Immune Globulins Form

The following are immune globulins requiring prior authorization: Alyglo™, Asceniv™, Bivigam®, Cutaquig®, Cuvitru™, Flebogamma® DIF, GamaSTAN®, GamaSTAN® S/D, Gammagard® liquid, Gammagard® S/D, Gammaked™, Gammaplex®, Gamunex®-C, Hizentra®, HyQvia®, Octagam®, Panzyga®, Privigen®, and Xembify®.
PI x x x x x IV IV IV SC SC IV FDA Approved Indication(s) Brand Name ROA Alyglo Asceniv Bivigam Cutaquig Cuvitru Flebogamma DIF
GamaSTAN, GamaSTAN
S/D Gammagard Liquid Gammagard S/D
Gammaked IV, SC IV IM x x x IV, SC IV IV, SC SC SC IV IV IV SC x x x x x x^ x x x Gammaplex Gamunex-C Hizentra HyQvia Octagam Panzyga Privigen Xembify ITP CIDP KS MMN CLL VPPX DM x# x x x x x# x x x x x x x x x x x x# If available as IV and SC, then = IV only; If available as 5% and 10%, then: # = 10% only, ^ = 5% only ROA = route of administration; CIDP = chronic inflammatory demyelinating polyneuropathy; CLL = B-cell chronic lymphocytic leukemia; DM = dermatomyositis; ITP = idiopathic thrombocytopenic purpura; KS = Kawasaki syndrome; MMN = multifocal motor neuropathy; PI = primary humoral immunodeficiency; VPPX = viral prophylaxis (for hepatitis A, measles, varicella, rubella)
Page 1 of 59

CLINICAL POLICY Immune Globulins Limitation(s) of use:
• Safety and efficacy of chronic use of recombinant human hyaluronidase in Hyqiva have not been established in conditions other than PI.
• Privigen maintance therapy in CIDP has not been studied beyond 6 months. Contents: I. Initial Approval Criteria A. Chronic Lymphocytic Leukemia Infection Prophylaxis B. Dermatomyositis/Polymyositis C. Fetal/Neonatal Alloimmune Thrombocytopenia
D. Inflammatory Demyelinating Polyneuropathy (Acute/Guillain-Barre Syndrome or Chronic) E. Idiopathic Thrombocytopenia Purpura (Acute or Chronic) F. Kawasaki Syndrome Aneurysm Prevention
G. Kidney Transplant H. Multifocal Motor Neuropathy I. Multiple Myeloma J. Multiple Sclerosis K. Myasthenia Gravis/Lambert Eaton Myasthenic Syndrome L. Paraneoplastic Neurologic Syndrome
M. Parvovirus B19 Infection and Anemia N. Pediatric Human Immunodeficiency Virus (HIV) Infection Prophylaxis
O. Pemphigus Vulgaris, Pemphigus Foliaceus, Bullous Pemphigoid, Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid, Epidermolysis Bullosa Acquisita)
P. Primary Immunodeficiencies Q. Stiff Person Syndrome R. Viral Prophylaxis for Hepatitis A, Measles, Varicella, Rubella Viruses II. Continued Therapy III. Diagnoses/Indications for which coverage is NOT authorized
IV. Appendices/General Information V. Dosage and Administration VI. Product Availability VII. References 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 immune globulins are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. B-Cell Chronic Lymphocytic Leukemia Infection Prophylaxis (must meet all):

1. Diagnosis of B-cell CLL;

   2. Prescribed by or in consultation with a hematologist, oncologist, or immunologist; Page 2 of 59

   CLINICAL POLICY Immune Globulins

2. Current (within the last 6 months) hypogammaglobulinemia as evidenced by two separate measurements of immunoglobulin G (IgG) level less than 500 mg/dL;
   4. Member has had recurrent serious bacterial infections (e.g., requiring IV antibiotics, hospitalization, or consultation with an infectious disease specialist) within the past 12 months;
3. Member meets one of the following (a, b, c, or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
4. Request meets one of the following (a or b) Dose does not exceed 400 mg per kg IV every 3 to 4 weeks; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
   Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Dermatomyositis, Polymyositis (off-label for polymyositis) (must meet all):
5. Diagnosis of dermatomyositis (DM) or polymyositis (PM);
   2. Prescribed by or in consultation with a dermatologist, rheumatologist, neurologist, or neuromuscular specialist;
6. Failure of a 4-month trial of a systemic corticosteroid (e.g., prednisone) in combination with one of the following immunosuppressive agents, both at up to maximally indicated doses unless clinically significant adverse effects are experienced or all are contraindicated: methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine (see Appendix D);
7. For dermatomyositis requests only: Failure of a trial of rituximab, unless contraindicated, clinically significant adverse effects are experienced, or the member is diagnosed with juvenile dermatomyositis plus calcinosis; Prior authorization may be required for rituximab

8. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); Page 3 of 59

   CLINICAL POLICY Immune Globulins c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

9. Request meets one of the following (a or b) Dose does not exceed 2 g per kg IV per month; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
   Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Fetal/Neonatal Alloimmune Thrombocytopenia (off-label) (must meet all):
10. Diagnosis of fetal/neonatal alloimmune thrombocytopenia (FNAIT);
    2. Prescribed by or in consultation with a hematologist, immunologist, perinatologist, or neonatologist;
11. Meets one of the following (a, b, c, or d): a. Previous pregnancy affected by FNAIT; b. Serological confirmation of FNAIT as evidenced by maternal-fetal HPA incompatibility; c. Nadir platelet count < 100 x 109/L at birth or within 7 days after birth of the affected child; d. Fetal intracranial hemorrhage;
12. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

13. Request meets one of the following (a or b):
    a. Dose does not exceed 2 g per kg IV per week; Page 4 of 59

    CLINICAL POLICY Immune Globulins b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer D. Inflammatory Demyelinating Polyneuropathy (Acute/Guillain-Barre Syndrome or Chronic) (must meet all):

    1. Diagnosis of acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain- Barre Syndrome (GBS) or CIDP;

14. Prescribed by or in consultation with a neurologist or neuromuscular specialist;

    3. Member meets one of the following (a or b): a. Diagnosis is AIDP/GBS and member meets one of the following (i-vii): i. Inability to stand or walk at least 30 feet without assistance; ii. ICU admission required for aspiration or mechanical ventilation; iii. Miller-Fisher syndrome; iv. Inability to raise head against gravity; v. Severe bulbar palsy (e.g., impaired gag reflex, dysarthria and/or dysphagia); vi. Bilateral facial weakness; vii. Autonomic dysfunction (e.g., unexplained dysrhythmia, blood pressure fluctuations, significant bowel or bladder involvement); b. Diagnosis is CIDP and member meets all of the following (i-v): i. Disease is progressive or relapsing for more than 2 months; ii. Member has either of the following (a or b): a) Both of the following, characterizing typical CIDP (i and ii):
       i) Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities;
       ii) Absent or reduced tendon reflexes in all extremities; b) One of the following, characterizing atypical CIDP (i-iii): i) Predominantly distal (distal acquired demyelinating symmetric, DADS) or asymmetric [multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), Lewis-Sumner syndrome] or focal (e.g., involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in one upper or lower limb) disease; ii) Pure motor symptoms; iii) Pure sensory symptoms (including chronic immune sensory polyradiculopathy affecting the central process of the primary sensory neuron); iii. Diagnosis has been confirmed via electrodiagnostic testing; iv. Member does not have any of the following (a-f): a) Borrelia burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure probably to have caused the neuropathy; b) Hereditary demyelinating neuropathy; c) Prominent sphincter disturbance; d) Diagnosis of multifocal motor neuropathy; Page 5 of 59

    CLINICAL POLICY Immune Globulins e) IgM monoclonal gammopathy with high titre antibodies to myelin- associated glycoprotein; f) Other causes for a demyelinating neuropathy including POEMS syndrome, osteosclerotic myeloma, diabetic and nondiabetic lumbosacral radiculoplexus neuropathy; v. For members who do not have pure motor symptoms, failure of at least one corticosteroid (e.g., prednisone) at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced;

15. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
16. Request meets one of the following (a, b, c, or d) For AIDP/GB: Dose does not exceed 0.4 g per kg per day IV for 5 days; b. For CIDP: Dose does not exceed a loading dose of 2 g per kg IV given in divided doses over 2 to 5 consecutive days, following by maintenance dose of 1 g per kg IV every 3 weeks; c. For CIDP: Dose does not exceed Hizentra 0.2 g per kg body weight SC per week, starting 1 week after last intravenous immune globulin (IVIG) infusion or 0.4 g per kg body weight SC per week if evidence is submitted demonstrating worsening symptoms; d. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer E. Idiopathic Thrombocytopenic Purpura (Acute or Chronic) (must meet all):

