State and School Employees' Health Insurance Plan - Immunoglobulin Therapy

POLICY NUMBER

S.8.01.05

Alyglo (intravenous IgG)

Asceniv (intravenous IgG)

Bivigam (intravenous IgG)

Cutaquig (subcutaneous IgG)

Cuvitru (subcutaneous IgG)

Flebogamma DIF (intravenous IgG)

GamaSTAN (intramuscular IgG)

Gammagard Liquid (intravenous and subcutaneous IgG)

Gammagard S/D (intravenous IgA)

Gammaked (subcutaneous IgG)

Gammaplex (intravenous IgG)

Gamunex-C (intravenous and subcutaneous IgG)

Hizentra (subcutaneous IgG)

Hyqvia (subcutaneous IgG)

Octagam (intravenous IgG)

Panzyga (intravenous IgG)

Privigen (intravenous IgG)

Xembify (subcutaneous IgG)

DESCRIPTION

Immunoglobulins are derived from human donor plasma and used in the treatment of an array of disorders, including primary and secondary immunodeficiency states and a variety of autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. Two formulations of human IgG are available: intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin. Intramuscular immunoglobulin depot injections have been largely abandoned.

Intravenous immunoglobulin is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. This product has been used to correct immunodeficiencies 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 indications have been investigated; some of the most common are inflammatory myopathies, neuropathies (eg, Guillain-Barre syndrome), myasthenia gravis, multiple sclerosis, and solid organ transplantation.

This policy only addresses nonspecific pooled preparations of IVIG; it does not address other immunoglobulin preparations specifically used for passive immunization to prevent or attenuate infection with specific viral diseases (e.g., respiratory syncytial virus, cytomegalovirus, hepatitis B).

Related medical policies - 

• State and School Employees' Health Insurance Plan - Immune Thrombocytopenia

POLICY

The use of samples by an individual will not be considered current or stable therapy for purposes of Medical Policy review. 

The following medications are not covered on the State Health Plan Medical Drug Formulary:

• Alyglo

• Asceniv

• Bivigam

• Cuvitru

• Flebogamma DIF

• Gammagard S/D

• Gammaplex

• GamaSTAN

• Hyqvia

• Panzyga

Formulary Intravenous Immunoglobulin (IVIG) therapy may be considered medically necessary when ALL of the following criteria are met:

1. The participant has one of the following:

   1. Acute humoral rejection;

   2. Autoimmune and inflammatory conditions:

      1. Dermatomyositis or polymyositis refractory to treatment with corticosteroids, in combination with other immunosuppressive agents;

      2. Neuromyelitis optica (attack prevention) as an alternative for children, with contraindication or lack of response to at least TWO first-line treatments (i.e., azathioprine, mycophenolate mofetil, corticosteroids);

      3. Kawasaki syndrome¹;

      4. Wegener’s granulomatosis;

   3. Autoimmune mucocutaneous blistering diseases that meet BOTH of the following:

      1. The participant has a documented diagnosis of ONE of the following:

         1. Pemphigus;

         2. Pemphigoid;

         3. Pemphigus vulgaris;

         4. Pemphigus foliaceus;

      2. The participant has failure of conventional agents (e.g., corticosteroids, azathioprine, cyclophosphamide);

   4. Hematological conditions:

      1. Catastrophic anti-phospholipid syndrome;

      2. Chronic lymphocytic leukemia with IgG levels less than 400 and persistent bacterial infections;

      3. Hemolytic disease of the fetus and newborn (aka erythroblastosis fetalis);

      4. Idiopathic thrombocytopenic purpura¹ (also known as primary immune thrombocytopenia):

         1. In conjunction with corticosteroids for the treatment of acute, severe ITP defined by ONE of the following:

            1. acute ITP with major bleeding (e.g., life-threatening bleeding and/or clinically important mucocutaneous bleeding);

            2. acute ITP with severe thrombocytopenia and at high risk for bleeding complications;

            3. acute ITP with severe thrombocytopenia and a slow or inadequate response to corticosteroids;

            4. 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);

         2. In conjunction with corticosteroids for the treatment of chronic ITP in participants with ALL of the following:

            1. at least 6 months of disease duration;

