ULTOMIRIS, Ravulizumab-cwvz Form

Ravulizumab-cwvz (Ultomiris®) is a complement inhibitor. FDA Approved Indication(s) Ultomiris is indicated for the treatment of: • Adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH) • Adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA) • Adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive Limitation(s) of use: Ultomiris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Ultomiris is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Paroxysmal Nocturnal Hemoglobinuria (must meet all):

1. Diagnosis of PNH;
   2. Prescribed by or in consultation with a hematologist;
   3. Age ≥ 1 month;
   4. Flow cytometry shows detectable glycosylphosphatidylinositol (GPI)-deficient hematopoietic clones or ≥ 5% PNH cells;
   5. Member meets one of the following (a or b): a. History of ≥ 1 red blood cell transfusion in the past 24 months and (i or ii): i. Documentation of hemoglobin < 7 g/dL in members without anemia symptoms; ii. Documentation of hemoglobin < 9 g/dL in members with anemia symptoms; b. History of thrombosis;

2. Ultomiris is not prescribed concurrently with Empaveli™ or Soliris®; Page 1 of 12

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3. Dose does not exceed the following (a, b, c, and d): a. IV loading dose on Day 1: i. Weight ≥ 5 to < 10 kg: 600 mg;
   ii. Weight ≥ 10 to < 20 kg: 600 mg; iii. Weight ≥ 20 to < 30 kg: 900 mg; iv. Weight ≥ 30 to < 40 kg: 1,200 mg; v. Weight ≥ 40 to < 60 kg: 2,400 mg;
   vi. Weight ≥ 60 to < 100 kg: 2,700 mg; vii. Weight ≥ 100 kg: 3,000 mg;
   b. If member is switching therapy from Soliris, administration of the IV loading dose should occur at the time of the next scheduled Soliris dose;
   c. Maintenance dose (i or ii): i. IV maintenance dose on Day 15 after IV Ultomiris loading dose (or starting 1 week after the last SC Ultomiris maintenance dose if switching from SC Ultomiris) and at the specified frequency thereafter: 1) Weight ≥ 5 to < 10 kg: 300 mg every 4 weeks;
   2) Weight ≥ 10 to < 20 kg: 600 mg every 4 weeks; 3) Weight ≥ 20 to < 30 kg: 2,100 mg every 8 weeks; 4) Weight ≥ 30 to < 40 kg: 2,700 mg every 8 weeks; 5) Weight ≥ 40 to < 60 kg: 3,000 mg every 8 weeks;
   6) Weight ≥ 60 to < 100 kg: 3,300 mg every 8 weeks;
   7) Weight ≥ 100 kg: 3,600 mg every 8 weeks; ii. SC maintenance dose on Day 15 after IV Ultomiris loading dose (or starting 8 weeks after the last IV Ultomiris maintenance dose if switching from IV Ultomiris) and at the specified frequency thereafter: 1) Age ≥ 18 years and weight ≥ 40 kg: 490 mg every week; d. If member has received plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg), a supplemental dose of Ultomiris may be administered within 4 hours following each PE/PP intervention or IVIg cycle (see section V). Approval duration: 6 months B. Atypical Hemolytic Uremic Syndrome (must meet all):
4. Diagnosis of aHUS (i.e., complement-mediated HUS);
   
   2. Prescribed by or in consultation with a hematologist or nephrologist;
   3. Age ≥ 1 month;
   4. Member has signs of TMA as evidenced by all of the following (a, b, and c): a. Platelet count ≤ 150 x 109/L; b. Hemolysis such as an elevation in serum lactate dehydrogenase (LDH); c. Serum creatinine above the upper limits of normal or member requires dialysis;
5. Documentation that member does not have either of the following: a. A disintegrin and metalloproteinase with thombospondin type 1 motif, member 13 (ADAMTS13) deficiency; b. STEC-HUS;

