

Continuation Therapy — PNH (Empaveli)

Covered when ALL of the following are met

PNH Continuation: 1. Member is currently receiving medication via the health plan benefit or previously met initial approval criteria, or is enrolled in continuity of care provisions. 2. Request is for Empaveli. 3. Member is responding positively to therapy as evidenced by improvement in measures of intravascular or extravascular hemolysis (e.g., LDH normalization, reduced reticulocyte count, reduced bilirubin), reduced transfusion need, increased/stable hemoglobin, less fatigue, improved health‑related quality of life, or fewer thrombotic events. 4. Empaveli is not prescribed concurrently with either: a) Syfovre; or b) another FDA‑approved product for PNH (e.g., Soliris, Ultomiris, Fabhalta, Voydeya, Bkemv, Epysqli, PiaSky). 5. If requesting a dose increase, new dose does not exceed 2,160 mg per week or 1,080 mg every 3 days (total 10 doses per month) with documentation of LDH > 2× ULN for higher dosing.

Continuation Therapy — C3G/IC‑MPGN (Empaveli)

Covered when ALL of the following are met

C3G Continuation: 1. Member is currently receiving medication via the health plan benefit or previously met initial approval criteria, or is enrolled in continuity of care provisions. 2. Request is for Empaveli. 3. Member is responding positively to therapy as evidenced by decreased UPCR from baseline or reduction in total urine protein per day from baseline. 4. Empaveli is not prescribed concurrently with either: a) Syfovre; or b) another FDA‑approved product for C3G/IC‑MPGN (e.g., Fabhalta). 5. If requesting a dose increase, new dose does not exceed the specified weight‑based regimens (≥50 kg: 1,080 mg twice weekly; 35–<50 kg: 810 mg twice weekly; <35 kg: 648 mg twice weekly).

Step Therapy and Concomitant Therapy Restrictions

Step	Requirement	Notes
1	Failure of at least a 12-week trial of a renin-angiotensin-aldosterone system (RAAS) inhibitor at up to maximally indicated doses (e.g., irbesartan, losartan, lisinopril, benazepril)	Required prior to initiating Empaveli for C3G or primary IC‑MPGN unless contraindicated or significant adverse effects; Appendix D lists agents and max doses
2	Documentation of UPCR ≥ 1 g/g and eGFR ≥ 30 mL/min/1.73 m2	Both lab criteria must be met per initial approval requirements
3	Prescribed by or in consultation with a nephrologist	Applies to members age ≥ 12 years
4	Empaveli is not prescribed concurrently with Syfovre or another FDA-approved product for C3G/IC‑MPGN (e.g., Fabhalta)	Concurrent use prohibited per policy
5	Dose does not exceed indicated weight-based regimens (≥50 kg: 1,080 mg twice weekly; 35–<50 kg: 810 mg twice weekly; <35 kg: 648 mg twice weekly)	Weight-based dosing limits required for approval

Concurrent Therapy	Policy Stance	Exception / Notes
Soliris (eculizumab)	Empaveli should not be prescribed concurrently with listed complement therapies for PNH	Exception: allowed short cross-titration (continue prior agent for up to 4 weeks when initiating Empaveli) per switching guidance
Ultomiris (ravulizumab)	Concurrent prescribing with Empaveli is avoided	When switching from Ultomiris initiate Empaveli within 4 weeks of last Ultomiris dose (timing requirement for switch)
Fabhalta, Voydeya, Bkemv, Epysqli, PiaSky and other listed complement therapies	Policy history expanded list of therapies with which Empaveli should not be prescribed concurrently	Short cross-titration exceptions limited and defined in switching guidance; otherwise concurrent use is prohibited

Step Therapy

RAAS inhibitor trial required before Empaveli for C3G/IC‑MPGN

For C3G or primary IC‑MPGN, the member must have failed a trial of a RAAS inhibitor for at least 12 weeks at up to maximally indicated doses unless contraindicated or significant adverse effects occurred.

Appendix D lists RAAS agents and maximum doses (e.g., irbesartan, losartan, lisinopril, benazepril).
Illinois HIM requests: step therapy requirements do not apply as of 1/1/2026 per IL HB 5395 (see policy notes).

