Eculizumab (Soliris®) and ravulizumab-cwvz (Ultomiris^TM) are recombinant humanized monoclonal antibodies that bind to complement protein C5 and inhibits its enzymatic cleavage, blocks formation of the terminal complement complex, and thus prevents red cell lysis. 

Pegcetacoplan (Empaveli™) binds to complement protein C3 which then regulates the binding of C3 and the sequence of downstream effectors of the activated complement protein.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) may be considered medically necessary when the following criteria are met:

• There is no evidence of an active meningococcal infection; and
• Individual has been immunized with a meningococcal vaccine at least two (2) weeks prior to administration of the first dose of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) (unless the clinical record documents that the risks of delaying eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) outweigh the risk of meningococcal infection); and
• Documented diagnosis of paroxysmal nocturnal hemoglobinuria (PNH); and
  • Flow cytometry demonstrates greater than or equal to 5% granulocyte or monocyte clone size; or
  • Flow cytometry demonstrates greater than or equal to 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); and
• Hemoglobin that is less than or equal to 7 g/dL, or the individual has symptoms of anemia and the hemoglobin is less than or equal to 9 g/dL; or
• Evidence of clinically elevated hemolysis lactate dehydrogenase (LDH) greater than or equal to 1.5 times the upper limit of normal (ULN); or
• Documented history of a major adverse vascular event (MAVE) from thromboembolism that may include ANY ONE of the following:
  • Deep vein thrombosis; or
  • Pulmonary embolism; or
  • Hepatic or portal vein thrombosis; or
  • Mesenteric or splenic venus thrombosis; or
  • Renal vein thrombosis; or
  • Thrombophlebitis; or
  • Embolic stroke; or
  • Myocardial infarction; or
  • Transient ischemic attack; or
  • Unstable angina; or
• Documentation of ANY ONE of the following:
  • Fatigue; or
  • Hemoglobinuria; or
  • Abdominal pain; or
  • Shortness of breath (dyspnea); or
  • Dysphagia; or
  • Erectile dysfunction; or
  • History of pRBC transfusion due to PNH; and
• Initial authorization will be for a period of 6 months.

Reauthorization Criteria

Continuation of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) for the treatment of PNH may be considered medically necessary when the following criteria met:

• Provider attestation the individual has demonstrated clinical improvement after the initial six (6) month trial (e.g increase in hemoglobin levels, decrease in LDH levels); and
• Reauthorization will be for a period of 12 months.

The use of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) not meeting the criteria as indicated in this policy is considered not medically necessary.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Pegcetacoplan (Empaveli) may be considered medically necessary when the following criteria are met:

• Documented diagnosis of paroxysmal nocturnal hemoglobinuria (PNH); and
  • Flow cytometry demonstrates greater than or equal to 5% granulocyte or monocyte clone size; or
  • Flow cytometry demonstrates greater than or equal to 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); and
• Individual has baseline hemoglobin level of less than 10.5 g/dL; and
• Documentation of ANY ONE of the following:
  • Fatigue; or
  • Hemoglobinuria; or
  • Abdominal pain; or
  • Shortness of breath (dyspnea); or
  • Dysphagia; or
  • Erectile dysfunction; and
• Individual received at least 1 red blood cell (RBC) transfusion in the 12 months prior to initiation; and
• Individual received vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B (Hib) prior to the first dose, or within two (2) weeks after starting treatment; or
  • Provider documented the individual is a non-responder to vaccination as evidenced by titers or display titer levels within acceptable local limits; and
• Individual is not concurrently receiving eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris); or
  • Individual transitioning to pegcetacoplan (Empaveli) should discontinue eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) within four (4) weeks of starting pegcetacoplan (Empaveli); and
• Initial authorization will be for a period of six (6) months.

Reauthorization Criteria

Continuation of pegcetacoplan (Empaveli) for the treatment of PNH may be considered medically necessary when the following criteria are met:

• Provider attestation that individual has demonstrated clinical improvement after the initial six (6) month trial (e.g increase in hemoglobin levels, decrease in LDH levels); and
• Reauthorization will be for a period of 12 months.

The use of pegcetacoplan (Empaveli) not meeting the criteria as indicated in this policy is considered not medically necessary.

Atypical Hemolytic Uremic Syndrome (aHUS)

Eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) may be considered medically necessary when the following criteria are met:

• There is no evidence of an active meningococcal infection; and
• Individual has been immunized with a meningococcal vaccine at least two (2) weeks prior to administration of the first dose of eculizumab (Soliris) (unless the clinical record documents that the risks of delaying eculizumab (Soliris) outweigh the risk of meningococcal infection); and
• The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection; and
• Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement; and
• Individual has thrombotic microangiopathy (TMA) (not related to disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metablolism) with evidence of TMA including ANY of the following lab values:
  • Low platelet count (thrombocytopenia); or
  • Microangiopathic hemolysis, thrombotic microangiopathy (breaking of red blood cells inside of blood vessels); or
  • Decreased kidney function (based on age) or requiring renal dialysis; or
• Individual with end stage renal disease (ESRD) reliant on hemodialysis resulting from probable aHUS meeting ALL of the following criteria:
  • Individual is a transplant candidate; and
  • Individual is initiating the transplant process; and
  • Treatment is being utilized as prophylaxis to prevent another flare of aHUS upon transplantation; and
• Initial authorization will be for a period of six (6) months.

