Immune Globulin Therapy*

Medical Policy: 05.01.17 
Original Effective Date: November 2007 
Reviewed: November 2011 
Revised: November 2011 

Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

Description: 

Human immune globulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens.  Three formulations of human IgG are available for delivery by intravenous infusion (IVIg), by subcutaneous infusion (SCIg), or by intramuscular (IMIg) depot injections.  IMIg has been largely abandoned in the U.S. because volume constraints and pain preclude delivery of sufficient product weekly into each buttock to yield therapeutic serum levels of IgG, leaving recipients susceptible to infections.  Thus, this policy focuses on IVIg and SCIg, for conditions that typically would be treated in an outpatient setting.

Intravenous immune globulin (IVIg) is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. IVIg has been used to correct immune deficiencies in patients with either inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis. Several IVIg products are available for clinical use in the United States. A variety of off-label uses have been investigated; some of the most common are inflammatory myopathies, neuropathies, (e.g., Guillain-Barré syndrome), myasthenia gravis, multiple sclerosis and solid organ transplantation.

Subcutaneous infusion immune globulin (SCIg) is used for treating patients with primary immunodeficiencies (PID). A genetic basis for more than 80 different types of PID has been discovered, the most common being primary antibody deficiency (PAD) that is associated with low levels or total lack of normal circulating immunoglobulins. The first FDA-approved SCIg product, Vivaglobin, is a pasteurized, polyvalent human normal immune globulin product that is manufactured from large pools of human plasma by cold alcohol fractionation with no chemical or enzymatic alterations. Vivaglobin administration produces relatively stable steady-state serum levels of IgG that are representative of those seen in a normal human population. Applications for this product for conditions other than primary immunodeficiencies are considered off-label in the United States and are not addressed in this policy. In recent years, other SCIg products have also received FDA-marketing approval.

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Prior Approval: 

Prior approval is recommended. Submit a prior approval/treatment request now. ( 100KB)

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Policy: 

Intravenous Immune globulin (IVIg) therapy may be considered medically necessary for the following indications:

Primary immune deficiency syndromes, including combined immunodeficiencies,

• X-linked agammaglobulinemia (Bruton’s)
• X-linked hyper-IgM syndrome
• Severe combined immunodeficiency (SCID)
• Wiskott-Aldrich syndrome
• Ataxia telangiectasia

Note: Patients with primary immunodeficiency syndromes should meet all of the following criteria for treatment with immune globulin:

• Laboratory evidence of immunoglobulin deficiency
• Documented inability to mount an adequate immunologic response to inciting antigens
• Persistent and severe infections despite treatment with prophylactic antibiotics

Acute humoral rejection

Autoimmune mucocutaneous blistering diseases, in patients with severe, progressive disease despite treatment with conventional agents (such as corticosteroids, azathioprine, cyclophosphamide)

• Pemphigus
• Pemphigoid
• Pemphigus vulgaris
• Pemphigus foliaceus
• Steven’s-Johnson syndrome
• Toxic epidermal necrolysis (TEN)

Autoimmune and inflammatory disorders

• Dermatomyositis refractory to treatment with steroids; in combination with other immunosuppressive agents
• Kawasaki syndrome

Neuroimmunological

• Myasthenia gravis in patients with chronic debilitating disease in spite of treatment with cholinesterase inhibitors, or complications from or failure of steroids and/or azathioprine
• Myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) in patients with contraindications to plasma exchange
• Guillain-Barré syndrome
• Chronic inflammatory demyelinating polyneuropathy; in patients with progressive symptoms for at least two months
• Multifocal motor neuropathy
• Eaton-Lambert myasthenic syndrome, in patients who have failed to respond to anticholinesterase medications and/or corticosteroids

Hematologic

• Treatment of chronic idiopathic, immune thrombocytopenic purpura (ITP); in patients with at least six months duration of disease, and persistent thrombocytopenia despite treatment with corticosteroids and splenectomy
• Neonatal alloimmune thrombocytopenia
• Allogeneic post-bone marrow transplant setting
• B-cell chronic lymphocytic leukemia (CLL); in patients with hypogammaglobulinemia and persistent bacterial infections
• Warm autoantibody autoimmune hemolytic anemia; refractory to steroids and immunosuppressive agents
• Anti-phospholipid syndrome

Infectious diseases

• HIV-infected patients
• Toxic shock syndrome
• Kawasaki disease
• Patients with primary defective antibody synthesis

Transplantation

• Prior to sold organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ
• Following solid organ transplant, treatment of antibody-mediated rejection

IVIg is considered not medically necessary as a treatment of relapsing/remitting multiple sclerosis.

