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Pharmacy Medical Policy Immunoglobulins Policy

Table of Contents
• Policy: Commercial • Policy History • Endnotes
• Policy: Medicare • Information Pertaining to All Policies
• Forms • Coding Information
• References

Policy Number: 310 BCBSA Reference Number: 8.01.05

Related Policies • RSV Immunoprophylaxis (RSV-IVIg), #422 • Medicare Advantage Part B Medical Utilization Management (Medicare IVIG), #125

Policy ☒ Prior Authorization ☐ Step Therapy ☐ Quality Care Dosing ☐ Administrative Reviewing Department Pharmacy Operations: Tel: 1-800-366-7778 Fax: 1-800-583-6289 To request for coverage: Providers may call, fax, or mail the attached form (Formulary Exception/Prior Authorization form) to the address below.
Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043
Tel: 1-800-366-7778 Fax: 1-800-583-6289

Individual Consideration for the atypical patient: Policy for requests that do not meet clinical criteria of this policy, see section labeled Individual Consideration
Policy Last Updated 1/15/2026 Pharmacy (Rx) or Medical (MED) benefit coverage ☒ Rx ☒ MED (MPBT-2) Policy applies to Commercial members with BCBSMA formulary:
• Managed Care (HMO/POS) • PPO/EPO
• Indemnity
• MEDEX with Rx plans • Managed Blue for Seniors Policy does NOT apply to: • Medicare Advantage
Provider Documentation Requirements: Documentation from the provider to support a reason preventing trial of formulary alternative(s) must include the name and strength of alternatives tried and failed (if alternatives were tried, including dates if available) and specifics regarding the treatment failure. Documentation to support clinical basis preventing switch to formulary alternative should also provide specifics around clinical reason.We may also use prescription claims records to establish prior use of formulary alternatives or to show if step therapy criteria has been met. We will require the provider to share additional information when prescription claims data is either

2 not available or the medication fill history fails to establish use of preferred formulary medications or that step therapy criteria has been met. Other documentation requirements, if any, are outlined in prior authorization criteria.

Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Intravenous Immunoglobulin Therapy Intravenous immunoglobulin (IVIG) therapy may be considered MEDICALLY NECESSARY for the following indications: Documented Immunodeficiency States • Individuals with primary immunodeficiencies: congenital agammaglobulinemia, severe combined immunodeficiency, X-linked agammaglobulinemia, and X-linked hyperimmunoglobulinemia M syndrome. OR • Individuals with primary immunodeficiencies: including hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and ataxia telangiectasia should meet all the following criteria for treatment with immunoglobulin: o Laboratory evidence of immunoglobulin deficiency, AND o Documented inability to mount an adequate immunologic response to inciting antigens (see Policy Guidelines section) AND o Persistent and severe infections, despite treatment with prophylactic antibiotics. OR • Ordered by or in consultation with a Board-certified Clinical Immunologist or Infectious Disease Specialist. OR • Individuals with chronic lymphocytic leukemia who have immunoglobulin G (IgG) levels less than 400 mg/dL and persistent bacterial infections. Infections • Individuals (children) with HIV who have IgG levels less than 400 mg/dL to prevent opportunistic infections. • Individuals with severe anemia associated with human parvovirus B19. • Individuals with toxic shock syndrome. Autoimmune and Inflammatory Conditions • Individuals with acute, severe idiopathic thrombocytopenic purpura (see Policy Guidelines section) or chronic idiopathic thrombocytopenic purpura with a disease duration of at least 6 months, presence of symptoms, and with persistent thrombocytopenia (platelet <20,000 per microliter [adult] or 30,000 per microliter [child])-despite treatment with corticosteroids and splenectomy. • Adults with Guillain-Barré syndrome as an equivalent alternative to plasma exchange. • Individuals with Kawasaki syndrome. • Individuals with Wegener granulomatosis. • Individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) with progressive symptoms for at least 2 months. • Individuals with multifocal motor neuropathy. • Individuals with Eaton-Lambert myasthenic syndrome who have failed to respond to anticholinesterase medications and/or corticosteroids. • Individuals with neuromyelitis optica as an alternative for those with contraindications or lack of response to first-line treatment, particularly in children.