Coding and Billing

HCPCS Codes referencedHCPCS

J2781	Injection, pegcetacoplan, intravitreal, 1 mg
J7799	Noc drugs, other than inhalation drugs, administered through dme

inv-13: Total GA area — ≥ 2.5 and ≤ 17.5 mm2

Total GA area≥ 2.5 and ≤ 17.5 mm2

Measurement methodConfirmed on fundus autofluorescence imaging

Disk area equivalence1 to 7 disk areas (DA) corresponding to 2.5–17.5 mm2

inv-14: Multifocal GA focal lesion — at least one focal lesion ≥ 1.25 mm2

Multifocal GA requirementAt least one focal lesion ≥ 1.25 mm2

Imaging modalityConfirmed on fundus autofluorescence imaging

Disk area equivalence

Quantity Limits and Dosing Limits

inv-40: Syfovre — 15 mg

Syfovre strength15 mg per intravitreal injection (0.1 mL of 150 mg/mL)

RouteIntravitreal injection to each affected eye

Maximum frequencyMaximum dosing frequency every 25 days per label

inv-41: Empaveli (PNH) — Maximum 2,160 mg per week or 1,080 mg every 3 days (total 10 doses per month)

Empaveli (PNH) maximum regimenMaximum 2,160 mg per week or 1,080 mg every 3 days (total 10 doses per month)

Typical adult dose regimen1,080 mg SC twice weekly

Product vial strength

Prior Authorization, Documentation, and Provider Responsibilities

Prior Authorization

Prior authorization required with clinical documentation

Prior authorization is required for Empaveli and Syfovre; requests must include diagnosis, prescriber specialty, patient age, and relevant laboratory or imaging criteria and must show exclusion of concurrent prohibited therapies and adherence to dosing limits per indication.

For GA (Syfovre) include fundus autofluorescence imaging confirming GA characteristics per policy thresholds.
For PNH and C3G include relevant labs (e.g., hemoglobin, flow cytometry, UPCR, eGFR) as applicable.

Prior Authorization

Prior authorization applies per payer clinical rules (policy pre-emptive / updated)

This policy contains pre-emptive criteria and was updated to align with FDA labeling; prior authorization determinations for pegcetacoplan products will be applied per the payer's clinical policy and coding rules.

HCPCS codes J2781 and J7799 are referenced in the policy for billing context; prior authorization decisions remain subject to payer clinical rules.

Administration Setting

Note

Administration routes: Syfovre intravitreal; Empaveli subcutaneous

Syfovre is administered via intravitreal injection to the affected eye(s); Empaveli is administered subcutaneously.

Document intended site of care and route when requesting authorization (intravitreal injection for Syfovre; subcutaneous injection for Empaveli).

Note

Site of care and product availability — Empaveli SC (on‑body injector noted); Syfovre intravitreal

Empaveli is given subcutaneously (on‑body injector referenced in product history) and may be administered in office, infusion center, or hospital outpatient settings; Syfovre is given by intravitreal injection in office or clinic settings.

When requesting coverage, specify site of care and device/formulation (Empaveli single‑dose vial 1,080 mg/20 mL; Syfovre single‑dose vial 150 mg/mL).

Definitions and Abbreviations

inv-30: PNH — Paroxysmal nocturnal hemoglobinuria (abbreviated in appendix).

PNH abbreviationParoxysmal nocturnal hemoglobinuria (PNH)

Appendix referenceSee Appendix A: Abbreviation/Acronym Key for definitions

Use in policyAbbreviation used throughout policy and appendix

inv-31: GA — Geographic atrophy (abbreviated in appendix).

GA abbreviationGeographic atrophy (GA)

Appendix referenceSee Appendix A: Abbreviation/Acronym Key for definitions

Context

Background and Clinical Context

Pegcetacoplan is a complement C3/C3b inhibitor available in two formulations: subcutaneous systemic formulation marketed as Empaveli for paroxysmal nocturnal hemoglobinuria (PNH) and for the newly FDA‑approved indication of C3 glomerulopathy/primary immune‑complex membranoproliferative glomerulonephritis (C3G/IC‑MPGN), and an intravitreal formulation marketed as Syfovre for geographic atrophy (GA) secondary to age‑related macular degeneration. Empaveli dosing and switching guidance address specific SC regimens, REMS‑related infection precautions, and restrictions on concurrent complement therapies; Syfovre is administered intravitreally (15 mg per affected eye) following the labeled interval.

