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Immune Globulin Therapy

Section: Injections
Effective Date: June 01, 2019
Revised Date: May 31, 2019

Description

Immune globulin is one of five closely-related proteins found in the human body. These proteins are capable of acting as antibodies. Gamma globulin is an intravenous, subcutaneous or intramuscular drug which has IgG antibodies and is used for the prevention and treatment of specific disease.

Criteria

Coverage is subject to the specific terms of the member's benefit plan.

Federal Employee Program members (FEP) should check with their Retail Pharmacy Program to determine if prior approval is required by calling the Retail Pharmacy Program at 1-800-624-5060 (TTY: 1-800-624-5077). FEP members can also obtain the list through the www.fepblue.org website.

Subcutaneous Immune Globulin (SCIG) Therapy

Primary Immunodeficiencies

Subcutaneous Immune Globulin may be considered medically necessary for the treatment of primary immunodeficiencies when ALL of the following criteria are met:

  • Standard therapies have failed, become intolerable, or are contraindicated; and
  • Laboratory evidence of immunoglobulin deficiency; and
  • Persistent and severe infections despite treatment with prophylactic antibiotics; and
  • Documented inability to mount an adequate immunologic response to inciting antigens; and
    • Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen. For example, an adequate response to the pneumococcal vaccine may be defined as at least a 4-fold increase in titers for at least 50% of serotypes tested; or
    • Lack of appropriate rise in antibody titer following provocation with a protein antigen. For example, an adequate response to tetanus/diphtheria vaccine may be defined as less than a 4-fold rise in titers 3-4 weeks after vaccine administration; and
  • Other unspecified disorder of immune mechanism may be given individual consideration.

Primary immunodeficiencies also include:

  • Congenital agammaglobulinemia; or
  • Hypogammaglobulinemia; or
  • Common variable immunodeficiency (CVID); or
  • Severe combined immunodeficiency; or
  • Wiskott-Aldrich syndrome; or
  • X-linked agammaglobulinemia (XLA).

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Subcutaneous Immune Globulin (Hizentra) may be considered medically necessary for the treatment of CIDP in Adults when ALL of the following criteria are met:

  • Individual has confirmed diagnosis of CIDP by genetic or molecular testing; and
  • Individual has shown improvement on intravenous immune globulin (IVIG) therapy.

Continuation of SCIg (Hizentra) may be medically necessary for individuals who demonstrate a clinically meaningful response as indicated by documentation of stable or improved symptoms.

Other applications of SCIg therapy are considered experimental/investigational, because their safety and/or effectiveness cannot be established by review of the published peer-reviewed literature.

Procedure Codes

90284 J1555 J1559 J1561 J1562 J1569 J1575

Intravenous Immune Globulin (IVIG) Therapy

Intravenous immune globulin (IVIG) may be considered medically necessary for treatment of ANY ONE of the following conditions when standard therapies have failed, become intolerable, or are contraindicated:

Acute Humoral Rejection; or

Autoimmune Mucocutaneous Blistering Disease used for short term therapy not maintenance therapy

  • Autoimmune mucocutaneous blistering disease for the following biopsy-proven conditions: pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid (cicatricial pemphigoid), epidermolysis bullosa acquisita, Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) when ANY ONE of the following criteria is met:
    • The individual failed conventional therapy (eg, steroids, methotrexate, immunosuppressive therapy) or conventional therapy is contraindicated; or
    • The individual has a rapidly progressive disease in which a clinical response could not be affected quickly enough using conventional agents. In this case, IVIG is given along with conventional treatments, and IVIG would be used only until conventional therapy could take effect; or

Autoimmune and inflammatory disorders

  • Dermatomyositis refractory to treatment with corticosteroids; in combination with other immunosuppressive agents; or
  • Kawasaki disease (mucocutaneous lymph node syndrome); or