3 • Individuals with severe refractory myasthenia gravis with chronic debilitating disease despite treatment with cholinesterase inhibitors, or complications from or failure of corticosteroids and/or azathioprine. • Individuals with myasthenic exacerbation (ie, an acute episode of respiratory muscle weakness) in whom plasma exchange is contraindicated. • Individuals with severe, progressive autoimmune mucocutaneous blistering diseases that include pemphigus, pemphigoid, pemphigus vulgaris, and pemphigus foliaceus who have failed treatment with conventional agents such as corticosteroids, azathioprine, and cyclophosphamide. • Individuals with dermatomyositis or polymyositis that is refractory to treatment with corticosteroids; in combination with other immunosuppressive agents. • Individuals with warm antibody hemolytic anemia who are refractory to prednisone and splenectomy. • Individuals with catastrophic antiphospholipid syndrome. Alloimmune Processes • Individuals with neonatal alloimmune thrombocytopenia. • Individuals with hemolytic disease of the fetus and newborn (erythroblastosis fetalis). Miscellaneous and BC Continuation • Individuals with stiff-person syndrome not controlled by other therapies. • Individuals with relapsing-remitting multiple sclerosis. • Bone marrow transplant patients (for prevention of infection or GVH prevention) • Multiple myeloma and immunoproliferative neoplasms • Immune neutropenia • Multiple myeloma without mention of remission • Multiple myeloma in remission • Other immunoproliferative neoplasms without mention of remission • Other immunoproliferative neoplasms in remission • Agranulocytosis • Prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ • Solid organ transplant recipients at risk for cytomegalovirus infections and pneumonia. • Hereditary and idiopathic peripheral neuropathy
• Peroneal muscular atrophy
• Hereditary sensory neuropathy • Idiopathic progressive polyneuropathy • Demyelinating polyneuropathy associated with IgM paraproteinemia • Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)

4 Subcutaneous Immunoglobulin Therapy Preferred Agents Non-preferred Agents Hizentra (human immunoglobulin g liquid) Cuvitru (immune globulin) Cutaquig (immunoglobulin g solution) HyQvia (immune globulin infusion) Xembify (human immune globulin klhw) Requires trial and failure of TWO (2) preferred agents Subcutaneous immunoglobulin therapy (SCIG) may be considered MEDICALLY NECESSARY for the following indications: Documented Immunodeficiency States • Individuals with primary immunodeficiencies: congenital agammaglobulinemia, severe combined immunodeficiency, X-linked agammaglobulinemia, and X-linked hyperimmunoglobulinemia M syndrome.
OR • Individuals with primary immunodeficiencies: including hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and ataxia telangiectasia should meet all the following criteria for treatment with immunoglobulin: o Laboratory evidence of immunoglobulin deficiency, AND o Documented inability to mount an adequate immunologic response to inciting antigens (see Policy Guidelines section) AND o Persistent and severe infections, despite treatment with prophylactic antibiotics. OR • Ordered by or in consultation with a Board-certified Clinical Immunologist or Infectious Disease Specialist.

Autoimmune and Inflammatory Conditions • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

If the request is for Cuvitru or HyQvia, the patient has tried and failed at least TWO (2) preferred agents: Hizentra, Cutaquig, or Xembify. Other applications of SCIG therapy are considered INVESTIGATIONAL, including but not limited to CIDP.

Intravenous immunoglobulin (IVIG) therapy is considered INVESTIGATIONAL for the following indications:

Immunodeficiency States • Individuals who have received solid organ transplant for prophylaxis or treatment of acute antibody- mediated rejection. • Individuals undergoing or who have undergone hematopoietic cell transplantation who have IgG levels less than 400 mg/dL. Infections • Individuals with neonatal sepsis (prophylaxis or treatment).

5 • Individuals (adults) with sepsis. Autoimmune and Inflammatory Conditions • Individuals with toxic epidermal necrolysis and Stevens-Johnson syndrome. • Individuals with inclusion body myositis. • Individuals with systemic lupus erythematosus. • Individuals with immune optic neuritis. • Individuals with Crohn disease. • Individuals with hemophagocytic lymphohistiocytosis. Alloimmune Processes • Individuals with recurrent spontaneous abortion. Miscellaneous • Individuals with autism spectrum disorder. • Individuals with complex regional pain syndrome. • Individuals with Alzheimer disease. • Individuals with paraproteinemic neuropathy. • Individuals with chronic fatigue syndrome. • Individuals with acute myocarditis. • Individuals with refractory recurrent pericarditis. • Individuals with noninfectious uveitis. • Individuals with postpolio syndrome. • Individuals with necrotizing fasciitis. • Individuals with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, paraneoplastic syndromes, epilepsy, chronic sinusitis, asthma, aplastic anemia, Diamond-Blackfan anemia, red cell aplasia, acquired factor VIII inhibitors, acute lymphoblastic leukemia, nonimmune thrombocytopenia, cystic fibrosis, recurrent otitis media, diabetes mellitus, Behçet syndrome, adrenoleukodystrophy, Fisher syndrome, IgG subclass deficiency, opsoclonus-myoclonus, birdshot retinopathy, epidermolysis bullosa acquisita, polyradiculoneuropathy (other than CIDP), refractory rheumatoid arthritis, other vasculitides besides Kawasaki disease, including polyarteritis nodosa, Goodpasture syndrome, and vasculitis associated with other connective tissue diseases. Other Information Blue Cross Blue Shield of Massachusetts (BCBSMA*) members (other than Medex®; Blue MedicareRx, Medicare Advantage plans that include prescription drug coverage) will be required to fill their prescriptions for the above medications at one of the providers in our retail specialty pharmacy network, see link below:

Link to Specialty Pharmacy List

Description Immunoglobulins are derived from human donor plasma and used to treat an array of disorders, including primary and secondary immune deficiency states and various autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G antibodies against a wide variety of bacterial and viral antigens. This evidence review addresses the use of human immunoglobulin therapy for preventing and/or treating disorders in inpatient and outpatient settings. Both intravenous immunoglobulin (IVIG) infusion and subcutaneous

6 immunoglobulin (SCIG) infusion are addressed. However, the review only considers nonspecific pooled preparations of IVIG; it does not consider other preparations used for passive immunization to specific antigens. Summary of Evidence Immunodeficiency States For individuals who have primary humoral immunodeficiency who receive intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG) therapy, the evidence includes multiple randomized controlled trials (RCTs) and noncomparative studies. Relevant outcomes are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment- related mortality and morbidity. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are undergoing hematopoietic cell transplantation who receive IVIG therapy (prophylaxis), the evidence includes a systematic review and meta-analysis. Relevant outcomes are disease-specific survival (DSS), symptoms, change in disease status, morbid events, quality of life (QOL), hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing hematopoietic cell transplantation was not associated with survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are at risk of acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence consists of a systematic review, National Institutes of Health (NIH)- sponsored RCT, and nonrandomized observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. The systematic review involving variable quality studies with high to very high risk of bias concluded that there is insufficient data to support or advise against the use of IVIG prophylaxis in solid organ transplant. More adequately powered RCTs are needed. Additionally, studies have shown conflicting results that prophylaxis with IVIG in patients with high panel reactive antibody (PRA) levels prior to solid organ transplant leads to a significant reduction in PRA levels. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high PRA levels was not consistently associated with a survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence includes retrospective case series and a systematic review. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG treatment for antibody-mediated rejection has shown potential benefits in retrospective or small prospective studies; however, larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have chronic lymphocytic leukemia with recurrent bacterial infections associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes multiple RCTs and a meta- analysis. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in chronic lymphocytic leukemia patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

7 Infections For individuals who are HIV-infected children with recurrent bacterial infection associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes a single RCT. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV- infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are preterm and low birth weight infants and at risk for sepsis who receive IVIG therapy (prophylaxis), the evidence includes a Cochrane review involving multiple RCTs. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection (considered of marginal clinical importance) with no improvement in any of the other clinically important outcomes, including mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are preterm and low birth weight infants with sepsis who receive IVIG therapy (treatment), the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are adults with sepsis who receive IVIG therapy, the evidence includes a meta-analysis involving multiple RCTs. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality in the meta-analysis. However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. They include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. Relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have toxic shock syndrome who receive IVIG therapy, the evidence includes a small RCT and multiple observational studies. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in patients has shown reductions in mortality in a small RCT and in multiple observational studies. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. Autoimmune and Inflammatory Conditions For individuals who have immune thrombocytopenic purpura (ITP) who receive IVIG therapy, the evidence includes multiple RCTs and noncomparative studies. Relevant outcomes are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with corticosteroids, IVIG