Policy Summary

Payermhn

PolicyClinical Policy: Pegcetacoplan (Empaveli, Syfovre)

Policy CodePolicy CP.PHAR.524

Change TypeMaterial updates: new C3G indicationrevised contraindicationsdosing frequency clarified for GA

Effective DateMay 14, 2021

Next Review Date

Key ActionObtain prior authorization with documentation of diagnosis, prescriber specialty, age, relevant labs or imaging, and exclusion of concurrent prohibited therapies.

SourceLink

On This Page

Initiate Empaveli no more than 4 weeks after the last Ultomiris (ravulizumab) dose.

Timing requirement defined for switch from Ultomiris.

Continuation Therapy — Geographic Atrophy (Syfovre)

Covered when ALL of the following are met

GA Continuation: 1. Member is currently receiving medication via the health plan benefit or previously met initial approval criteria, or is enrolled in continuity of care provisions. 2. Request is for Syfovre. 3. Member is responding positively to therapy. 4. Syfovre is not prescribed concurrently with Empaveli. 5. If requesting a dose increase, new dose does not exceed 15 mg (0.1 mL of 150 mg/mL) in each affected eye every 25 days.

Continuation rules

Continuation therapy is allowed when members are already established on therapy and show clinical response; continuity of care provisions apply.

Continuation eligibility: Member currently receiving medication via the health plan benefit, previously met initial approval criteria, or is enrolled in state/product continuity of care provisions (refer to state addendums).

Continued therapy for PNH

Continued approval guidance updates referenced in policy history.

PNH continued approval: Continued approval duration for PNH was revised from 6 months to 12 months; examples of positive response expanded to include improvement of extravascular hemolysis.

3Q 2025 annual review updates reflected in policy history.

1.25 mm2 ≈ 0.5 disk area (DA)

inv-15: PNH hemoglobin — < 10.5 g/dL

Hemoglobin threshold (PNH initial)Hemoglobin < 10.5 g/dL documented

Documentation sourceProvider-submitted laboratory results in prior authorization request

Role in criteriaRequired element for initial Empaveli approval in PNH

inv-16: PNH PNH cells by flow — detectable GPI‑deficient clones or ≥ 10% PNH cells

PNH flow cytometry requirementDetectable GPI‑deficient hematopoietic clones or ≥ 10% PNH cells by flow cytometry

Test modalityFlow cytometry of peripheral blood

Use in decision-makingRequired documentation for initial Empaveli approval in PNH

inv-17: C3G/IC‑MPGN UPCR — ≥ 1 g/g

UPCR threshold (C3G/IC‑MPGN)Urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g

ContextRequired documentation for initial Empaveli approval in C3G/primary IC‑MPGN

Source of confirmationUrine laboratory testing results submitted with request

inv-18: C3G/IC‑MPGN eGFR — ≥ 30 mL/min/1.73 m2

eGFR threshold (C3G/IC‑MPGN)Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2

ContextRequired documentation for initial Empaveli approval in C3G/primary IC‑MPGN

UseDetermines eligibility; must be met alongside UPCR criterion

inv-19: PNH dose LDH requirement for higher dose — LDH > 2 × ULN for doses up to 2,160 mg/week

LDH requirement for higher Empaveli dosing (PNH)Lactate dehydrogenase (LDH) > 2 × ULN required to support doses up to 2,160 mg/week

Dosing capMaximum 2,160 mg per week or 1,080 mg every 3 days (total 10 doses per month)

DocumentationPrior authorization must include LDH value > 2×ULN to justify higher dosing

inv-20: Syfovre dosing interval — every 25 to 60 days (maximum every 25 days per label)

Syfovre dosing interval (GA)Administer intravitreal injections once every 25 to 60 days; per updated labeling maximum frequency is every 25 days

Dose per administration15 mg (0.1 mL of 150 mg/mL) per affected eye

Maximum frequency noteLabel specifies maximum dosing frequency of 15 mg every 25 days

Single-dose vial: 1,080 mg/20 mL (Empaveli)

inv-42: Empaveli (C3G/IC‑MPGN) — Weight‑based regimens (≥50 kg: 1,080 mg twice weekly; 35–<50 kg: 810 mg twice weekly; <35 kg: 648 mg twice weekly)

Empaveli weight-based C3G/IC‑MPGN regimens≥50 kg: 1,080 mg SC twice weekly; 35–<50 kg: 810 mg SC twice weekly; <35 kg: 648 mg SC twice weekly