Hematologic

  • Idiopathic thrombocytopenia purpura (ITP)
    • Treatment of acute, severe ITP defined by ANY ONE of the following parameters:
      • Acute ITP with major bleeding, e.g., life-threatening bleeding and/or clinically important mucocutaneous bleeding; or
      • Acute ITP with severe thrombocytopenia and at high risk for bleeding complications; or
      • Acute ITP with severe thrombocytopenia and a slow or inadequate response to corticosteroids; or
      • Acute ITP with severe thrombocytopenia and a predictable risk of bleeding in the future, e.g., a procedure or surgery with a high bleeding risk; or
    • Treatment of chronic ITP; in patients with BOTH of the following:
      • Duration of disease has been at least six (6) months; and
      • Individual has persistent thrombocytopenia despite treatment with corticosteroids and splenectomy; or
  • Fetal/neonatal alloimmune thrombocytopenia; or
  • Hemolytic disease of the fetus and newborn (e.g. erythroblastosis fetalis); or
  • Post allogeneic bone marrow transplant setting; or
  • Individuals with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia, multiple myeloma or post-transplant lymphoproliferative disorder (PLD); or
  • Warm antibody autoimmune hemolytic anemia, refractory to corticosteroids and immunosuppressive agents; or
  • Antiphospholipid syndrome; or
  • Severe anemia due to parvovirus B19; or

Infectious Disease

  • Prevention of infection in EITHER of the following:
    • Prevention of infection in pre-term (less than 37 weeks gestational age) and/or low birth weight (less than 2500g) neonates; or
    • Neonates predisposed to group B streptococcal infections; or
  • Toxic shock syndrome caused by staphylococcal or streptococcal organisms refractory to conventional therapy; or
  • HIV infected patients; or
  • Patients with primary defective antibody synthesis; or

Neuroimmunological

  • Myasthenia gravis chronic, severe, refractory to standard therapy (i.e., interferons, steroids/myasthenia crisis); or
  • Guillain Barre syndrome (acute infective polyneuritis); or
  • Chronic inflammatory demyelinating polyneuropathy (CIDP) in individuals with progressive symptoms for at least two (2) months when ALL of the following criteria are met:
    • Progressive or relapsing motor sensory, rarely only motor or sensory, dysfunction of more than one (1) limb or a peripheral nerve nature, developing over at least two (2) months; and
    • Hypo- or areflexia. This will usually involve all four (4) limbs; and
    • Nerve conduction studies including studies of proximal nerve segments in which the predominant process is demylination. (Must have 3 of the following):
      • Reduction in conduction velocity (CV) in two (2) or more motor nerves:
      • Less than 80% of lower limit of normal (LLN) is amplitude greater than 80% of LLN; and
      • Less than 70% of LLN is amplitude less than 80% of LLN; or
      • Partial conduction block or abnormal temporal dispersion and possible conduction block one (1) or more motor nerves:
        Partial conduction block:
      • Less than 15% change in duration between proximal an distal sites; and
      • Greater than 20% drop in negative peak (p) area or peak to peak (p-p) amplitude between proximal and distal sites.
        OR
      • Abnormal temporal dispersion and possible conduction block:
      • Less than 15% change in duration between proximal and distal sites; and
      • Greater than 20% drop in p area or p-p amplitude between proximal and distal sites; and
      • Greater than 20% drop in p or p-p amplitude between proximal and distal sites; or
      • Prolonged distal latencies in two (2) or more nerves:
      • Greater than 125% of upper limit of normal (LEN) if compound muscle action potential (CMAP) amplitude greater than 80% of LLN; and
      • Greater than 150% of LEN if CMAP amplitude less than 80% of LLN; or
      • Absent F waves or prolonged minimum
      • Greater than 120% of ULN if CMAP amplitude greater than 80% of LLN; and
      • Greater than 150% of ULN if CMAP amplitude less than 80% of LLN; and
    • Pathological findings are tested using the following:
      • Nerve biopsy showing unequivocal evidence of demyelination and remyelination; and
      • Demyelination by either electron microscopy (more than 5 fibers) or teased fiber studies more than 12% of 50 fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination; and
    • Cerebrospinal fluid studies (CSF) studies include the following tests:
      • Cell count less than 10 per cubic mm if HIV-seronegative or less than 50 per cubic mm is HIV seropositive; and
      • Negative Venereal Disease Research Laboratory test (VDRL); or
  • Multifocal motor neuropathy in patients with anti GM1 antibodies and conduction block; or
  • Lambert-Eaton myasthenic syndrome when there is failure, contraindication, or intolerance to other therapies (i.e. anticholinesterase and diaminopyridine); or
  • Relapsing-remitting multiple sclerosis (RRMS) when ALL the following criteria are met:
    • Other therapy (e.g., interferon beta, glatiramer) has failed, become intolerable, and/or is contraindicated; and
    • The individual has impaired function measured by a standard clinical scale and/or objective findings on a physical exam at the time of initial therapy; and
    • Documentation of an MS exacerbation or progression (worsening) of the patient's clinical status from the visit prior to the one prompting the decision to initiate immune globulin therapy; or