17. Diagnosis of acute or chronic ITP;

    2. Prescribed by or in consultation with a hematologist;
    3. Member meets one of the following (a or b): a. Failure of one of the following at up to maximally indicated doses, unless clinically significant adverse effects are experienced or both are contraindicated (i or ii): i. Systemic corticosteroids (e.g., prednisone); Page 6 of 59

    CLINICAL POLICY Immune Globulins ii. Rho(D) immune globulin (RhIG); Prior authorization is required for RhIG b. Pregnant;

18. Member meets one of the following (a – e): a. Current (within the last 30 days) platelet count less than 30,000/µL; b. Actively bleeding; c. High risk of life-threatening hemorrhage; d. Splenectomy is scheduled; e. Pregnant;
19. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
20. Request meets one of the following (a, b, c, or d) Dose does not exceed 1 g per kg per day IV for 1 to 2 days; b. Dose does not exceed 400 mg per kg per day IV for up to 5 days; c. For Gammagard S/D: Dose does not exceed 1 g per kg for up to 3 total doses QOD; d. Dose is supported by practice guidelines or peer-reviewed literatures for the relevant off-label use (prescriber must submit supporting evidence). Approval duration: Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer F. Kawasaki Syndrome Aneurysm Prevention (must meet all):
21. Diagnosis of Kawasaki syndrome or incomplete (atypical) Kawasaki disease;
    
    2. Prescribed by or in consultation with a cardiologist, allergist, immunologist, infectious disease specialist, or rheumatologist;

22. Prescribed concurrently with aspirin therapy, unless contraindicated or clinically significant adverse effects are experienced;

    4. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); Page 7 of 59

    CLINICAL POLICY Immune Globulins c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

23. Request meets one of the following (a, b, c, or d): a. Dose does not exceed 1 g per kg IV as a single infusion; b. Dose does not exceed 400 mg per kg IV daily for 4 consecutive days; c. Dose does not exceed 2 g per kg IV as a single infusion; d. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration: One time approval (1 month) G. Kidney Transplant (off-label) (must meet all):
    1. Member meets one of the following (a or b): a. If prescribed prior to kidney transplant, member has high levels of “anti-donor” antibodies (i.e., member is highly sensitized to the tissue of the majority of living or cadaveric donors because of “non-self” human leukocyte antigen (HLA) or ABO incompatibility); b. If prescribed following kidney transplant, used for the treatment of antibody- mediated rejection;
24. Prescribed by or in consultation with a nephrologist, transplant specialist, or hematologist;
25. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

26. Request meets one of the following (a or b) Dose does not exceed 140 g IV per infusion; Page 8 of 59

    CLINICAL POLICY Immune Globulins b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer H. Multifocal Motor Neuropathy (must meet all):

27. Diagnosis of MMN;
    2. Prescribed by or in consultation with a neurologist or neuromuscular specialist;
    3. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
28. Request meets one of the following (a or b) Dose does not exceed 2.4 g per kg IV per month; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer I. Multiple Myeloma Infection Prophylaxis (off-label) (must meet all):
29. Diagnosis of multiple myeloma (MM) with stable plateau phase disease;
    2. Prescribed by or in consultation with an hematologist, oncologist, or immunologist;
    3. Current (within the last 6 months) hypogammaglobulinemia as evidenced by two separate measurements of immunoglobulin G (IgG) level less than 400 mg/dL;
    4. Member has had recurrent serious bacterial infections (e.g., requiring IV antibiotics, hospitalization, or consultation with an infectious disease specialist) within the past 12 months;

30. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred Page 9 of 59

    CLINICAL POLICY Immune Globulins immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

31. Request meets one of the following (a or b) Dose does not exceed 400 mg per kg IV every 3 weeks; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer J. Multiple Sclerosis (off-label) (must meet all):
32. Diagnosis of relapsing-remitting multiple sclerosis (MS);
    2. Prescribed by or in consultation with a neurologist;
    3. Failure of three FDA-approved disease-modifying MS therapies (e.g., Avonex, Aubagio, Betaseron, Rebif, Copaxone, Tecfidera, Gilenya) (see Appendix B) at up to maximally indicated doses, unless clinically significant side effects are experienced or all are contraindicated; Prior authorization is required for MS therapies
33. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

34. Request meets one of the following (a or b) Dose does not exceed an initial loading dose of 400 mg per kg per day IV for 5 days, followed by maintenance dose of 1 g per kg IV per month; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Page 10 of 59

    CLINICAL POLICY Immune Globulins Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer K. Myasthenia Gravis (MG)/Lambert Eaton Myasthenic Syndrome (LEMS) (off-label) (must meet all):

    1. Diagnosis of myasthenia gravis (MG) or Lambert Eaton myasthenic syndrome (LEMS);
35. Prescribed by or in consultation with a neurologist or neuromuscular specialist;
    3. Member meets one of the following (a, b, or c): a. Acute crisis (e.g., vital capacity less than 1 L/min, inability to walk 100 ft without assistance, intubation, dysphagia with aspiration, mechanical ventilation); b. Thymectomy surgery is scheduled; c. Failure of all of the following at up to maximally indicated doses, unless clinically significant adverse effects are experienced or both are contraindicated (i, ii, and iii): i. Amifampridine (for LEMS) or a cholinesterase inhibitor (e.g., pyridostigmine; for MG); ii. Systemic corticosteroid (e.g., prednisone);
       iii. Immunosuppressant (e.g., azathioprine) (see Appendix B); Prior authorization may be required for amifampridine
36. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

37. Request meets one of the following (a or b) Dose does not exceed 2 g per kg IV divided over 2 to 5 consecutive days per treatment course; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer Page 11 of 59

    CLINICAL POLICY Immune Globulins L. Paraneoplastic Neurological Syndrome (off-label) (must meet all):

38. Diagnosis of one of the following subtypes of paraneoplastic neurological syndrome (a or b): a. Opsoclonus-myoclonus syndrome (OMS); b. Anti-NMDA encephalitis;
39. Prescribed by or in consultation with a neurologist, neuromuscular specialist, or oncologist;
40. For opsoclonus-myoclonus syndrome: Failure of at least one systemic corticosteroid (e.g., prednisone) at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated;
41. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
42. Request meets one of the following (a, b, c, or d) Dose does not exceed 2 g per kg IV per month; b. Dose does not exceed 0.4 g per kg IV per day; c. Dose does not exceed 200 mg per kg SC per week; d. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer M. Parvovirus B19 Infection and Anemia (off-label) (must meet all):
43. Diagnosis of anemia secondary to chronic parvovirus B19 infection;
    2. Prescribed by or in consultation with a hematologist, infectious disease specialist, or immunologist;
44. Current (within the last 30 days) severe anemia (i.e., Hgb <10 or Hct < 30) due to bone marrow suppression;

45. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); Page 12 of 59

    CLINICAL POLICY Immune Globulins c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

46. Request meets one of the following (a or b) Dose does not exceed an initial dose of 2 g per kg per day for up to 5 days, followed by maintenance dose of 400 mg per kg IV every 4 weeks; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer N. Pediatric Human Immunodeficiency Virus (HIV) Infection Prophylaxis (off-label) (must meet all):
    1. Prescribed for prophylaxis of serious bacterial infection in a child who has human immunodeficiency virus (HIV);
47. Prescribed by or in consultation with an HIV or infectious disease specialist;
    3. Current (within the last 6 months) hypogammaglobulinemia as evidenced by two separate measurements of serum IgG concentration less than 400 mg/dL;
48. Member meets one of the following (a – e): a. Recurrent serious bacterial infections (defined as two or more infections such as bacteremia, meningitis, or pneumonia in a 12-month period); b. Inadequate antibody response to protein/polysaccharide antigens (e.g., measles, pneumococcal, and/or Haemophilus influenzae type b);
    c. Lives in an area where measles is highly prevalent and has not developed an antibody response after two doses of measles, mumps, and rubella virus live vaccine; d. Exposure to measles (requires a single dose); e. Chronic bronchiectasis that is suboptimally responsive to antimicrobial and pulmonary therapy;

49. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Page 13 of 59

    CLINICAL POLICY Immune Globulins Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

50. Request meets one of the following (a or b): a. Dose does not exceed 400 mg per kg IV every 2 to 4 weeks; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer O. Pemphigus Vulgaris, Pemphigus Foliaceus, Bullous Pemphigoid, Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid), Epidermolysis Bullosa Acquisita (off-label) (must meet all):
    1. Diagnosis of one of the following (a, b, c, d, or e): a. Pemphigus vulgaris; b. Pemphigus foliaceus; c. Bullous pemphigoid; d. Mucous membrane pemphigoid (a.k.a. cicatricial pemphigoid); e. Epidermolysis bullosa acquisita;
51. Prescribed by or in consultation with a dermatologist;
    3. Failure of at least one corticosteroid (e.g., prednisone) at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced;
52. Failure of at least one immunosuppressive agent (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil) (see Appendix B) at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced;
    5. Failure of rituximab unless contraindicated or clinically significant adverse effects are experienced; Prior authorization is required for rituximab

53. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
    Page 14 of 59

    CLINICAL POLICY Immune Globulins

54. Request meets one of the following (a, b, c, or d) Dose does not exceed 2 gm per kg IV every 4 weeks; b. Dose does not exceed 400 mg per kg per day IV for 5 days (1 cycle only; may repeat up to three times in a 6-month period); c. Dose does not exceed 300 mg per kg per day IV for 5 days at monthly intervals (for up to 3 cycles); d. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer P. Primary Immunodeficiencies (must meet all):
55. Diagnosis of primary immunodeficiencies (PI), including any of the following (a – h): a. Agammaglobulinemia (e.g., X-linked, congenital); b. Common variable immunodeficiency (CVID); c. Congenital hypogammaglobulinemia;
    d. Immunodeficiency with near/normal IgM (absent IgG, IgA) (also known as Hyper IgM syndrome); e. Selective immunodeficiency (e.g., selective IgA, IgM, or IgG subclass); f. Severe combined immunodeficiency disorders (SCID) (e.g., X-SCID, jak3, ZAP70, adenosine deaminase (ADA) deficiency, PNP, RAG defects, Ataxia Telangiectasia, Wiskott-Aldrich syndrome, DiGeorge syndrome); g. Subclass deficiency (see Appendix D); h. Functional/specific antibody deficiency (see Appendix D);

56. Prescribed by or in consultation with an immunologist or hematologist;

    3. Member meets one of the following (a or b): a. For functional/specific antibody deficiency, meets all of the following (i, ii, and iii):
       i. Normal immune globulin levels; ii. Inadequate antibody response to polysaccharide antigens (e.g., pneumococcal); iii. Recurrent serious bacterial infections (e.g., requiring IV antibiotics, hospitalization, or consultation with an infectious disease specialist) within the past 12 months; b. Current (within the last 6 months) total or subclass immune globulin deficiency (below normal for age) as evidenced by two separate measurements of immunoglobulin level (see Appendix E) and one of the following (i, ii, iii, or iv): i. For ADA-SCID: failure (defined as experiencing continued recurrent serious bacterial infections) of Revcovi™, or hematopoietic stem cell transplant, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization is required for Revcovi ii. SCID (not including ADA-SCID); Page 15 of 59

    CLINICAL POLICY Immune Globulins iii. Recurrent serious bacterial infections (e.g., requiring IV antibiotics, hospitalization, or consultation with an infectious disease specialist) within the past 12 months; iv. Inadequate antibody response to protein/polysaccharide antigens (e.g., tetanus, diphtheria, pneumococcal);

57. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request
58. Request meets one of the following (a, b, c, or d) Dose does not exceed 800 mg per kg IV every 3 to 4 weeks;
    b. Dose does not exceed 600 mg per kg SC every 3 to 4 weeks; c. Dose does not exceed SC: initial dose of 1.37 x previous initial IV dose given 1 week after last IVIG infusion (refer to section V. for product-specific dosing frequency); d. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer Q. Stiff Person Syndrome (off-label) (must meet all):
59. Diagnosis of stiff person syndrome (also known as Moersch-Woltmann syndrome);
    
    2. Prescribed by or in consultation with a neurologist or neuromuscular specialist;
    3. Failure of a benzodiazepine (e.g., diazepam) or baclofen at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;

60. Member meets one of the following (a, b, c or d): a. Request is for Gammagard unless there is a specific health plan-preferred immune globulin product; b. Failure of Gammagard (or health plan-preferred immune globulin product); c. Member has intolerance or contraindication to Gammagard (or health plan- preferred immune globulin product), or if Gammagard (or health plan-preferred immune globulin product) is unavailable due to shortage, member must use Gamunex®-C or Gammaked®, unless clinically significant adverse effects are experienced or both are contraindicated; Page 16 of 59

    CLINICAL POLICY Immune Globulins d. Gammagard (or health plan-preferred immune globulin product), Gamunex-C, and Gammaked, are all unavailable due to shortage, and request is for an immune globulin product other than those listed; Immune globulin products are generally interchangeable and it is at the health plan’s discretion to prefer a clinically appropriate alternative product based on the time of request

61. Request meets one of the following (a or b) Dose does not exceed 2 g per kg IV divided over 2 to 5 consecutive days per treatment course; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer R. Viral Prophylaxis for Hepatitis A, Measles, Varicella, Rubella Viruses (must meet all):

    1. Request is for intramuscular formulation;
    2. Request is for one of the following indications (a, b, c, or d): a. Hepatitis A post-exposure/high-risk prophylaxis and meets both of the following (i and ii): i. Hepatitis A exposure or at high risk for exposure as evidenced by (a or b): a) Exposure to hepatitis A in the past 2 weeks (e.g., household contact, sexual contact, sharing illicit drugs with someone positive for hepatitis A, regular babysitters/caretakers, food handlers at the same establishment as one who is positive for hepatitis A) AND does not have clinical manifestations of hepatitis A; b) Traveling to or working in an area endemic for hepatitis A; ii. Meets at least one of the following (a, b, or c): a) Hepatitis A vaccine is locally unavailable; b) History of severe allergic reaction (anaphylaxis) to the hepatitis A vaccine; c) If either exposed to the virus or traveling in ≤ 2 weeks to an area endemic for hepatitis A, then (1, 2, or 3): 1) Age < 1 year or > 40 years; 2) Chronic liver disease or other chronic medical condition; 3) Immunocompromised; b. Measles (rubeola) post-exposure prophylaxis and meets all of the following (i, ii, iii, and iv): i. Exposure to measles within the past 6 days; ii. Member has not previously received a measles vaccine; iii. Member has not previously had measles; iv. Meets at least one of the following (a – f): a) Measles vaccine is locally unavailable; b) History of severe allergic reaction (anaphylaxis) to the measles vaccine; c) Pregnancy; d) Immunocompromised; Page 17 of 59

    CLINICAL POLICY Immune Globulins e) Has been > 3 days since exposure; f) Age < 12 months; c. Chickenpox (varicella) post-exposure prophylaxis and meets all of the following (i, ii, iii, and iv): i. Exposure to varicella within the past 10 days; ii. Member lacks immunity to varicella; iii. Varicella zoster immune globulin (Varizig) is currently unavailable; iv. Meets any of the following (a – e): a) Varicella vaccine is locally unavailable; b) History of a severe allergic reaction (anaphylaxis) to the varicella vaccine; c) Pregnancy; d) Immunocompromised; e) Newborn of mother who had varicella from 5 days before to 2 days after delivery; d. Rubella post-exposure prophylaxis (i and ii): i. Recent exposure to rubella; ii. Member is pregnant;

62. Request meets one of the following (a – e) Hepatitis A (i, ii, or iii): Dose does not exceed: i. 0.1 mL/kg IM once; ii. For anticipated exposure up to 2 months: 0.2 mL/kg IM once; iii. For anticipated exposure 2 months or longer: 0.2 mL/kg IM every 2 months; b. Measles: Dose does not exceed 15 mL IM once; c. Varicella: Dose does not exceed 1.2 mL/kg IM once; d. Rubella: Dose does not exceed 0.55 mL/kg IM once; e. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Approval duration:
    Hepatitis A: Duration of request or 6 months, whichever is less All other indications: One time approval (1 month) S. Other diagnoses/indications (must meet 1 or 2):

63. 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 Page 18 of 59

    CLINICAL POLICY Immune Globulins

64. 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. Kawasaki Syndrome/Incomplete (Atypical) Kawasaki Disease, Viral Prophylaxis (Hep A, Measles, Varicella, Rubella)
    1. Re-authorization is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable B. All Other Indications in Section I (must meet all):
    2. 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);
65. Member is responding positively to therapy (see Appendix D for examples);
    3. If request is for a dose increase due to inadequate response to previous dose, request meets one of the following (a or b) Dose titration or conversion is appropriate per package insert labeling; b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence);
    4. For adults with diagnoses other than primary immunodeficiency or cancer-related infection prophylaxis: the requested dose is calculated based on TBW or IBW, whichever is less, and for obese members adjBW is used for dose calculation, unless documentation supports the inability to adjust dosing in this manner (See Appendix F for weight-based dosing calculations). Approval duration:
       Medicaid – 6 months HIM – 12 months for primary immunodeficiency; 6 months for all other indications Commercial – 6 months or to the member’s renewal date, whichever is longer C. Other diagnoses/indications (must meet 1 or 2):

66. 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 Page 19 of 59

    CLINICAL POLICY Immune Globulins 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