Reauthorization Criteria

Continuation of therapy for eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) following an initial six (6) month trial for the treatment of aHUS may be considered medically necessary the following criteria are met:

• Provider attestation that individual has demonstrated clinical improvement after the initial trial (for example, normalization of platelet count or laboratory evidence of reduced hemolysis); and
• Reauthorization will be for a period of 12 months.

The use of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) not meeting the criteria as indicated in this policy is considered not medically necessary.

Myasthenia Gravis

Eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris)  may be considered medically necessary for the treatment of individuals 18 years of age or older with a diagnosis of myasthenia gravis when ALL the following criteria are met:

• There is no evidence of an active meningococcal infection; and
• Individual has been immunized with a meningococcal vaccine at least two (2) weeks prior to administration of the first dose of eculizumab (Soliris) (unless the clinical record documents that the risks of delaying eculizumab (Soliris) outweigh the risk of meningococcal infection); and
• Individual is positive for antiacetylcholine receptor (AchR) antibodies; and
• Individual meets Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV*; and
• Individual has a Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score of six (6) or greater at initiation*; and
• Individual has refractory myasthenia gravis, with documentation that treatment with two (2) or more immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, methotrexate, chronic plasmapheresis, or tacrolimus), used alone or in combination for one year, was ineffective contraindicated or not tolerated; and
• Initial authorization will be for a period of 26 weeks.

Reauthorization Criteria

Continuation of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) may be considered medically necessary when the following criteria are met:

• Provider attestation that individual has demonstrated clinically meaningful response regarding daily activities (greater than or equal to a three (3) point improvement in the MG-ADL from baseline); and
• Reauthorization will be for a period of 12 months.

The use of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) not meeting the criteria as indicated in this policy is considered not medically necessary.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Eculizumab (Soliris) and ravulizumab-cwvz (Ultomiris) may be considered medically necessary for the treatment of an individual 18 years of age or older with Neuromyelitis Optica Spectrum Disorder (NMOSD) when the following criteria are met:

• There is no evidence of an active meningococcal infection; and
• Individual has been immunized with a meningococcal vaccine at least two (2) weeks prior to administration of the first dose of treatment  (unless the clinical record documents that the risks of delaying treatment  outweigh the risk of meningococcal infection); and
• Individual is positive for anti-aquaporin-4 (AQP4) antibody; and
• Individual exhibits ONE of the following core clinical characteristics of NMOSD:
  • Optic neuritis; or
  • Acute myelitis; or
  • Area postrema syndrome (episode of otherwise unexplained hiccups or nausea and vomiting); or
  • Acute brainstem syndrome; or
  • Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; or
  • Symptomatic cerebral syndrome with NMOSD-typical brain lesions; and
• Individual will not receive concomitant treatment with rituximab or mitoxantrone 
• Intial authorization will be for a period of six (6) months.

Reauthorization Criteria

Continuation of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris)  may be considered medically necessary when the following criteria are met:

• Provider attestation that individual has demonstrated a clinically meaningful response ( i.e. reduction in the number of relapses or improvement in activities of daily living, etc); and
• Reauthorization will be for a period of 12 months.

The use of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) not meeting the criteria as indicated in this policy is considered not medically necessary.

Eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) may be considered medically necessary for individuals 18 years of age and older when applicable clinical criteria for individual medication policies are met and when administered in a physician’s office not affiliated with a hospital, specialized infusion centers not affiliated with a hospital or in the home.

Outpatient facility (Outpatient Hospital IV Infusion Department or Hospital-based Outpatient Clinical Level of Care) administration may be considered medically necessary if ANY of the following criteria are present to indicate the member is medically unstable for infusions in other than an outpatient facility setting:

• Member’s home is considered unsuitable for care by the home infusion provider; or
• Individual’s medical status requires enhanced monitoring beyond that which would routinely be needed for infusion therapy; or
• Previous severe adverse reaction (including but not limited to anaphylaxis, seizure, thromboembolism, myocardial infarction, renal failure) during or following administration of prescribed medication despite standard pre-medication; or
• Individual is receiving other medications that require close monitoring with a higher level of care (e.g., cytotoxic chemotherapy or blood products); or
• Individual is at high risk for complications due to medication administration (e.g., at risk for post-transplant complications, increased risk of infusion reactions due to presence of circulating antibodies, unstable vascular access, cardiopulmonary condition at risk for severe adverse reactions, unstable renal function with inability to safely tolerate IV volume loads, etc.); or 
• Individual is initiating therapy or re-initiating therapy after a period of at least 6 months with no therapy; or
• Physically and/or cognitively impaired AND a home caregiver is not available to comply with the required treatment regimen and schedule.

Home health services may be considered medically necessary when utilized for the administration of home infusion therapy and when provided by licensed eligible provider. Each case will be addressed on an individual basis.

The medications identified in this policy will be considered not medically necessary if administered in an unapproved hospital outpatient setting when an approved site of care is a viable option for treatment.

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits. 

Evidence-based guidelines support the administration of injectable medications in alternative sites of care such as the non-hospital physician’s office, non-hospital infusion center or in the home.  Administration of the injectable medications subject to this policy at alternate sites of care is based upon the professional judgment of the provider, and takes into account the clinical appropriateness for each individual member. Requests for administration of any dose of eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) received from a hospital-based facility, physician’s office or specialized infusion center will be assessed for meeting the policy exception criteria based on the clinical documentation provided by the requesting practitioner.

Pegcetacoplan (Empaveli)  is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.