Primary immune deficiency syndromes, including combined immunodeficiencies

  • Treatment of primary immunodeficiencies, including congenital agammaglobulinemia (total IgG less than 200 mg/dl); or
  • Common variable immunodeficiency (hypogammaglobulinemia (total IgG less than 400 mg/dl or at least 2 standard deviations below normal, on at least 2 occasions)); or
  • Severe combined immunodeficiency; or
  • Wiskott-Aldrich syndrome; or
  • X-linked agammaglobulinemia (total IgG less than 200 mg/dl); or
  • X-linked Hyper-IgM Syndrome; or
  • Ataxia telangiectasia; or

Individuals with primary immunodeficiency syndromes should meet ALL of the following criteria for treatment with IVIG:

  • Laboratory evidence of immunoglobulin deficiency; and
  • Persistent and severe infections despite treatment with prophylactic antibiotics; and
  • Documented inability to mount an adequate immunologic response to inciting antigens and EITHER of the following:
    • Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen. For example, an adequate response to the pneumococcal vaccine may be defined as at least a 4-fold increase in titers for at least 50% of serotypes tested; or
    • Lack of appropriate rise in antibody titer following provocation with a protein antigen. For example, an adequate response to tetanus/diphtheria vaccine may be defined as less than a 4-fold rise in titers 3-4 weeks after vaccine administration; and
  • Other unspecified disorder of immune mechanism may be given individual consideration; or

Transplantation

  • Prior to solid organ transplant, for treatment of patients at high risk of antibody-mediated rejection (AMR) after steroid or other immunosuppressant failure, including highly sensitized patients, and those receiving an ABO incompatible organ; or
  • Following solid organ transplant, for treatment of AMR.

The use of IVIG for any other indication is considered experimental/investigational and therefore non-covered. Scientific evidence does not support of the use of any other indications than those listed above.

Procedure Codes

90283 J1572 J1459 J1556 J1557 J1561
J1566 J1568 J1569 J1599 S9338

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

Professional Statements and Societal Positions Guidelines

The latest technology assessment published by the American Academy of Neurology on therapies for multiple sclerosis offered the following recommendations regarding intravenous immunoglobulin:

  • The studies of intravenous immunoglobulin to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned.
  • The current evidence suggests that intravenous immunoglobulin is of little benefit with regard to slowing disease progression.

Diagnosis Codes

Covered diagnosis codes for procedure codes J1459, J1556, J1557, J1561, J1568, J1569, and J1572.