67. 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. The following are conditions for which treatment with immune globulins is considered not medically necessary:
    1. Acquired factor VIII inhibitors;
    2. Adrenoleukodystrophy;
    3. Alzheimers Disease;
    4. Amyotrophic lateral sclerosis;
    5. Angioedema;
    6. Antiphospholipid syndrome (APS) [note: coverage exclusion of catastrophic antiphospholipid syndrome (CAPS) does not apply];

68. Aplastic anemia;

    8. Asthma;
    9. Autism;
    10. Autoimmune chronic urticaria;
    11. Behçet's syndrome;
    12. Cardiomyopathy, acute;
    13. Chronic fatigue syndrome;
    14. Chronic sinusitis;
    15. Complex pain regional syndrome (CPRS);
    16. Congenital heart block;
    17. Critical illness myopathy (necrotizing myopathy) (ICD10: G7281);
    18. Cystic fibrosis;
    19. Diabetes mellitus;
    20. Diamond-Blackfan anemia;
    21. Dysautonomia, acute idiopathic;
    22. Eczema;
    23. Encephalopathy, acute;
    24. Endotoxemia;
    25. Epilepsy;
    26. Goodpasture’s syndrome;
    27. Hemolytic transfusion reaction;
    28. Hemolytic-uremic syndrome; Page 20 of 59

    CLINICAL POLICY Immune Globulins

69. Hemophagocytic syndrome; 30. Idiopathic lumbosacral flexopathy;
    
    31. Idiopathic progressive neuropathy (ICD10: G603);
    32. Immune-mediated neutropenia;
    33. Inclusion body myositis;
    34. Infection prevention and control in newborns;
    35. Intractable seizures;
    36. Iridocyclitis, unspecified (ICD10: H209);
    37. Lower motor neuron syndrome;
    38. Multiple sclerosis - primary progressive or secondary types;
    39. Myalgia, myositis, unspecified;
    40. Myelopathy, HTLV-I associated;
    41. Nephropathy, membranous;
    42. Nephrotic syndrome;
    43. Non-immune thrombocytopenia;
    44. Ophthalmopathy, euthyroid;
    45. Oral use;
    46. Orbital myositis, bilateral (ICD10: H05123);
    47. Other diseases of capillaries [Clarkson disease (systemic capillary leak syndrome)] (ICD10: I788);

70. Otitis media, recurrent;

    49. Paraneoplastic cerebellar degeneration;
    50. Paraproteinemic neuropathy;
    51. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) [note: coverage exclusion of PANDAS does not apply to requests from Arkansas, Illinois, Indiana, New Hampshire, and Oregon];
    52. POEMS syndrome (see General Information – Section IV for definition);
    53. Polyarteritis nodosa;
    54. Progressive lumbosacral plexopathy;
    55. Radiculoneuritis, Lyme;
    56. Rasmussen's syndrome;
    57. Recurrent otitis media;
    58. Recurrent spontaneous pregnancy loss;
    59. Refractoriness to platelet transfusion;
    60. Reiter's syndrome;
    61. Renal failure, acute;
    62. Rheumatoid arthritis (adult and juvenile);
    63. Scleroderma;
    64. Secondary immunodeficiencies induced by biologic therapies;
    65. Sensory neuropathy;
    66. Systemic lupus erythematosis;
    67. Thrombocytopenia (non-immune);
    68. Vasculitis associated with other connective tissue diseases;
    69. Vogt-Koyanagi-Harada syndrome. Page 21 of 59

    CLINICAL POLICY Immune Globulins IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ACTH: adrenocorticotropic hormone ADA: adenosine deaminase adjBW: adjusted body weight AIDP: acute inflammatory demyelinating polyneuropathy
    CIDP: chronic inflammatory demyelinating polyneuropathy
    CLL: chronic lymphocytic leukemia
    CVID: common variable immunodeficiency DIF: dual inactivation plus nanofiltration
    DM: dermatomyositis FNAIT: fetal/neonatal alloimmune thrombocytopenia FDA: Food and Drug Administration
    GBS: Guillain Barre Syndrome HIV: human immunodeficiency virus HLA: human leukocyte antigen HPA: human platelet antigen IBW: ideal body weight IG: immune globulin IgA: immune globulin A
    IgG: immune globulin G IgM: immune globulin M IGIV: immune globulin intravenous IMIG: intramuscular immune globulin ITP: immune thrombocytopenic purpura
    IVIG: intravenous immune globulin
    LEMS: Lambert Eaton myasthenic syndrome MG: myasthenia gravis MM: multiple myeloma MMN: multifocal motor neuropathy
    NAIT: neonatal alloimmune thrombocytopenia NF: nanofiltered NMDA: N-methyl D-aspartate OMS: opsoclonus-myoclonus syndrome PI: primary [humoral] immunodeficiency
    PM: polymyositis POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes RhIG: Rho(D) immune globulin SC: subcutaneous SCID: severe combined immunodeficiency disorders SCIG: subcutaneous immune globulin S/D: solvent/detergent treated
    TBW: total body weight VZIG: varicella zoster immune globulin 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 baclofen (Lioresal®) diazepam (Valium®) Stiff Person Syndrome 20 mg PO BID or TID, or 50 to 1,600 mcg/day intrathecally Stiff Person Syndrome 20 to 80 mg/day PO (given in divided doses) Firdapse® (amifampridine) LEMS Page 22 of 59 Dose Limit/ Maximum Dose PO: 80 mg/day IT: 1600 mcg/day Daily doses needed to control the disease can be as high as 100 to 200 mg/day in some patients 80 mg/day (20 mg/dose)

    CLINICAL POLICY Immune Globulins Drug Name Dosing Regimen Ruzurgi® (amifampridine) pyridostigmine (Mestinon®); Mestinon® Timespan (pyridostigmine extended release) Revcovi™ (elapegademase-lvlr) Rhophylac, WinRho SDF (Rho(D) immune globulin) Rituxan® (rituximab) Adults: 15 mg to 30 mg PO in 3 to 4 divided doses daily. Dose can be increased by 5 mg daily every 3 to 4 days.
    LEMS Pediatric (age 6 to <17 years) and weight ≥ 45 kg: 15 to 30 mg PO in 2 to 3 divided doses. Dose can be increased by 5 mg to 10 mg increments daily, divided in up to 5 doses per day.
    Pediatric (age 6 to <17 years) and weight < 45 kg: 7.5 mg to 15 mg PO in 2 to 3 divided doses. Dose can be increased by 2.5 mg to 5 mg increments daily, divided in up to 5 doses per day.
    MG Immediate Release (IR) tablets and syrup Adults: 60 to 1,500 mg PO daily in divided doses (avg 600 mg PO daily) Pediatrics: 1 mg/kg PO Q4 to 6 hrs Extended Release 180 to 540 mg PO QD or BID ADA-SCID Adagen-naïve: 0.2 mg/kg twice a week IM Transitioning from Adagen: 0.2 mg/kg weekly IM
    ITP in non-splenectomized, Rho(D) antigen positive patients Initial: 50 mcg/kg IV Maintenance Therapy: 25 to 60 mcg/kg IV
    Pemphigus Vulgaris Initial: Two-1000 mg IV infusions separated by 2 weeks in combination with a tapering course of glucocorticoids Maintenance Therapy: 500 mg IV at month 12 and every 6 months thereafter DM/PM 1,000 mg/m2 IV weekly x 2 weeks Dose Limit/ Maximum Dose 100 mg/day (30 mg/dose) for weight ≥ 45 kg; 50 mg/day (15 mg/dose) for weight < 45 kg) IR: 1,500 mg/day (adults) or 7 mg/kg/day (pediatrics) ER: 1,080 mg/day 0.4 mg/kg/week 75 mcg/kg 500 mg/6 months Immunosuppressive agents azathioprine (Imuran®) DM/PM, MG*
    3 mg/kg/day 2 mg/kg PO QD or 50 mg/day PO up to 2 to 3 mg/kg/day Page 23 of 59

    CLINICAL POLICY Immune Globulins Drug Name Dosing Regimen cyclophosphamide (Cytoxan®) cyclosporine (Gengraf®, Neoral®, Sandimmune®) methotrexate (Rheumatrex®) mycophenolate mofetil (Cellcept®) tacrolimus (Prograf®) Pemphigus vulgaris and associated conditions 2 to 3 mg/kg/day PO DM/PM 1 to 3 mg/kg/day PO QD or 500 mg IV every 2 weeks for 6 doses
    Pemphigus vulgaris and associated conditions 50 to 75 mg/day PO or pulsed regimen of 500 mg IV on day, and then every 4 weeks thereafter in combination with oral cyclophosphamide and dexamethasone
    DM/PMs, MG 5 to 10 mg/kg/day PO
    DM/PMs 10 to 25 mg/week PO/IV Dose Limit/ Maximum Dose Not applicable Not applicable 50 mg/week DM/PM 250 to 500 mg PO BID, increasing to a target dose of 1,500-3,000 mg/day DM/PM: 3 g/day PV, etc: 2 g/day MG 1 g PO BID Pemphigus vulgaris and associated conditions 35 to 45 mg/kg/day PO or 1 g PO BID
    DM/PM 0.075mg/kg/day PO BID OR begin at 1 mg PO BID, increase to reach trough of 5- 10 ng/ml Not applicable 2 mg/kg/day 14 mg/day MG* 3 mg PO QD An equivalent dose of prednisone 1 mg/kg/day (with or without tapering) Systemic corticosteroids (e.g., prednisone, prednisolone, methylprednisolone) Disease-modifying therapies for relapsing remitting MS Aubagio® (teriflunomide) 7 or 14 mg PO QD Page 24 of 59