8 therapy improved platelet counts. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have Guillain-Barré syndrome (GBS) who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes a systematic review and meta-analysis of multiple RCTs. Relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. Compared with aspirin, IVIG therapy has shown significant decreases in new coronary artery abnormalities. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes a systematic review with a single RCT. Relevant outcomes are disease- specific mortality, change in disease status, and treatment-related mortality and morbidity. The success of IVIG in Kawasaki disease has led to the investigation of IVIG therapy for other vasculitides such as Wegener granulomatosis. A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial found significantly more responders in the IVIG treatment group at 3 months, but no significant differences after 3 months, or in the frequency of relapse or use of other medications. The evidence is sufficient to determine that that the technology results in an improvement in the net health outcome. For individuals who have chronic inflammatory demyelinating polyneuropathy (CIDP) who receive IVIG therapy, the evidence includes a systematic review and RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have CIDP who receive SCIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Only 1 RCT has directly compared SCIG with IVIG in patients who had CIDP and conclusions about the relative efficacy of the treatments cannot be drawn due to methodologic limitations (eg, 45% of patients withdrew from the trial). The other RCT demonstrated that the use of SCIG for the maintenance of CIDP might be effective, with relatively low adverse events, but this trial also had a number of limitations (eg, small sample, 30% dropout rate). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have multifocal motor neuropathy (MMN) who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes a RCT and multiple observational studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have neuromyelitis optica who receive IVIG therapy, the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-

9 related mortality and morbidity. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have relapsing-remitting multiple sclerosis (RRMS) who receive IVIG therapy, the evidence includes a technology assessment. Relevant outcomes are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. According to the technology assessment, IVIG therapy is no longer considered a treatment of choice for RRMS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes 2 RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A systematic review found improvements in over 90% of patients. Randomized controlled trials have reported benefits in disease activity in the population as a whole (1 trial) or in a subgroup of patients with severe disease (1 trial). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have toxic epidural necrolysis (TEN) or Stevens-Johnson syndrome (SJS) who receive IVIG therapy, the evidence includes systematic reviews of observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. No RCTs have evaluated IVIG for TEN or SJS; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes systematic reviews of observational studies and RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. In 1 of the RCTs, compared with placebo, IVIG therapy showed significant improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have systemic lupus erythematosus (SLE) who receive IVIG therapy, the evidence includes systematic reviews of multiples studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are mainly retrospective. More RCTs are needed to demonstrate

10 improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review and case series. Relevant outcomes are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data and a case report. Relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients with refractory autoimmune hemolytic anemia. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. Relevant outcomes are OS, change in disease status, QOL, and treatment- related mortality and morbidity. Observed improvements in outcomes have suggested a potential mortality benefit with IVIG therapy in catastrophic antiphospholipid syndrome. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Alloimmune Processes For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs, a large observational study, and a systematic review. Relevant outcomes are DSS, change in disease status, and treatment-related mortality and morbidity. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have a recurrent spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are DSS, treatment-related mortality, and treatment-related morbidity. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

11 Miscellaneous Indications For individuals who have pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are symptoms, change in disease status, and treatment-related mortality and morbidity. The trials had mixed findings and both had small sample sizes and short intervention duration. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although improvements were observed in 1 case series, the other 2 reported negative findings. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have complex regional pain syndrome (CRPS) who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. In 1 trial, compared with placebo, IVIG therapy was associated with improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 13 patients. In the other RCT, low-dose IVIG was ineffective in relieving pain in CRPS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have Alzheimer disease who receive IVIG therapy, the evidence includes 3 RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. With the exception of a few subgroup analyses using mild cognitive impairment (MCI) status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and 2 of the 3 had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are a change in disease status, QOL and treatment-related mortality and morbidity. Compared with placebo, IVIG showed mild and transitory improvements in 1 trial but failed to show any improvement in another. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes a RCT and anecdotal reports. Relevant outcomes are symptoms, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown no therapeutic benefits. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes a meta- analysis, RCTs, and a retrospective study. Results from a Cochrane review concluded that, after pooling the available data, there was uncertain evidence of the effect of IVIG in preventing deaths. More RCT evidence is required before IVIG can be routinely recommended in the setting of myocarditis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes a systematic review of multiple case reports and case series. Relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Although improvements were observed in some patients, controlled trials are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

12 For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes a small randomized crossover study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes 2 small case series. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. The case series reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs and nonrandomized prospective studies. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes a RCT. Relevant outcomes are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (eg, the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member. A draft of future ICD-10 Coding related to this document, as it might look today, is included below for your reference.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity:

HCPCS Codes HCPCS codes: Code Description J1552 Injection, immune globulin (alyglo), 500 mg (Alyglo) C9072 Injection, immune globulin Asceniv , 500 mg J0850 Injection, cytomegalovirus immune globulin intravenous (human), per vial [Cytogam] J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg J1551 Injection, immune globulin (Cutaquig), 100 mg J1554 Injection, immune globulin (Asceniv), 500 mg