            2. persistent thrombocytopenia (i.e., platelet <20,000/µL or <30,000/µL and severe bleeding);

            3. inadequate response to corticosteroids (i.e., failure to achieve and maintain a platelet count ≥ 30,000/µL for 3-6 months following completion of treatment);

      5. Neonatal alloimmune thrombocytopenia;

      6. Post-allogenic bone marrow transplant setting;

      7. Warm antibody hemolytic anemia, refractory to prednisone and splenectomy;

   5. Infections:

      1. HIV [human immunodeficiency virus] in children with IgG levels less than 400 mg/dL to prevent opportunistic infections;

      2. Severe anemia associated with human parvovirus B19;

      3. Toxic shock syndrome;

   6. Neuroimmunological conditions:

      1. Severe refractory myasthenia gravis in participants with chronic debilitating disease and ALL of the following:

         1. Documented inadequate response to treatment with cholinesterase inhibitors;

         2. Documented inadequate response to glucocorticoid maintenance treatment;

         3. Documented inadequate response to glucocorticoid sparing therapies (e.g., azathioprine, mycophenate, cyclosporine, tacrolimus);

      2. Myasthenic exacerbation (i.e., an acute episode of respiratory muscle weakness) in participants with contraindications to plasma exchange;

      3. Guillain-Barre syndrome in adults as an equivalent alternative to plasma exchange within four weeks of symptom onset;

      4. Chronic inflammatory demyelinating polyneuropathy (CIDP)¹ in participants with progressive symptoms for at least two months;

         1. Participants with chronic inflammatory demyelinating neuropathy (CIDP) should meet the diagnostic criteria established by the American Academy of Neurology. There is currently no criterion standard set of clinical or electrophysiologic criteria for the diagnosis of CIDP and its variants;

         2. IVIG treatment in CIDP should be limited to participants with pure motor CIDP OR participants with CIDP who do not respond to initial therapy with 6 weeks of oral prednisolone starting at 60mg daily and are experiencing serious clinical worsening. In participants treated for chronic diseases, such as CIDP, multifocal motor neuropathy, and dermatomyositis, the effect of IVIG is transitory and therefore periodic infusions of IVIg are needed to maintain treatment effect. The frequency of transfusions is titrated to the treatment response; typically, biweekly or monthly infusions are needed;

      5. Multifocal motor neuropathy¹;

      6. Eaton-Lambert myasthenic syndrome in participants who have failed to respond to anticholinesterase medications and/or corticosteroids;

   7. Prevention of infection in preterm (<37 weeks’ gestational age) and/or low-birth weight (<2500g) neonates;

   8. Primary Humoral Immune Deficiency Syndromes¹, including Combined Immunodeficiencies that meet BOTH of the following:

      1. The participant has a documented diagnosis of ONE of the following:

         1. Ataxia telangiectasia;

         2. Common variable immunodeficiency;

         3. Congenital agammaglobulinemia;

         4. Hypogammaglobulinemia;

         5. Severe combined immunodeficiency (SCID);

         6. X-linked agammaglobulinemia (Bruton agammaglobulinemia);

         7. X-linked hyper-IgM syndrome;

         8. Wiskott-Aldrich syndrome;

      2. The participant has ALL of the following:

         1. Laboratory evidence of immunoglobulin deficiency documented as ONE of the following:

            1. Agammaglobulinemia (total IgG <200 mg/dL);

            2. Persistent hypogammaglobulinemia (total IgG less than 400mg/dL, or at least two standard deviations below normal, on at least two occasions);

            3. Absence of B lymphocytes;

         2. Documented inability to mount an adequate immunologic response to inciting antigens as evidenced by ONE of the following:

            1. Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen as defined by antibody concentrations of less than 0.1IU/mL;

            2. Lack of appropriate rise in antibody titer following provocation with a protein antigen as defined by ONE the following:

               • If age <6: less than 50% of serotypes of protective (i.e., ≥1.3 mcg/mL per serotype);

               • if age ≥ 6: less than 70% of serotypes are protective (i.e., ≥ 1.3 mcg/mL per serotype);