    CLINICAL POLICY Immune Globulins Drug Name Dosing Regimen Avonex®, Rebif® (interferon beta-1a) Avonex: 30 mcg IM Q week Rebif: 22 mcg or 44 mcg SC TIW Betaseron®, Extavia® (interferon beta-1b) glatiramer acetate (Copaxone®, Glatopa®) 250 mcg SC QOD Copaxone: 20 mg SC QD or 40 mg SC TIW Glatopa: 20 mg SC QD Gilenya™ (fingolimod) 0.5 mg PO QD Lemtrada® (alemtuzumab) Novantrone® (mitoxantrone) Ocrevus™ (ocreliuzmab) Plegridy® (peginterferon beta-1a) IV infusion for 2 treatment courses:
    • First course: 12 mg/day on 5 consecutive days • Second course: 12 mg/day on 3 consecutive days 12 months after first course 12 mg/m2 given as a short (approximately 5 to 15 minutes) IV every 3 months Initial: 300 mg IV, then 300 mg IV 2 weeks later Maintenance: 600 mg IV every 6 months 125 mcg SC Q2 weeks Dose Limit/ Maximum Dose Avonex: 30 mcg/week Rebif: 44 mcg TIW 250 mg QOD Copaxone: 20 mg/day or 40 mg TIW Glatopa: 20 mg/day 0.5 mg/day See regimen Cumulative lifetime dose of ≥ 140 mg/m2 600 mg/6 months 125 mcg/2 weeks Tecfidera® (dimethyl fumarate) 120 mg PO BID for 7 days, followed by 240 mg PO BID 480 mg/day Tysabri® (natalizumab) 300 mg IV every 4 weeks 300 mg/4 weeks Zinbryta® (daclizumab) 150 mg SC once monthly 150 mg/month 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 Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o History of anaphylactic or severe systemic reactions to human immune globulin o IgA-deficient patients with antibodies against IgA and a history of hypersensitivity • Boxed warning(s): thrombosis, renal dysfunction, and acute renal failure Page 25 of 59

    CLINICAL POLICY Immune Globulins Appendix D: General Information
    • CLL: o These patients have a pattern of infection caused by encapsulated bacteria (Haemophilus influenzae, pneumococci, streptococci) which tends to be chronic and/or recurrent and does not demonstrate improvement with an adequate course of PO antibiotics and/or prophylactic antibiotics. Recurrent infections may include sinus infections, otitis media, bronchiectasis and pyogenic pneumonias.
    • DM or PM: o Per the 2020 American Academy of Dermatology treatment guidelines for DM, in cases where a combination of systemic corticosteroids and an oral immunosuppressant fail, rituximab is the appropriate next step in therapy. In individuals with vasculopathic or calcinotic lesions, adults with anti-MDA5 positivity, or children with NXP-2 positivity, rituximab plus systemic corticosteroids can be considered first-line treatment. Additionally, patients with juvenile dermatomyositis and calcinosis should be preferentially treated with IVIG because it has the best data supporting its use for calcinosis specifically. o IVIG may be medically necessary after less than 4 months trial of prednisone or prednisone combination therapies if the patient has profound, rapidly progressive and/or potentially life threatening muscular weakness (e.g., life-threatening aggressive disease with involvement of respiratory musculature, possibly requiring hospitalization, elective intubation and mechanical ventilatory support) and is refractory to or intolerant of previous therapy.
    o Failure or clinically significant adverse effects to continual high dose steroids in combination with other immunosuppressive agents is defined as the patient being unresponsive or poorly responsive to therapy (persistently elevated serum creatine kinase (CK) levels and/or lack of improvement on muscle strength improvement scales) or intolerant of therapy (i.e., steroid myopathy or severe osteoporosis).
    o Inclusion body myositis (IBM) is classified as one of the idiopathic inflammatory myopathies. However, despite some histologic similarities, the clinical manifestations, treatment and prognosis are different from DM and PM. IBM is relatively resistant to standard immunosuppressive therapy. In two clinical studies, IVIG was unable demonstrate objective improvement in the treatment of IBM. • ITP: o Definitions of acute vs. chronic ITP:  Per an International Working Group consensus panel of ITP experts, ITP is defined as newly diagnosed (diagnosis to 3 months), persistent (3 to 12 months from diagnosis), or chronic (lasting for more than 12 months). Although not formally validated, these definitions are supported and used by the American Society of Hematology (ASH). In clinical trials evaluating the efficacy and safety of IVIG in ITP, acute ITP was defined as condition duration of up to 6 months while chronic ITP was defined as condition duration of greater than 12 months.  o Response to treatment was defined by the following:  Per the 2019 ASH guidelines:
    Page 26 of 59

    CLINICAL POLICY Immune Globulins • Early response is as a platelet count ≥ 30,000/µL and at least doubling • baseline at 1 week Initial response is defined as a platelet count ≥ 30,000/µL and at least doubling baseline at 1 month • Durable response is defined as a platelet count ≥ 30,000/µL and at least doubling baseline at 6 month  Per the 2009 International Working Group consensus panel of ITP excerpts:
    • Platelet counts should be confirmed on at least 2 separate occasions (at least 7 days apart when used to define complete response [CR] or response [R]) or 1 day apart when used to define no response [NR] or loss of response • CR: platelet ≥ 100,000/µL and absence of bleeding
    • R: platelet count ≥ 30,000/µL and at least 2-fold increase the baseline count and absence of bleeding • NR: platelet < 30,000/µL or less than 2-fold increase of baseline platelet count or bleeding • Loss of CR or R: platelet count below 100,000/µL or bleeding (from CR) or below 30,000/µL or less than 2-fold increase of baseline platelet count or bleeding (from R) o There have been reports of fatal intravascular hemolysis with Rho(D) immune globulin and specific monitoring is required. This therapy is not necessarily recommended over IVIG but can be used instead in patients who are Rh positive, have a negative direct antiglobulin test (DAT), and have not had a splenectomy. o For acute ITP, a single dose of IVIG is used as first line treatment. For adults, a second dose may be given if necessary. • AIDP or GBS: o GBS subtypes include the following: acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor- sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS). o Miller Fisher syndrome is a rare, acute polyneuropathy characterized by ataxia (abnormal muscle coordination), ophthalmoplegia (paralysis of the eye muscles), and areflexia (absence of the reflexes).
    o Elevated CSF protein, with a normal CSF white blood cell count, is often present; fifty to 66 percent the first week of symptoms and ≥75 percent the third week. o GBS and AIDP typically progresses over 2 weeks, and the majority of patients achieve nadir of the disease by four weeks.
    o Initiation of IVIG within 2 weeks of symptom onset appears to be as effective as plasma exchange (PE). o The combination of IVIG and plasmaphoresis used together is not better than either treatment used alone. o The combination of IVIG and IV methylprednisolone was not more effective than IVIG alone. o Immunoabsorption is an alternative technique to PE that removes immunoglobulins.
    There is insufficient evidence to recommend the use of immunoabsorption for GBS. o CSF filtration is as effective as PE for treatment of GBS. o Pulmonary function risk factors include one or more of the following:  Forced vital capacity < 20 mL/kg Page 27 of 59