A48.3 B20 B34.3 B95.0 B95.1 B95.4 B95.5
B95.61 B95.62 B95.7 B95.8 B97.35 B97.6 C46.0
C46.1 C46.2 C46.3 C46.4 C46.7 C90.00 C90.01
C90.02 C91.10 C91.11 C91.12 C91.90 D47.Z1 D59.1
D68.312 D68.61 D69.3 D69.49 D69.6 D76.1 D76.2
D76.3 D80.0 D80.1 D80.2 D80.3 D80.4 D80.5
D80.6 D80.7 D80.8 D80.9 D81.0 D81.1 D81.2
D81.6 D81.7 D81.9 D82.0 D82.3 D83.0 D83.1
D83.2 D83.8 D83.9 D84.8 D84.9 D89.40 D89.41
D89.42 D89.43 D89.49 D89.9 G11.3 G13.0 G13.1
G35 G60.0 G60.1 G60.2 G60.3 G60.8 G60.9
G61.0 G61.81 G61.82 G61.89 G61.9 G62.81 G62.89
G62.9 G63 G64 G65.0 G65.1 G65.2 G70.00
G70.01 G70.80 G70.81 G73.1 G73.3 I45.9 L10.0
L10.1 L10.2 L10.3 L10.4 L10.5 L10.81 L10.89
L10.9 L12.0 L12.1 L12.30 L12.31 L12.35 L12.8
L12.9 L13.8 L51.1 L51.2 L51.3 L51.8 M30.3
M33.00 M33.01 M33.02 M33.09 M33.10 M33.11 M33.12
M33.19 M33.20 M33.21 M33.22 M33.29 M33.90 M33.91
M33.92 M33.99 M35.9 M36.0 N18.1 N18.2 N18.3
N18.4 N18.5 N18.6 N18.9 O35.8XX0 O35.8XX1 O35.8XX2
O35.8XX3 O35.8XX4 O35.8XX5 O35.8XX9 O36.8210 O36.8211 O36.8212
O36.8213 O36.8214 O36.8215 O36.8219 O36.8220 O36.8221 O36.8222
O36.8223 O36.8224 O36.8225 O36.8229 O36.8230 O36.8231 O36.8232
O36.8233 O36.8234 O36.8235 O36.8239 O36.8290 O36.8291 O36.8292
O36.8293 O36.8294 O36.8295 O36.8299 O36.8990 O98.711 O98.712
O98.713 O98.719 O99.820 O99.824 O99.825 P03.2 P07.00
P07.01 P07.02 P07.03 P07.10 P07.14 P07.15 P07.16
P07.17 P07.18 P07.20 P07.21 P07.22 P07.23 P07.24
P07.25 P07.26 P07.30 P07.31 P07.32 P07.33 P07.34
P07.35 P07.36 P07.37 P07.38 P07.39 P55.0 P55.1
P55.8 P55.9 P61.0 Q21.0 Q81.8 Q81.9 R29.2
R78.81 T86.00 T86.01 T86.02 T86.03 T86.09 T86.10
T86.11 T86.12 T86.13 T86.19 T86.20 T86.21 T86.22
T86.23 T86.290 T86.298 T86.30 T86.31 T86.32 T86.33
T86.39 T86.40 T86.41 T86.42 T86.43 T86.49 T86.5
T86.810 T86.811 T86.812 T86.818 T86.819 T86.830 T86.831
T86.832 T86.838 T86.839 T86.850 T86.851 T86.852 T86.858
T86.859 T86.890 T86.891 T86.892 T86.898 T86.899 T86.90
T86.91 T86.92 T86.93 T86.99 V50.8 Z21 Z22.321
Z22.322 Z22.330 Z41.8 Z48.21 Z48.22 Z48.23 Z48.24
Z48.280 Z48.288 Z48.290 Z48.298 Z94.0 Z94.1 Z94.2
Z94.3 Z94.4 Z94.5 Z94.6 Z94.7 Z94.81 Z94.82
Z94.83 Z94.84 Z94.89 Z94.9 Z95.3 Z95.4

Covered diagnosis codes for procedure codes J1559.

D80.0 D80.1 D80.2 D80.3 D80.4 D80.5 D80.6
D80.7 D80.8 D80.9 D81.0 D81.1 D81.2 D81.6
D81.7 D81.9 D82.0 D82.3 D82.8 D82.9 D83.0
D83.1 D83.2 D83.8 D83.9 G61.81

Covered diagnosis codes for procedure codes J1555, J1562, and J1575.

D80.0 D80.1 D80.2 D80.3 D80.4 D80.5 D80.6
D80.7 D80.8 D80.9 D81.0 D81.1 D81.2 D81.6
D81.7 D81.9 D82.0 D82.3 D82.8 D82.9 D83.0
D83.1 D83.2 D83.8 D83.9

Place of Service: Outpatient – Infusion

Experimental/Investigational (E/I) services are not covered regardless of place of service.