Age/weight applicabilityApplies to adults and pediatric members meeting weight bands (age ≥ 12 years for indication)

Maximum per-dose guidancePer regimen; maximum dose determined by weight-based schedule

inv-43: Empaveli — per regimen (weight-based dosing up to 1,080 mg per dose)

Per-regimen dosing noteEmpaveli dosing is specified per regimen with weight-based dosing up to 1,080 mg per dose

UseApplies to both PNH and C3G/IC‑MPGN regimens where weight-based dosing is referenced

DocumentationDosing regimen must be documented in prior authorization request

inv-44: Syfovre — 15 mg per injection; maximum frequency every 25 days

Syfovre per-injection dose and max frequency15 mg per injection; maximum frequency every 25 days

Interval rangeDosing interval may be every 25 to 60 days depending on regimen

Administration siteIntravitreal injection to each affected eye

Documentation Required

Submit clinical documentation to support that criteria are met

Provider must submit supporting documentation (such as office chart notes, lab results, imaging or other clinical information) demonstrating that the member meets all applicable approval criteria.

Examples: flow cytometry reports, hemoglobin and LDH values for PNH; kidney biopsy, UPCR and eGFR for C3G/IC‑MPGN; fundus autofluorescence and BCVA for GA.

Documentation Required

Document dosing regimen, formulation, vial strength and billing codes

Document the dosing regimen and product formulation for the requested indication, including route (subcutaneous vs intravitreal), vial strength, and dose limits; reference HCPCS codes J2781 (pegcetacoplan intravitreal, 1 mg) and J7799 as applicable for billing.

Empaveli (SC) dosing by indication and weight bands must be recorded (e.g., 1,080 mg twice weekly for adults; weight‑based regimens for C3G/IC‑MPGN).
Syfovre (intravitreal) dosing: 15 mg per affected eye every 25 to 60 days (maximum every 25 days).

Denial Risk

Non‑FDA indications require off‑label justification per policy

Requests for non‑FDA approved (off‑label) indications that are not addressed in this policy will not be authorized unless sufficient documentation of efficacy and safety is provided per the referenced off‑label use policies.

Off‑label use must meet the criteria in CP.CPA.09 (commercial), HIM.PA.154 (health insurance marketplace), or CP.PMN.53 (Medicaid) as applicable.

Billing Rule

Coding/coverage caution — codes listed do not ensure payment

Inclusion or exclusion of codes in the policy is informational only and does not guarantee coverage; providers must check current professional coding guidance before submitting claims.

Policies reference HCPCS codes (e.g., J2781, J7799) for informational purposes; payer coding rules govern reimbursement.

Step Therapy

Therapy‑sequencing and concurrent‑use restrictions (PNH) — 4‑week cross‑titration exception

The policy history documents restrictions on concurrent prescribing of Empaveli with several complement therapies for PNH; exceptions permit a short 4‑week cross‑titration period for switching from Soliris, Bkemv, or Epysqli.

Policy history expanded the list of therapies Empaveli should not be co‑prescribed with (e.g., Fabhalta, Voydeya, Bkemv, Epysqli, PiaSky) and allows a 4‑week overlap when switching from certain agents.
Any sequencing or cross‑titration must follow the timing and attestation requirements in the main policy.

Abbreviation used in GA criteria and dose sections

inv-32: Paroxysmal nocturnal hemoglobinuria; indication for Empaveli with specific SC dosing and switching instructions from other complement inhibitors.

PNH indication summaryPNH: Empaveli systemic SC indication with specific SC dosing and switching instructions from other complement inhibitors

Switching guidanceWhen switching from Soliris/Bkemv/Epysqli, initiate Empaveli while continuing prior agent for 4 weeks before discontinuation; for Ultomiris, initiate within 4 weeks of last dose

Documentation requirementProvider must document switching timeline and dosing in prior authorization request

inv-33: Geographic atrophy secondary to age-related macular degeneration; indication for intravitreal pegcetacoplan (Syfovre) with 15 mg injections every 25-60 days per regimen.

GA (Syfovre) indication summaryGeographic atrophy (GA) secondary to AMD: intravitreal pegcetacoplan (Syfovre) with 15 mg injections every 25 to 60 days per regimen

Maximum frequencyUpdated labeling specifies maximum dosing every 25 days

Supporting referencesOAKS/DERBY studies and Syfovre prescribing information cited in policy references