    CLINICAL POLICY Immune Globulins  Maximal inspiratory pressure < 30 cm H2O  Maximal inspiratory pressure < 40 cm H2O  30% reduction in vital capacity from baseline • CIDP: o The definition of CIDP includes multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) variant or when Sensory CIDP exists with other causes of neuropathy such as diabetes and Charcot-Marie-Tooth (CMT), as evidenced by superimposed features of CIDP. o IVIG, corticosteroids, and plasmapheresis are all considered first-line treatments for patients with moderate to severe disability. Patient-specific factors may determine the appropriate choice of therapy. o As evidence of progression is more significant than the level of disability, mild cases of CIDP may not need to be treated aggressively if they are stable, but any signs of progression warrants effective treatment with IVIG to begin immediately. o Plasmapheresis has not been shown to be more effective than IVIG, however, it may be used in patients who are unresponsive to both IVIG and corticosteroid therapy. • Kawasaki Disease: o The efficacy of IVIG administered in the acute phase of Kawasaki disease in reducing the prevalence of coronary artery abnormalities is well-established. The mechanism of action of IVIG in treating Kawasaki disease is unknown; however IVIG appears to have a generalized anti-inflammatory effect. o For patients with persistent or recurrent fever after initial IVIG infusion, IVIG retreatment may be useful. Failure to respond usually is defined as persistent or recrudescent fever ≥36 hours after completion of the initial IVIG infusion. Most experts recommend retreatment with IVIG, 2 g/kg. The putative dose-response effect of IVIG forms the theoretical basis for this approach. • Kidney Transplant: o Centene considers the combination of IVIG and Rituxan (rituximab) for desensitization prior to renal transplantation, investigational at this time. Larger, prospective, randomized controlled trials are needed to evaluate the long-term efficacy and safety of this treatment and to compare this protocol with the current treatment of IVIG alone.
    o In a retrospective analysis of 50 kidney transplant patients at Johns Hopkins Hospital, all patients were live donor HLA incompatible recipients. Desensitization included plasmapheresis with low dose IVIG, mycophenolate and tacrolimus, and intraoperative induction therapy with anti-IL2 receptor antibodies. Twenty five of the higher risk patients also received rituximab (375 mg/m2) the day prior to transplant.
    There was no significant difference in the incidence of acute rejection within the first 3 months of transplant between the two groups. Further randomized, controlled trials are still needed. • MMN: o Although not required for diagnosis, the presence of a high titer (>1:1000) of serum Immunoglobulin M (IgM) antibody directed against ganglioside-monodialic acid (IgM Anti-GM1 antibodies) provides independent support for MMN (> 80% of patients). Page 28 of 59

    CLINICAL POLICY Immune Globulins o Although no reports exist of controlled trials of immunosuppressive drugs in patients with multifocal motor neuropathy, there are a series of anecdotal reports of patients who transiently responded to oral or pulsed doses of cyclophosphamide, however, this treatment was associated with significant side effects, related in part to the cumulative dose of cyclophosphamide. • MM: o Plateau phase is defined as the time when other causative organisms that may be present due to dysfunction in other immunologic cells besides the B-cell lines of defense are less likely to be present. IVIG in any other phase is considered not medically necessary. o These patients have a pattern of infection caused by encapsulated bacteria (Haemophilus influenzae, pneumococci, streptococci) which tends to be chronic and/or recurrent and does not demonstrate improvement with an adequate course of PO antibiotics and/or prophylactic antibiotics. Recurrent infections may include sinus infections, otitis media, bronchiectasis and pyogenic pneumonias.
    • MS: o The clinical course of MS usually falls within one of the following categories, with the potential for progression from one pattern to a more serious one:  Relapsing-remitting MS: This form of MS is characterized by clearly defined acute attacks with full recovery or with some remaining neurological signs/symptoms and residual deficit upon recovery. The periods between disease relapses are characterized by a lack of disease progression.
     Secondary progressive MS: The disease begins with an initial relapsing-remitting course, followed by progression at a variable rate that may also include occasional relapses and minor remissions.  Progressive-relapsing MS: Persons with progressive-relapsing MS experience progressive disease from onset, with clear, acute relapses that may or may not resolve with full recovery. Unlike relapsing-remitting MS, the periods between relapses are characterized by continuing disease progression.  Primary progressive MS: The disease shows gradual progression of disability from its onset, without plateaus or remissions or with occasional plateaus and temporary minor improvements. • MG: o MG is a disorder of neuromuscular function that is characterized by fatigue and weakness of the muscular system without atrophy or sensory deficits. o Myasthenia “Crisis” refers to exacerbation sufficient to endanger life, and usually involves respiratory failure in MG, therefore would not include disabled patients who are able to walk with or without assistance. o IVIG has not been shown to be superior to plasmapheresis in the treatment of life- threatening myasthenia gravis.
    o High-dose IVIG may temporarily modify the immune system and suppress autoantibody production to improve severe myasthenia gravis symptoms. The effect of IVIG is seen typically in less than a week, and the benefit can last for three to six weeks. IVIG is used to quickly reverse an exacerbation of myasthenia.
    Page 29 of 59

    CLINICAL POLICY Immune Globulins o According to the European Federation of Neurological Studies (EFNS) guidelines on the use of intravenous immunoglobulin in treatment of neurological diseases, the efficacy of IVIG has been proven acute exacerbations of myasthenia gravis and short- term treatment of severe MG (level A recommendation).
    o A small clinical trial conducted by Wegner and Ahmed showed that long-term IVIG was effective. This trial included six patients who were anti-AChR-Ab-positive.
    These patients received IVIG at a dosage of 400 mg/kg/day for 5 days then a maintenance therapy of 400 mg/kg for 1 day every 3 to 4 months. After a 2 year follow up, all patients maintained a good functional status and side effects from IVIG did not increase.
    • NAIT: o NAIT is caused by maternal alloantibodies directed against fetal (paternally inherited) platelet antigens as a result of feto-maternal transplacental passage of incompatible platelets during pregnancy.
    o HPA-1a is the platelet-specific antigen implicated in most cases of neonatal alloimmune thrombocytopenia.
    o Administering IVIG to the mother during pregnancy is the most successful strategy for increasing the fetal platelet count and has become the recommended standard treatment of known fetal alloimmune thrombocytopenia.
    o Studies have shown that weekly infusions (1 g/kg maternal body weight) beginning at 20 to 24 weeks' gestation stabilize or increase the fetal platelet count in fetuses with documented alloimmune thrombocytopenia.
    o In very high-risk pregnancies (intracranial hemorrhage in a previous sibling before 30 weeks' gestation), some investigators recommend starting IVIG therapy as early as 12 to 14 weeks' gestation. o Although the mechanism of action of IVIG in FAIT is not clearly defined, it is postulated that IVIG decreases maternal alloantibodies and may also block transplacental transport of maternal antiplatelet antibodies. o There is still no consensus on the optimal protocol for managing IVIG after it is begun.
    • Paraneoplastic Syndromes o Paraneoplastic syndromes are the remote effects of a cancer unrelated to the effects of the tumor or its metastasis. Sometimes they are associated with low immune globulin values and sometimes they are associated with autoantibodies. o The combination of IVIG, cyclophosphamide, and methylprednisolone in patients with paraneoplastic cerebellar degeneration and antineuronal antibodies in is not effective. o Anti-NMDA encephalitis  Although no standard of care for anti-NMDA encephalitis exists, on the basis of data from the reviews completed, concurrent IVIG (0.4 g/kg per day for 5 days) and methylprednisolone (1 g/day for 5 days) is preferred over plasma exchange.
    If no response is seen after 10 days, a second-line therapy is started.   Although there is a paucity of randomized controlled and comparative trials regarding the use of IVIG for this disorder, because of the severity of anti-NMDA encephalitis and on the basis of data from the completed reviews and case series, it has been noted that individuals who received early tumor treatment (usually Page 30 of 59

    CLINICAL POLICY Immune Globulins  with immunotherapy) had better outcome and fewer neurological relapses than the rest of the patients. IVIG given concurrently with corticosteroids has been determined to assist with full or substantial recovery in approximately 75% of the individuals with anti- NMDA encephalitis. o OMS or "dancing eyes-dancing feet" syndrome is a rare neurological disorder that affects infants and young children and has been described in adult patients with cancer.  The current therapeutic strategies for OMS provide a broad spectrum of nonselective immunotherapies, including noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, adrenocorticotropic hormone (ACTH) and plasma exchange. Intravenous immunoglobulin G is occasionally used as an alternative to ACTH.
      Altogether, the available evidence suggests that IVIG may be an effective treatment in parainfectious and idiopathic OMS.
     Treatment with IVIG has been reported in a few idiopathic adult-onset OMS cases in literature and they have concluded that idiopathic OMS presents an age dependent prognosis and immunotherapy. IVIG seems to be associated with a faster recovery.
     Trends in the standard of care of OMS report that ACTH, prednisone, and intravenous immunoglobulin were used with equal frequency, but ACTH was associated with the best early response. • Parvovirus B19 Infection o Human parvovirus B19 infection can give rise to the loss of mature red blood cells, severe anemia and the formation of immune complexes. o A robust antibody response is necessary for virus clearance and control of the infection. o IVIG has been shown to be effective in recurrent infection in augmenting the inadequate humoral immune response. Based on the evidence available, IVIG therapy has become the standard of care if the aplastic crisis becomes prolonged, even though there are no definitive clinical trials demonstrating the efficacy of HPV B19-induced anemia. o Use of IVIG for treatment in parvovirus B19 infection is a category 2A NCCN recommendation. • Pemphigus Vulgaris and related conditions: o IVIG therapy for Pemphigus Vulgaris must be used only for short-term therapy and not as a maintenance therapy. o For Pemphigus Vulgaris, Pemphigus Foliaceus, Bullous Pemphigoid, Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid), Epidermolysis Bullosa Acquisita: the treatment is considered complete when the patient is free of disease after a 16-week interval between the last two infusion cycles. o Examples of clinically significant adverse effects to corticosteroids, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil) are diabetes or fractures from chronic steroid use. Page 31 of 59