Other applications of IVIg therapy are considered investigational, including, but not limited to, the following conditions:

• Chronic progressive multiple sclerosis
• Refractory rheumatoid arthritis and other connective tissue diseases including systemic lupus erythematosus
• Recurrent spontaneous abortion
• Inclusion-body myositis
• Polymyositis, including refractory polymyositis
• Other vasculitides besides Kawasaki disease, including vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA; e.g., Wegener’s granulomatosis, polyarteritis nodosa), Goodpasture’s syndrome, and vasculitis associated with other connective tissue diseases
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome
• Paraneoplastic syndromes, other than Eaton-Lambert myasthenic syndrome
• Demyelinating polyneuropathy associated with IgM paraproteinemia
• Epilepsy
• Chronic sinusitis
• Asthma
• Chronic fatigue syndrome
• Aplastic anemia
• Diamond-Blackfan anemia
• Red cell aplasia
• Acquired factor VIII inhibitors
• Hemophagocytic syndrome
• Acute lymphoblastic leukemia
• Multiple myeloma
• Immune-mediated neutropenia
• Nonimmune thrombocytopenia
• Cystic fibrosis
• Recurrent otitis media
• Diabetes mellitus
• Behçet’s syndrome
• Adrenoleukodystrophy
• Stiff person syndrome
• Organ transplant rejection other than as described above
• Uveitis
• Demyelinating optic neuritis
• Recent-onset dilated cardiomyopathy
• Fisher syndrome
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
• Autism
• Complex regional pain syndrome
• Alzheimer disease
• IGG sub-class deficiency

Subcutaneous Immune globulin (SCIg) Therapy

SCIg may be considered medically necessary for the treatment of primary immunodeficiencies, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency (CVID), severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked agammaglobulinemia (XLA).

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Procedure Codes and Billing Guidelines: 

• To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes
• J1557 Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g., liquid), 500 mg
• J1559 Injection, immune globulin (Hizentra), 100 mg
• J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), 500 mg 
• J1568 Injection, immune globulin, (Octogam), intravenous, non-lyophilized, (e.g. liquid), 500 mg
• J1569 Injection, immune globulin, (Gammagard liquid), intravenous, non-lyophilized, (e.g. liquid), 500 mg
• J1572 Injection, immune globulin, (Flebogamma), intravenous, non-lyophilized, (e.g. liquid), 500 mg
• J1561 Injection, immune globulin, (Gamunex), intravenous, non-lyophilized, (e.g. liquid), 500 mg
• J1562 Injection, immune globulin (Vivaglobin), 100 mg
• J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
• 90283 Immune globulin (IgIV), human, for intravenous use
• 90284 Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
• 96369 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to 1 hour, including pump set-up and establishment of subcutaneous infusion site(s)
• 96370 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
• 96371 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); additional pump set-up with establishment of new subcutaneous infusion site(s) (List separately in addition to code for primary procedure)       

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Selected References: 

• Orange JS, Hossny EM, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53.
• Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21^st century. Ann Allergy Asthma Immunol 2008; 101(2):114-21.
• Hoffmann F, Grimbacher B, Thiel J et al. Home-based subcutaneous immunoglobulin G replacement under real-life condition in children and adults with antibody deficiency. Eur J Med Res 2010; 15(6):238-45.
• Relkin NR, Szabo P, Adamiak B et al. 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 2009; 30(11):1728-36.
• Goebel A, Baranowski A, Maurer K et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome. Ann Intern Med 2010; 152(3):152-8.
• Gurcan HM, Jeph S, Ahmed AR. Intravenous immunoglobulin therapy in autoimmune mucocutaneous blistering diseases: a review of the evidence for its efficacy and safety. Am J Clin Dermatol 2010; 11(5):315-26.
• Feasby T, Banwell B, Benstead T et al. Guidelines on the ise on intravenous immune globulin for neurologic conditions. Transfus Med Rev 2007; 21(2 Suppl 1): S57-107
• Shehata N, Palda VA, Meyer RM et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev 2010; 24(Suppl 1):S7-27.
• Bucuvalas JC, Anand R. treatment with immunoglobulin improves outcome for pediatric liver transplant recipients. Liver Transpl 2009; 15(1):1594-9.
• Anderson D, Ali K, Blanchette V et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfuse Med Rev 2007; 21(2 Suppl 1): S9-56.
• Hughes RA, Swan AV, Raphael JC et al. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain 2007; 130(Pt 9):2245-57.
• Cordonnier C, Chevret S, Legrand M et al. Should immunoglobulin therapy be used in allogeneic stem cell transplantation? A randomized, double-blind, dose effect, placebo-controlled multicenter trial. Ann Intern Med 2003; 139(1):8-18.
• Shehata N, Palda V, Bowen T et al. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev 2010; 24(Suppl 1): S28-50.

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Policy History: 

Date                                        Reason                               Action

September 2010                     Annual review                     Policy renewed

November 2011                      Annual review                     Policy revised

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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.