6. Ultomiris is not prescribed concurrently with Soliris; Page 2 of 12

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7. Dose does not exceed the following (a, b, c, and d): a. IV loading dose on Day 1: i. Weight ≥ 5 to < 10 kg: 600 mg;
   ii. Weight ≥ 10 to < 20 kg: 600 mg; iii. Weight ≥ 20 to < 30 kg: 900 mg; iv. Weight ≥ 30 to < 40 kg: 1,200 mg; v. Weight ≥ 40 to < 60 kg: 2,400 mg; vi. Weight ≥ 60 to < 100 kg: 2,700 mg; vii. Weight ≥ 100 kg: 3,000 mg; b. If member is switching therapy from Soliris, administration of the IV loading dose should occur at the time of the next scheduled Soliris dose;
   c. Maintenance dose (i or ii): i. IV maintenance dose on Day 15 after IV Ultomiris loading dose s(or starting 1 week after the last SC Ultomiris maintenance dose if switching from SC Ultomiris) and at the specified frequency thereafter: 1) Weight ≥ 5 to < 10 kg: 300 mg every 4 weeks;
   2) Weight ≥ 10 to < 20 kg: 600 mg every 4 weeks; 3) Weight ≥ 20 to < 30 kg: 2,100 mg every 8 weeks; 4) Weight ≥ 30 to < 40 kg: 2,700 mg every 8 weeks; 5) Weight ≥ 40 to < 60 kg: 3,000 mg every 8 weeks;
   6) Weight ≥ 60 to < 100 kg: 3,300 mg every 8 weeks;
   7) Weight ≥ 100 kg: 3,600 mg every 8 weeks; ii. SC maintenance dose on Day 15 after IV Ultomiris loading dose (or starting 8 weeks after the last IV Ultomiris maintenance dose if switching from IV Ultomiris) and at the specified frequency thereafter: 1) Age ≥ 18 years and weight ≥ 40 kg: 490 mg every week; d. If member has received PE, PP, or IVIg, a supplemental dose of Ultomiris may be administered within 4 hours following each PE/PP intervention or IVIg cycle (see section V). Approval duration: 6 months C. Generalized Myasthenia Gravis (must meet all):
8. Diagnosis of gMG;
   2. Prescribed by or in consultation with a neurologist;
   3. Age ≥ 18 years;
   4. Myasthenia Gravis Activities of Daily Living (MG-ADL) score ≥ 6 at baseline;
   5. Myasthenia Gravis Foundation of America (MGFA) clinical classification of Class II to IV;
9. Member has positive serological test for anti-AChR antibodies;
   7. Failure of a corticosteroid (see Appendix B), unless contraindicated or clinically significant adverse effects are experienced;
10. Failure of a cholinesterase inhibitor (see Appendix B), unless contraindicated or clinically significant adverse effects are experienced;
11. Failure of at least one immunosuppressive therapy (see Appendix B), unless clinically significant adverse effects are experienced or all are contraindicated;

12. Ultomiris is not prescribed concurrently with Soliris or Vyvgart®; Page 3 of 12

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13. Dose does not exceed the following (a, b, c, and d): a. IV loading dose on Day 1: i. Weight ≥ 40 to < 60 kg: 2,400 mg; ii. Weight ≥ 60 to < 100 kg: 2,700 mg; iii. Weight ≥ 100 kg: 3,000 mg; b. If member is switching therapy from Soliris, administration of the IV loading dose should occur at the time of the next scheduled Soliris dose;
    c. IV maintenance dose on Day 15 after IV Ultomiris loading dose and at the specified frequency thereafter: i. Weight ≥ 40 to < 60 kg: 3,000 mg every 8 weeks; ii. Weight ≥ 60 to < 100 kg: 3,300 mg every 8 weeks; iii. Weight ≥ 100 kg: 3,600 mg every 8 weeks; d. If member has received PE, PP, or IVIg, a supplemental dose of Ultomiris may be administered within 4 hours following each PE/PP intervention or IVIg cycle (see section V). Approval duration: 6 months D. Other diagnoses/indications (must meet 1 or 2):
14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
15. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. All Indications in Section I (must meet all):

16. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B); Page 4 of 12

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17. Member is responding positively to therapy as evidenced by, including but not Improved measures of intravascular hemolysis (e.g., normalization of LDH); limited to, improvement in any of the following parameters (a, b, or c): a. PNH: i. ii. Reduced need for red blood cell transfusions; iii. Increased or stabilization of hemoglobin levels; iv. Less fatigue; v. Improved health-related quality of life; vi. Fewer thrombotic events; Improved measures of intravascular hemolysis (e.g., normalization of LDH); b. aHUS: i. ii. Increased or stabilized platelet counts; iii. Improved or stabilized serum creatinine or estimated glomerular filtration rate (eGFR); iv. Reduced need for dialysis; c. gMG:
    i. Improved MG-ADL total score as evidenced by a 2-point reduction from baseline;
18. Ultomiris is not prescribed concurrently with (a, b, or c): a. PNH: Empaveli or Soliris; b. aHUS: Soliris; c. gMG: Soliris or Vyvgart;