    CLINICAL POLICY Immune Globulins • PI: o Common variable immunodeficiency (CVID), the most frequently diagnosed primary immunodeficiency, is characterized by a low serum IgG level antibody deficiency at least 2 SDs below the mean for age, with most patients having concurrent deficiencies of IgA and IgM. Many Patients with CVID have IgG levels below 639 that require IVIG. However, there are rare instances when a patient will have normal IgG levels. The serum immunoglobulin measurement alone does not establish a diagnosis of CVID. A definitive diagnosis of CVID is established when a patient does not demonstrate a prolonged antibody response to immunization with protein antigens (e.g., tetanus) or carbohydrate antigens (e.g., pneumococcal capsular polysaccharides such as pneumovax). o Subclass deficiency or IgG subclass deficiency (IGGSD) is diagnosed in patients with recurrent infections, deficiency in one or more IgG subclass levels (less than the 5th percentile or 2 standard deviations below), and normal total concentrations of IgG, IgM, and IgA.
    o Specific antigen deficiency or functional antibody deficiency is diagnosed in patients 2 years and older who present with recurrent respiratory tract infections, normal immunoglobulin and IgG subclass levels, and impaired IgG response to pneumococcal capsular polysaccharide.
    o The gamma globulin band consists of 5 immunoglobulins: about 80% immunoglobulin G (IgG), 15% immunoglobulin A (IgA), 5% immunoglobulin M (IgM), 0.2% immunoglobulin D (IgD), and a trace of immunoglobulin E (IgE). o The use of intravenous immune globulin should be reserved for patients with serious defects of antibody function. All immune deficiency conditions require ongoing monitoring of the patient’s clinical condition with measurement of pre-infusion (trough) serum IgG levels. o For lifelong treatment serum trough IgG levels should be measured before the infusion, and then monitored every 3 months to maintain low normal level (usually 400 – 600 mg/dl). o See Appendix E: Reference Ranges for Immune Globulin Levels • Stiff person syndrome o Stiff person syndrome (also known as Moersch-Woltmann syndrome) is a rare progressive neurological disorder characterized by progressive rigidity and stiffness of the axial musculature, associated with painful spasms, primarily in the lower limbs, neck and trunk. o Symptoms are related to autoantibodies directed against glutamic acid decarboxylase in the nervous system called anti-GAD antibodies. This antibody marker, which is an antibody to an enzyme found both in the pancreas and in nerve tissue, is found in high concentrations in classical Stiff-man syndrome. o In most cases, improvement in symptoms occurs with combinations of diazepam and baclofen, often in reasonably high dosage. Where all drug treatments fail to give sufficient relief from spasms and pain, treatment is directed against the underlying immunologic condition with drug choices consisting of steroids (either intravenous or orally), plasma exchange or pooled IVIG. o Current treatments do not offer or lead to a cure. However, they are able to control symptoms in the majority of patients. Page 32 of 59

    CLINICAL POLICY Immune Globulins • Coverage is excluded for the following indications. The use of immune globulins for these indications is considered investigational due to lack of conclusive, evidence-based data with randomized controlled trials. As such, alternative therapies for these indications include: o Critical illness myopathy (necrotizing myopathy): corticosteroids (e.g., prednisone, methylprednisolone), immunosuppressive agents (e.g., cyclophosphamide, methotrexate, azathioprine) o Idiopathic progressive neuropathy: corticosteroids o Iridocyclitis, unspecified: corticosteroids o Orbital myositis, bilateral: corticosteroids o Other diseases of capillaries • On February 2018, CSL Behring announced product discontinuation of Carimune NF given the preference among healthcare professionals and patients for newer, more advanced immune globulin options.
    https://www.fffenterprises.com/assets/downloads/PR-carimune-nf-letter-of-discontinuation.pdf Appendix E: Reference Ranges for Immune Globulin Levels • The Mayo Clinic suggests the following reference ranges of immune globulins: Total IgM 26-122 mg/dL
    32-132 mg/dL 40-143 mg/dL 46-152 mg/dL 37-184 mg/dL 37-224 mg/dL 38-251 mg/dL 41-255 mg/dL 45-244 mg/dL 49-201 mg/dL 37-286 mg/dL Age 0 to < 5 months 5 to < 9 months 9 to < 15 months 15 to < 24 months 2 to < 4 years 4 to < 7 years 7 to < 10 years 10 to < 13 years 13 to < 16 years 16 to < 18 years ≥ 18 years Total IgG 100-334 mg/dL 164-588 mg/dL 246-904 mg/dL 313-1,170 mg/dL 295-1,156 mg/dL 386-1,470 mg/dL 462-1,682 mg/dL 503-1,719 mg/dL 509-1,580 mg/dL 487-1,327 mg/dL 767-1,590 mg/dL Total IgA 7-37 mg/dL
    16-50 mg/dL 27-66 mg/dL 36-79 mg/dL 27-246 mg/dL 29-256 mg/dL 34-274 mg/dL 42-295 mg/dL 52-319 mg/dL 60-337 mg/dL 61-356 mg/dL • Some primary immunodeficiency disorders, such as functional antibody deficiency or specific antibody deficiency exhibit normal total IgG concentration but deficiencies in one or more IgG subclasses. The Mayo Clinic suggests the following references ranges: IgG2 Age ≤ 82 mg/dL
    0 to < 5 months 56-215 mg/dL 5 to < 9 months 102-369 mg/dL ≤ 89 mg/dL IgG1 IgG4 IgG3 7.6-82.3 mg/dL ≤ 19.8 mg/dL ≤ 20.8 mg/dL 11.9-74.0 mg/dL 17.3-63.7 mg/dL 21.9-55.0 mg/dL 17.0-84.7 mg/dL 0.4-49.1 mg/dL ≤ 22.0 mg/dL ≤ 23.0 mg/dL 9 to < 15 months 15 to < 24 months 2 to < 4 years 160-562 mg/dL 24-98 mg/dL 209-724 mg/dL 35-105 mg/dL 158-721 mg/dL 39-176 mg/dL Page 33 of 59

    CLINICAL POLICY Immune Globulins Age 4 to < 7 years IgG1 209-902 mg/dL 44-316 mg/dL IgG2 7 to < 10 years 253-1,019 mg/dL 54-435 mg/dL 10 to < 13 years 280-1,030 66-502 mg/dL mg/dL 13 to < 16 years 289-934 mg/dL 82-516 mg/dL 16 to < 18 years 283-772 mg/dL 98-486 mg/dL IgG3 10.8-102.6 mg/dL 8.5-102.6 mg/dL 11.5-105.3 mg/dL 20.0-103.2 mg/dL 31.3-97.6 mg/dL ≥ 18 years 341-894 mg/dL 171-632 mg/dL 18.4-106.0 mg/dL IgG4 0.8-81.9 mg/dL 1.0-108.7 mg/dL 1.0-121.9 mg/dL 0.7-121.7 mg/dL 0.3-111.0 mg/dL 2.4-121.0 mg/dL Appendix F: Weight-based Dose Calculations • Cost-effective dosing of immune globulins is achieved by dosing based on the lesser of either total body weight (TBW; i.e., actual body weight) or ideal body weight (IBW).
    o IBW for males: 50 kg + (2.3 x inches over 5 feet) o IBW for females: 45.5 kg + (2.3 x inches over 5 feet) • For obese members (e.g., BMI is ≥ 30 kg/m2 or TBW is > 20-30% over IBW), adjusted body weight (adjBW) should be used for dose calculations. o AdjBW = IBW + [0.4 x (TBW-IBW)] • Online adult IBW and adjBW calculator: https://www.mdcalc.com/ideal-body-weight- adjusted-body-weight
    • Online BMI calculator: https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm V. Dosage and Administration
    Refer to full prescribing information for specific dosage instructions. Dosage must be individualized and is highly variable depending on the nature and severity of the disease and on the individual patient response (e.g., serum IgG trough levels). There is no absolute maximum dosage of immune globulin or hyaluronidase.
    Drug Name
    Alyglo Maximum Dose Not applicable Indication PI Dosing Regimen
    300 to 800 mg/kg IV every 21 or 28 days Asceniv PI [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 300 to 800 mg/kg IV every 3 to 4 weeks [Use TBW or IBW, whichever is less; if member Not applicable Page 34 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Bivigam PI Cutaquig PI Cuvitru PI Maximum Dose Not applicable Not applicable Not applicable Dosing Regimen
    is obese, use adjBW – see Appendix F.] Initial: 300 to 800 mg/kg IV every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Previous immune globulin intravenous (IGIV) dose in grams divided by number of weeks between IV doses and multiplied by 1.30. Provided the total weekly dose is maintained, any dosing interval from daily up to weekly can be used. [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial: Previous IGIV/HyQvia dose in grams divided by number of weeks between IV doses and multiplied by 1.30. Prorate the weekly dose and give SC at regular intervals QD to every 2 weeks beginning 1 week after last IV or HyQvia dose. [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Page 35 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Flebogamma 5% Indication PI Dosing Regimen
    Initial: 300 to 600 mg/kg IV every 3 to 4 weeks Maximum Dose Not applicable Flebogamma 10% ITP PI Gamastan, Gamastan S/D Hepatitis A prophylaxis Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD for 2 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial: 300 to 600 mg/kg IV every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Household and institutional case contacts: 0.1 mL/kg IM once Travel to Hepatitis A- endemic areas:
    Up to 1 month stay: 0.1 mL/kg IM once Up to 2 months stay: 0.2 mL/kg IM once 2 months or longer stay: 0.2 mL/kg IM every 2 months Page 36 of 59 Not applicable Not applicable 0.1 mL/kg as a single dose or 0.2 mL/kg every 2 months