         3. Persistent and severe infections, despite treatment with prophylactic antibiotics; OR

   9. Transplantation

      1. Hematopoietic cell transplantation;

      2. Prior to solid organ transplant, treatment for individuals at high risk of antibody-medicated rejection, including highly sensitized individuals and those receiving an ABO-incompatible organ;

   10. Individuals with stiff-person syndrome not controlled by other therapies.

2. The prescriber is a specialist or has consulted with a specialist in an area of the member's diagnosis (i.e., hematologist, immunologist neurologist, etc.);

3. The member does not have any FDA-labeled contraindication(s) to therapy with the requested agent; AND

4. The prescribed dosage is within the program quantity limits based on FDA approved labeled dosage. 

Length of Approval: Up to 12 months¹FDA-labeled indications

 Intravenous immunoglobulin (IVIG) therapy is considered investigational for all other conditions, including, but not limited to:

• Acquired factor VIII inhibitors;

• Acute lymphoblastic leukemia;

• Acute myocarditis;

• Adrenoleukodystrophy;

• Alzheimer’s disease;

• Aplastic anemia;

• Asthma;

• Autism spectrum disorder;

• Behcet’s syndrome;

• Birdshot retinopathy;

• Chronic fatigue syndrome;

• Chronic sinusitis;

• Complex regional pain syndrome;

• Crohn's disease;

• Cystic fibrosis;

• Diabetes mellitus;

• Diamond-Blackfan anemia;

• Epidermolysis bullosa acquisita;

• Epilepsy;

• Fisher syndrome;

• Hemolytic uremic syndrome;

• Hemophagocytic lymphohistiocytosis;

• IgG sub-class deficiency;

• Immune-mediated neutropenia;

• Immune optic neuritis;

• Inclusion-body myositis;

• Multiple myeloma;

• Necrotizing fasciitis;

• Neonatal sepsis (prophylaxis or treatment);

• Nonimmune thrombocytopenia;

• Noninfectious uveitis;

• Opsoclonus-myoclonus;

• Organ transplant rejection;

• Paraneoplastic syndromes;

• Paraproteinemic neuropathy;

• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS);

• Polyradiculoneuropathy (other than CIDP);

• Postpolio syndrome;

• Prophylaxis or treatment of acute antibody mediated rejection in patients that have received solid organ transplant;

• Recurrent otitis media;

• Recurrent spontaneous abortion (see below for related laboratory tests);

• Red cell aplasia;

• Refractory recurrent pericarditis;

• Refractory rheumatoid arthritis;

• Relapsing remitting multiple sclerosis (RRMS);

• Sepsis;

• Stevens-Johnson syndrome and toxic epidermal necrolysis;

• Systemic lupus erythematosus;

• Thrombotic thrombocytopenic purpura;

• Vasculities besides Kawasaki disease, including polyarteritis nodosa, Goodpasture syndrome, and vasculitis associated with other connective tissue diseases.

Formulary Subcutaneous Immune Globulin (SCIG) therapy may be considered medically necessary when ALL of the following criteria are met:

1. The participant has one of the following:

   1. Primary immunodeficiencies;

   2. Congenital agammaglobulinemia;

   3. Hypogammaglobulinemia;

   4. Common variable immunodeficiency (CVID);

   5. Severe combined immunodeficiency;

   6. Wiskott-Aldrich syndrome;

   7. X-linked agammaglobulinemia (XLA); OR

   8. CIDP

2. The prescriber is a specialist or has consulted with a specialist in an area of the member's diagnosis (i.e., hematologist, immunologist neurologist, etc.);

3. The participant does not have any FDA-labeled contraindication(s) to therapy with the requested agent; AND

4. The prescribed dosage is within the program quantity limits based on FDA approved labeled dosage.

Length of Approval: Up to 12 months 

Other applications of SCIG therapy are considered investigational.

Services related to delivery and/or administration of a medication which have not been approved through the BCBSMS review process will be considered not medically necessary.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the participant's specific benefit plan language.