19. If request is for a dose increase, new dose does not exceed one of the following (a, b, or c): a. PNH/aHUS (i or ii): i. IV (at least 1 week must have elapsed since last dose of SC Ultomiris if switching): 1) Weight ≥ 5 to < 10 kg: 300 mg every 4 weeks;
    2) Weight ≥ 10 to < 20 kg: 600 mg every 4 weeks; 3) Weight ≥ 20 to < 30 kg: 2,100 mg every 8 weeks; 4) Weight ≥ 30 to < 40 kg: 2,700 mg every 8 weeks; 5) Weight ≥ 40 to < 60 kg: 3,000 mg every 8 weeks; 6) Weight ≥ 60 to < 100 kg: 3,300 mg every 8 weeks; 7) Weight ≥ 100 kg: 3,600 mg every 8 weeks; ii. SC (at least 8 weeks must have elapsed since last maintenance dose of IV Ultomiris if switching):
    1) Age ≥ 18 years and weight ≥ 40 kg: 490 mg every week; b. gMG:
    i. Weight ≥ 40 to < 60 kg: 3,000 mg every 8 weeks; ii. Weight ≥ 60 to < 100 kg: 3,300 mg every 8 weeks; iii. Weight ≥ 100 kg: 3,600 mg every 8 weeks; c. All indications: If member has received PE, PP, or IVIg, a supplemental dose of Ultomiris may be administered within 4 hours following each PE/PP intervention or IVIg cycle (see section V). Approval duration: 6 months
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    B. Other diagnoses/indications (must meet 1 or 2):

20. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

21. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents; B. Amyotrophic lateral sclerosis. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AChR: acetylcholine receptor
    ADAMTS13: a disintegrin and metalloproteinase with thombospondin type 1 motif, member 13 aHUS: atypical hemolytic uremic syndrome FDA: Food and Drug Administration gMG: generalized myasthenia gravis GPI: glycosyl phosphatidylinositol IVIg: intravenous immunoglobulin
    LDH: lactate dehydrogenase MG-ADL: Myasthenia Gravis Activities of Daily Living MGFA: Myasthenia Gravis Foundation of America PE: plasma exchange
    PNH: paroxysmal nocturnal hemoglobinuria PP: plasmapheresis STEC-HUS: Shiga toxin E. coli related hemolytic uremic syndrome TMA: thrombotic microangiopathy Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Corticosteroids betamethasone Oral: 0.6 to 7.2 mg PO per day 7.2 mg/day Page 6 of 12

    Dose Limit/ Maximum Dose 9 mg/day 40 mg/day 60 mg/day See regimen See regimen 3 mg/kg/day 2 g/day CLINICAL POLICY Ravulizumab-cwvz
    Drug Name Dosing Regimen dexamethasone methylprednisolone prednisone Oral: 0.75 to 9 mg/day PO
    Oral: 12 to 20 mg PO per day; increase as needed by 4 mg every 2-3 days until there is marked clinical improvement or to a maximum of 40 mg/day Oral: 15 mg/day to 20 mg/day; increase by 5 mg every 2-3 days as needed. Maximum: 60 mg/day
    Oral immediate-release: 600 mg daily in divided doses (range, 60-1500 mg daily in divided doses) Oral sustained release: 180-540 mg QD or BID IV or IM: 2 mg every 2-3 hours Oral: 15 mg TID. The daily dosage should be gradually increased at intervals of 1 or more days. The usual maintenance dosage is 15-375 mg/day (average 150 mg) IM or SC: 0.5 mg based on response to therapy Cholinesterase Inhibitors pyridostigmine (Mestinon, Regonol) neostigmine (Bloxiverz) Immunosuppressants azathioprine (Imuran) mycophenolate mofetil (Cellcept) Oral: 50 mg QD for 1 week, then increase gradually to 2 to 3 mg/kg/day
    Oral: Dosage not established. 1 gram BID has been used with adjunctive corticosteroids or other non-steroidal immunosuppressive medications Oral: initial dose of cyclosporine (non- modified), 5 mg/kg/day in 2 divided doses IV: 375 mg/m2 once a week for 4 weeks; an additional 375 mg/m2 dose may be given every 1 to 3 months afterwards
    5 mg/kg/day cyclosporine (Sandimmune) Rituxan (rituximab), Riabni™ (rituximab- arrx), Ruxience™ (rituximab-pvvr), Truxima (rituximab- abbs)† Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Off-label †Prior authorization is required for rituximab products See regimen Appendix C: Contraindications/Boxed Warnings • Contraindication(s): patients with unresolved Neisseria Meningitidis infection; patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Ultomiris treatment outweigh the risks of developing a meningococcal infection • Boxed warning(s): serious meningococcal infections Page 7 of 12