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Dosing Regimen
    Maximum Dose Measles postexposure prophylaxis Rubella postexposure prophylaxis Varicella postexposure prophylaxis Gammagard Liquid MMN PI 0.25 mL/kg 0.55 mL/kg 1.2 mL/kg Not applicable Not applicable [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 0.25 mL/kg IM once [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 0.55 mL/kg IM once [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 0.6 to 1.2 mL/kg IM once [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 0.5 to 2.4 g/kg/month IV [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial:
    IV: 300 to 600 mg/kg every 3 to 4 weeks SC: Previous IGIV dose in grams divided by number of weeks between IV doses and multiplied by 1.37
    Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response Page 37 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Gammagard S/D
    CLL ITP KS PI Gammaked CIDP Dosing Regimen
    SC: given once weekly with dose adjusted per PI [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 400 mg/kg IV every 3 to 4 weeks [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV, up to 3 doses on alternate days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV single dose or 400 mg/kg IV QD for four consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial:
    IV: 300 to 600 mg/kg every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Loading dose: 2 g/kg IV given in divided doses over Maximum Dose Not applicable Not applicable Not applicable Not applicable Not applicable Page 38 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication ITP PI Gammaplex ITP Maximum Dose Not applicable Not applicable Not applicable Dosing Regimen
    2 to 4 consecutive days Maintenance dose: 1 g/kg IV every 3 weeks [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD given on 2 consecutive days or 0.4 g/kg IV QD given on 5 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial:
    IV: 300 to 600 mg/kg every 3 to 4 weeks SC: Previous IGIV dose in grams divided by number of weeks between IV doses and multiplied by 1.37 Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response SC: given once weekly with dose adjusted per PI [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD for 2 consecutive days [Use TBW or IBW, whichever is less; if member Page 39 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication PI Gamunex-C CIDP ITP PI Maximum Dose Not applicable Not applicable Not applicable Not applicable Dosing Regimen
    is obese, use adjBW – see Appendix F.] Initial: 300 to 800 mg/kg IV every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial: 2 g/kg IV given in divided doses over 2 to 4 consecutive days Maintenance: 1 g/kg IV on one day or 0.5 g/kg IV on two consecutive days, every 3 weeks [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD on 2 consecutive days, or 0.4 g/kg IV QD given on 5 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial:
    IV: 300 to 600 mg/kg every 3 to 4 weeks SC: Previous IGIV dose in grams divided by number of weeks between IV doses and multiplied by 1.37 Page 40 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Hizentra CIDP PI HyQvia PI Maximum Dose Not applicable Not applicable Not applicable Dosing Regimen
    Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response SC: given once weekly with dose adjusted per PI [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 0.2 to 0.4 g/kg SC per week, administered in 1 or 2 sessions over 1 or 2 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial weekly dose: previous IGIV dose in grams divided by number of weeks between IV doses and multiplied by 1.37. Prorate the weekly dose to give SC at regular intervals QD to every 2 weeks beginning 1 to 2 weeks after last IV or SC dose depending on dosing regimen. [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] If IG therapy naïve or switching from IGSC: 300 to 600 mg/kg every 3 to 4 weeks after initial ramp-up (see manufacturer labeling) Page 41 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Octagam 5% PI Octagam 10% ITP DM Panzyga PI Maximum Dose Not applicable Not applicable Not applicable Not applicable Dosing Regimen
    If switching from IGIV therapy: Give SC at same dose and frequency as previous IV therapy after initial ramp-up (see manufacturer labeling) [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial: 300 to 600 mg/kg IV every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD for 2 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 2 g/kg divided in equal doses given over 2-5 consecutive days every 4 weeks [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 300 to 600 mg/kg IV every 3 to 4 weeks [Use TBW or IBW, whichever is less; if member Page 42 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication ITP CIDP Privigen CIDP ITP PI Dosing Regimen
    is obese, use adjBW – see Appendix F.] 1g/kg IV QD for 2 consecutive days Maximum Dose Not applicable [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Loading dose: 2 g/kg (20 mL/kg), divided into 2 daily doses of 1 g/kg (10 mL/kg) given on 2 consecutive days Maintenance dose: 1-2 g/kg (10-20 mL/kg) every 3 weeks divided in 2 doses given over 2 consecutive days Loading dose: 2 g/kg IV in divided doses over 2 to 5 consecutive days Maintenance dose: 1 g/kg IV every 3 weeks [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] 1 g/kg IV QD for 2 consecutive days [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Initial: 200 to 800 mg/kg IV every 3 to 4 weeks Maintenance: IV: given every 3 to 4 weeks with dose adjusted per serum IgG level and clinical response Not applicable Not applicable Not applicable Not applicable Page 43 of 59

    CLINICAL POLICY Immune Globulins Drug Name
    Indication Xembify PI VI. Product Availability
    Maximum Dose Not applicable Dosing Regimen
    [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Previous IGIV dose in grams divided by number of weeks between IV doses and multiplied by 1.37. Prorate the weekly dose and give SC at regular intervals QD to every week beginning 1 week after last IV dose. Or Previous SC weekly dose administered in regular intervals every week. [Use TBW or IBW, whichever is less; if member is obese, use adjBW – see Appendix F.] Availability
    Drug IV administration - ready to use Alyglo (10%) Asceniv (10%) Bivigam (10%) Flebogamma DIF (5%) Flebogamma DIF (10%) Gammaplex (5%) Gammaplex (10%) Octagam (5%) Octagam (10%) Panzyga (10%) Privigen (10%) IV administration - freeze dried for reconstitution Gammagard S/D Single-use vials: 5, 10, 20 gram Single-use vial: 5 gram Single-use vials: 5, 10 gram
    Single-use vials: 0.5, 2.5, 5, 10, 20 gram
    Single-use vials: 5, 10, 20 gram
    Single-use bottles: 5, 10, 20 gram
    Single-use bottles: 5, 10, 20 gram Single-use bottles: 1, 2.5, 5, 10, 25 gram
    Single-use bottles: 2, 5, 10, 20, 30 gram
    Single-use bottles: 1, 2.5, 5, 10, 20, 30 gram
    Single-use vials: 5, 10, 20, 40 gram
    5% single-use bottle: 5 gram
    10% single-use bottle: 10 gram
    IV or SC administration - ready to use Gammagard Liquid (10%) Gammaked (10%) Gamunex-C (10%) SC administration - ready to use Single-use bottles: 1, 2.5, 5, 10, 20, 30 gram
    Single-use bottles: 1, 2.5, 5, 10, 20 gram
    Single-use vials: 1, 2.5, 5, 10, 20, 40 gram Page 44 of 59

    CLINICAL POLICY Immune Globulins Drug Cutaquig (16.5%) Cuvitru (20%) Hizentra (20%) HyQvia (10%) IgG and 160 U/mL recombinant human hyaluronidaseHyaluronidase increases permeability of the local SC tissue for approximately 24 to 48 hours. Xembify (20%) IM administration – ready to use GamaSTAN (16.5%) GamaSTAN S/D (15-18%) Availability
    Single-use vials: 1 g, 1.65 g, 2 g, 3.3 g, 4 g, 8 g (165 mg/mL) Single-use vials: 1, 2, 4, 8, 10 gram
    Single-use vials: 1, 2, 4, 10 gram
    Single-use prefilled syringes: 1, 2, 4, 10 gram Single-use dual vial sets: 2.5 g/25 mL and 200 U/1.25 mL, 5 g/50 mL and 400 U/2.5 mL, 10 g/100 mL and 800 U/5 mL, 20 g/200 mL and 1,600 U/10 mL, 30 g/300 mL and 2,400 U/15 mL Single-use vials: 1, 2, 4, 10 gram Single-use vials: 2 mL and 10 mL Single-use vials: 2 mL and 10 mL
    VII.