Black Box Warnings and Precautions

For the intravenous immunoglobulin (IVIG):

• Thrombosis may occur with immunoglobulin products. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• For participants at risk of thrombosis, administer immunoglobulin products at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in participants at risk for hyperviscosity.

• Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with the administration of human IVIG products in predisposed participant Participants predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes, age greater than 65, volume depletion, sepsis, paraproteinemia, or participants receiving known nephrotoxic drugs.

• Renal dysfunction and acute renal failure occur more commonly in participants receiving IVIG products that contain sucrose.

• For participants at risk of renal dysfunction or renal failure, administer IVIG at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration.

Additional warnings and precautions include:

• Immunoglobulin A (IgA)-deficient participants with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions.

• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output, in participants at risk of developing acute renal failure.

• Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in participants receiving IVIG therapy.

• Thrombosis may occur. Monitor participants with known risk factors for thrombosis and consider baseline assessment of blood viscosity for those at risk of hyperviscosity.

• Aseptic meningitis syndrome may occur in participants receiving IVIG therapy, especially with high doses or rapid infusion.

• Hemolytic anemia can develop subsequent to IVIG treatment. Monitor participants for signs and symptoms of hemolysis and hemolytic anemia.

• Monitor participants for pulmonary adverse reactions (transfusion-related acute lung injury).

• Participants receiving IVIG for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for developing fever, chills, nausea, and vomiting.

• IVIG is made from human plasma and may contain infectious agents (eg, viruses and, theoretically, the Creutzfeldt-Jakob disease agent).

• Passive transfer of antibodies may confound serologic testing.

The subcutaneous immunoglobulin (SCIG) product information labels note that reactions similar to other immunoglobulin products may occur. The most common adverse events with subcutaneous injections include local reactions (ie, swelling, redness, heat, pain, and itching at the injection site).

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat an participant's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the participant's condition, illness, or injury; and 

2. appropriate with regard to standards of good medical practice; and 

3. not solely for the convenience of the participant, his or her Provider; and 

4. the most appropriate supply or level of care which can safely be provided to participant. When applied to the care of an Inpatient, it further means that services for the participant's medical symptoms or conditions require that the services cannot be safely provided to the participant as an Outpatient.

For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

BCBSMS may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

Medication Failure

Medication failure is defined as disease progression at generally accepted doses (for >3 months use) as appropriate for the disease state being treated. Dosages below the recommended dose for the specific condition being treated and/or experience of common side effects of medication will not be considered medication failure or lack of response for the purpose of this review.

BCBSMS determines patient medication trial and adherence by a review of pharmacy claims data over the preceding twelve months. Additional information may be requested on a case-by-case basis to allow for proper review. If participant is new to BCBSMS and pharmacy records are needed to confirm medication trials and adherence, it is the responsibility of the participant and/or requesting provider to obtain said records and to submit them to BCBSMS upon request. Medical records from the provider that list previously prescribed medications will not be sufficient to show medication trials or adherence.

POLICY HISTORY

07/01/2023: New policy added.

07/06/2023: Code Reference section updated to add new HCPCS code J1576, effective 07/01/2023.

09/01/2023: Policy reviewed. Policy section updated to change the following: "Primary Humoral Immune Deficiency Syndromes" to "Primary Immunodeficiencies," "Patients" to "Individuals," "Myasthenic crisis" to "Myasthenic exacerbation," "anti-phospholipid syndrome" to "Catastrophic anti-phospholipid syndrome," and "not medically necessary" to "investigational." Policy Guidelines updated regarding CIDP.