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    Appendix D: General Information • Ultomiris is only available through a REMS (Risk Evaluation and Mitigation Strategy) program due to the risk of life-threatening and fatal meningococcal infection. Patients should be vaccinated with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of Ultomiris and revaccinated according to current medical guidelines for vaccine use. Patients should be monitored for early signs of meningococcal infections, evaluated immediately if infection is suspected, and treated with antibiotics if necessary. • Examples of symptoms of anemia include but are not limited to: dizziness or lightheadedness, fatigue, pale or yellowish skin, shortness of breath, chest pain, cold hands and feet, and headache. • Ultomiris is a humanized monoclonal antibody to complement component C5 that was engineered from Soliris. It is virtually identical to Soliris but has a longer half-life that allows for less frequent dosing intervals. In August 2021, Alexion announced it is discontinuing the global CHAMPION-ALS phase 3 clinical study of Ultomiris in adults with amyotrophic lateral sclerosis due to an interim data review showing a lack of efficacy. • • The MGFA classification has some subjectivity in it when it comes to distinguishing mild (Class II) from moderate (Class III) and moderate (Class III) from severe (Class IV). Furthermore, it is insensitive to change from one visit to the next.
    • gMG: a 2-point reduction in MG-ADL total score is considered a clinically meaningful improvement. The scale can be accessed here: https://myasthenia.org/Portals/0/ADL.pdf V. Dosage and Administration
    Maximum Dose IV: 3,600 mg/
    8 weeks SC: 490 mg/week Indication Dosing Regimen* PNH, aHUS IV dosing: Day 1: Loading dose IV Day 15 and thereafter: Maintenance dose IV. If currently receiving SC Ultomiris, administer IV Ultomiris maintenance dose starting 1 week after last SC Ultomiris maintenance dose Body Weight Range (kg) ≥ 5 to < 10
    ≥ 10 to < 20
    ≥ 20 to < 30
    ≥ 30 to < 40
    ≥ 40 to < 60
    ≥ 60 to < 100
    ≥ 100
    Maintenance
    Dose (mg) 300 every 4 weeks 600 every 4 weeks 2,100 every 8 weeks 2,700 every 8 weeks 3,000 every 8 weeks 3,300 every 8 weeks 3,600 every 8 weeks Loading Dose (mg) 600 600 900 1,200 2,400 2,700 3,000 SC dosing (maintenance only for age ≥ 18 years and weight ≥ 40 kg): 490 mg SC per week, starting 2 weeks after IV Ultomiris loading dose or 8 weeks after last IV Ultomiris maintenance dose Page 8 of 12

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    Indication Dosing Regimen gMG Body Weight Range (kg) ≥ 40 to < 60
    ≥ 60 to < 100
    ≥ 100
    Loading Dose (mg) 2,400 2,700 3,000 Maintenance
    Dose (mg) 3,000 every 8 weeks 3,300 every 8 weeks 3,600 every 8 weeks Maximum Dose 3,600 mg/
    8 weeks See regimen Supple- mental doses Day 1: Loading dose IV
    Day 15 and thereafter: Maintenance dose IV A supplemental dose of Ultomiris is required within 4 hours of PE, PP, or IVIg as they have been shown to reduce Ultomiris serum levels: Most Recent Ultomiris Dose (mg) Supplemental Dose (mg) Body Weight Range (kg) ≥ 40 to < 60 ≥ 60 to < 100 ≥ 100 2,400 3,000 2,700 3,300 3,000 3,600 After IVIg 600 After PE/PP 1,200 1,500 1,500 1,800 1,500 1,800 For patients switching from Soliris to Ultomiris, administer the loading dose of Ultomiris IV at the time of the next scheduled Soliris dose, and then administer maintenance doses at the specified frequency, starting 2 weeks after loading dose administration. VI. Product Availability
    • Single-dose vials for IV injection: 300 mg/30 mL, 300 mg/3 mL, 1,100 mg/11 mL • Single-dose prefilled cartridge for use with supplied single-use on-body injector for SC injection: 245 mg/3.5 mL VII.