Links

I-14

 

  1. Hizentra®, Immune Globulin Subcutaneous (Human) [package insert].Kankakee, IL: CSL Behring LLC; 3/201
  2. Gamunex®-C [package insert]. Research Triangle Park, NC: Grifols Therapeutics Inc; 03/2017.
  3. Octagam [package insert]. Hoboken, NJ: Octapharma USA INC; 5/2018
  4. GAMMAGUARD LIQUID [package insert]. Westlake Village, CA: Baxter International Inc; 06/2016.
  5. Privigen® [package insert]. Kankakee, IL: CSL Behring LLC; 09/2017.
  6. Gammaplex® 5% [package insert]. Raleigh, NC: BPL Inc; 12/2016.
  7. Crabol Y, Terrier B, Rozenberg F, et al. Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus B19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis. 2013;56(7):968-977.
  8. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev.2013;7:CD000361. Jordan JA, PhD. Treatment and prevention of parvovirus B19 infection. UpToDate. Literature review current through: March 2014.
  9. Schrier SL, MD. Treatment of autoimmune hemolytic anemia: Warm agglutinins. UpToDate. Literature review current through: March 2014.
  10. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs.2013;73(12):1307-19.
  11. Souayah N, Hasan A, Khan H, et al. The safety profile of home infusion of intravenous immunoglobulin in patients with neuroimmunologic disorders. J Clin Neuromuscul Dis. 2011;12.
  12. Ayer G, Souayah N. Efficacy and safety of home infusion of intravenous immunoglobulin in multifocal motor neuropathy: A longitudinal study. J Amer Academy Neurol. 2014;10(82). Sup P7.111
  13. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, Rezaei N. Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta-analysis. J Clin Immunol. 2012;32(6):1180-92
  14. American Academy of Allergy Asthma & Immunology (AAAAI). 8 guiding principles for effective use of IVIG for patients with primary immunodeficiency.
  15. AxelaCare Health Solutions, LLC in collaboration with Bio Products Laboratory (BPL) are currently recruiting patients for a trial to demonstrate monitoring of 5% Treatment Naïve Intravenous Immunoglobulin (IVIg) Primary Immunodeficiency Disease (PIDD) Patients Using the CareExchange® System: A Pilot Study Using 5% Gammaplex® IVIg in the Home Setting.
  16. Hasan A. Reducing adverse reactions in home IVIG administration; Large walgreen study shows clinical protocols affect outcomes. Neuropathy Association. 2014.
  17. HyQvia Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase [FDA package insert]. 9/2016.
  18. Huang YH, Chen HC, Huang KW, et al. Intravenous immunoglobulin for postpolio syndrome: a systematic review and meta-analysis. BMC Neurol. 2015; 15:39 
  19. Olyaeemanesh A, Rahmani M, et al. Safety and effectiveness assessment of intravenous immunoglobulin in the treatment of relapsing-remitting multiple sclerosis: A meta-analysis. Med J Islamic Repub of Iran.2016;1-11.
  20. Brandt-Wouters E, Gerlach O HH, Hupperts RMM. The effect of postpartum intravenous immunoglobulins on the relapse rate among patients with multiple sclerosis. Int J Gyn Obs.2016;194-196.
  21. Williams KA, Swedo SE, Farmer CA, et al. Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry.2016;55(10):860–867.
  22. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012;27;78(13):1009-15.
  23. Elovaara I, Apostolski S, van Doorn P, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neuro. 2008;893-908.
  24. Cuvitru Immune Globulin Subcutaneous (Human), 20% Solution. [FDA package insert]. 06/2018.
  25. American Academy of Allergy Asthma and Immunology. Guidelines for the site of care for administration of IGIV therapy. December 2011.
  26. MCG™ Care Guidelines, 22nd edition, 2018, Home Infusion Therapy, CMT: CMT-0009(SR).
  27. Katzberg H, Rasutis V, Bril V Home iVIG for CIDP: A Focus on Patient Centered Care Can J Neurol Sci.2013;40:384-388.
  28. Polinski JM, Kowal MK, Gagnon M, et al. Home infusion: safe clinically effective, patient preferred, and cost saving. Healthcare. 2016. 
  29. Van Schaid I, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2018; 17:35-46.
  30. MICROMEDEX® SOLUTIONS Compendia. 2018. Immune Globulin (Hizentra).
  31. Clinical Pharmacology Compendia. 2018 Tampa FL: Gold Standard, Inc. Hizentra.
  32. Gammaplex® 10% [package insert]. Durham, NC: BPL Inc; 2017,
  33. Carimun NF [package insert]. Kankakee, IL: CSL Behring LLC. 11/2016,
  34. Flebogamma [package insert]. Barcelona, Spain: Grifols S.A. 07/2017,
  35. Bivigam [package insert]. Boca Raton, FL: Biotest Pharmaceuticals Corp.01/2017,