11/01/2024: Policy reviewed and approved by Pharmacy & Therapeutics (P&T) Committee. Policy description revised to list the formulary agents of intravenous and subcutaneous immunoglobulin products. Added related medical policy. Policy section updated to add that the use of samples by an individual will not be considered current or stable therapy for purposes of Medical Policy review. Medically necessary criteria for Formulary IVIG extensively revised. Added medically necessary criteria for Formulary SCIG therapy. Policy statement updated to state that Alyglo, Asceniv, Bivigam, Cuvitru, Flebogamma DIF, Gammagard S/D, Gammaplex, GamaSTAN, Hyqvia, and Panzyga are not covered. Added statement that services related to delivery and/or administration of a medication which have not been approved through the BCBSMS PA review process will be considered not medically necessary. Policy Guidelines revised to move information regarding primary immunodeficiency syndromes and chronic inflammatory demyelinating polyneuropathy to the Policy section. Added information regarding BCBSMS request for medical records and medication failure. Sources updated. Code Reference section updated to remove HCPCS code J1562 (Vivaglobin) as it is no longer on the market. Added HCPCS code J1558 to the Covered Codes table. Added HCPCS codes J1555, J1556, J1557, J1560, J1572, J1575, and J1576 to the Not Covered/Non-Formulary Codes table. Effective 01/01/2025.

01/01/2025: Code Reference section updated to add new HCPCS code J1552.

01/23/2025: Policy reviewed. Policy section updated to change CIDP from investigational to medically necessary for subcutaneous immune globulin therapy. Added statement that other applications of SCIG therapy are considered investigational.

09/09/2025: Policy reviewed by Pharmacy & Therapeutics (P&T) Committee; no changes to policy statement. Sources updated.

SOURCE(S)

1. Alyglo prescribing information. GC Biopharma Corp. December 2023. Last accessed

   June 2025.

2. Asceniv prescribing information. ADMA Biologics, Inc. 

   May 2025.

   Last accessed

   June 2025.

3. Blue Cross Blue Shield Association Policy # 8.01.05

4. Bivigam prescribing information. ADMA Biologics, Inc. 

   May 2025. Last accessed June 2025.

5. Cunningham-Rundles C.

   Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults.

   In: UpToDate, Connor RF (Ed), Wolters Kluwer. Accessed on June 24, 2025. Available at:

   https://www.uptodate.com/contents/clinical-manifestations-epidemiology-and-diagnosis-of-common-variable-immunodeficiency-in-adults

6. Cutaquig prescribing information.

   Pfizer Laboratories Div Pfizer Inc. March 2025. Last accessed June 2025.

7. Cuvitru prescribing information. Takeda Pharmaceuticals America, Inc. 

   March 2025. Last accessed June 2025.

8. Flebogamma DIF prescribing information. Grifols USA,

   LLC.

   November 2024. Last accessed June 2025.

9. GamaSTAN prescribing information. Grifols USA, LLC. September 2024. Last accessed 

   June 2025.

10. Gammagard Liquid prescribing information. Takeda Pharmaceuticals America, Inc.

    November 2024. Last accessed June 2025.

11. Gammagard S/D prescribing information. Takeda Pharmaceuticals America, Inc.

    March 2025. Last accessed June 2025.

12. Gammaked prescribing information. Kedrion Biopharma, Inc. January 2020. Last accessed 

    June 2025.

13. Gammaplex prescribing information. Bio Products Laboratory Limited. October 2024. Last accessed 

    June 2025.

14. Gamunex-C prescribing information. Grifols USA, LLC. April 2022. Last accessed

    June 2025.

15. Hizentra prescribing information. CSL Behring AG. April 2023. Last accessed 

    June 2025

    .

16. Hyqvia prescribing information. Takeda Pharmaceuticals America, Inc.

    November

    2024. Last accessed 

    June 2025.

17. Arnold DM, Cuker. Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis. UpToDate.

    In: UpToDate, Connor RF (Ed), Wolters Kluwer. Accessed on June 24, 2025. Available at:

    https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-clinical-manifestations-and-diagnosis

18. N

    eunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 2019; 3:3829-3866. doi:  https://doi.org/10.1182/bloodadvances.2019000966

19. Octagam prescribing information. Pfizer Laboratories Div Pfizer Inc. January 2024. Last accessed 

    June 2025.

20. Panzyga prescribing information. Pfizer Laboratories Div Pfizer Inc.

    April 2025. Last accessed June 2025.

21. Privigen prescribing information. CSL Behring AG. 

    May 2025. Last accessed June 2025.

22. Xembify prescribing information. Grifols USA, LLC. 

    March 2025. Last accessed June 2025.

23. Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology 2021; 96:114-122.

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes        

Not Covered/Non-Formulary Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.