13 J1555 Injection, immune globulin (Cuvitru), 100 mg J1556 Injection, immune globulin Bivigam , 500 mg J1557 Injection, immune globulin, Gammaplex, intravenous, nonlyophilized (e.g., liquid), 500 mg J1558 Injection, immune globulin Xembify, 100 mg J1559 Injection, immune globulin Hizentra, 100 mg J1561 Injection, immune globulin, Gamunex / Gamunex-C / Gammaked , nonlyophilized (e.g., liquid), 500 mg J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), 500 mg
[Carimune, Panglobulin ] J1568 Injection, immune globulin, Octagam, intravenous, nonlyophilized (e.g., liquid), 500 mg J1569 Injection, immune globulin, Gammagard liquid, intravenous, nonlyophilized, (e.g., liquid), 500 mg J1572 Injection, immune globulin, Flebogamma/Flebogamma Dif, intravenous, nonlyophilized (e.g., liquid), 500 mg J1575 Injection, immune globulin/hyaluronidase, Hyqvia, 100 mg immunoglobulin J1576 Injection, immune globulin (Panzyga), intravenous, non-lyophilized (e.g., liquid), 500 mg J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg J3590 Unclassified biologics (e.g. Yimmugo)

Other Information Preferred Home Infusion Therapy Network Referring providers are encouraged to use these preferred Home Infusion providers to obtain these medications.

Preferred Home Infusion Therapy Provider Contact Information:

Accredo Health Group Phone: 1 866-759-1557 For Hemophilia therapies only, 1-866-712-5007 Website: www.accredo.com Caremark, LLC. Phone: 1-866-846-3096 Website: www.caremark.com Coram™ Specialty Infusion Services Phone: 1-800-678-3442 For Hemophilia therapies only, 1-888-699-7440

Website: www.coramhc.com

Individual Consideration Our medical policies are written for most people with a given condition. Each policy is based on peer reviewed clinical evidence. We also take into consideration the needs of atypical patient populations and diagnoses.
If the coverage criteria outlined is unlikely to be clinically effective for the prescribed purpose, the health care provider may request an exception to cover the requested medication based on an individual’s unique clinical circumstances. This is also referred to as “individual consideration” or an “exception request.”
Some reasons why you may need us to make an exception include: therapeutic contraindications; history of adverse effects; expected to be ineffective or likely to cause harm (physical, mental, or adverse reaction).

14 To facilitate a thorough and prompt review of an exception request, we encourage the provider to include additional supporting clinical documentation with their request. This may include: • Clinical notes or supporting clinical statements. • The name and strength of formulary alternatives tried and failed (if alternatives were tried) and specifics regarding the treatment failure, if applicable. • Clinical literature from reputable peer reviewed journals. • References from nationally recognized and approved drug compendia such as American Hospital Formulary Service® Drug Information (AHFS-DI), Lexi-Drug, Clinical Pharmacology, Micromedex or Drugdex®; and • References from consensus documents and/or nationally sanctioned guidelines.

Providers may call, fax or mail relevant clinical information, including clinical references for individual patient consideration, to:

Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043
Phone: 1-800-366-7778 Fax: 1-800-583-6289

We may also use prescription claims records to establish prior use of formulary alternatives or to show if step therapy criteria has been met. We will require the provider to share additional information when prescription claims data is either not available or the medication fill history fails to establish use of preferred formulary medications or that step therapy criteria has been met.

Policy History Date Action 1/15/2026 Added Yimmugo; updated Alyglo to own HCPCS code 1/1/2026 Updated policy to require a trial and failure of two SQ preferred agents for HyQvia and Cuvitru requests. Xembify added to list of preferred SQ agents. 7/2025 HyQvia moving to non-preferred.
2/2025 Clarified coding for Immunodeficiency States. 1/2025 Updated to add a preferred section to SubQ IG section of the policy. 8/2024 Clarified policy with Association
4/2024 Updated to add Alyglo to Medical UM.
11/2023 Updated criteria for Myasthenia Gravis and updated IC to align with 118E MGL § 51A. 7/2023 Reformatted Policy. 4/2023 Clarified not covering Organ Rejection. 7/2022 Renamed policy to be inclusive of IV and SubQ products. 12/2021 BCBSA National medical policy review. No changes to policy statements. New references added. 2/2021 Updated to add PANDAS & PANS in line with state mandate. 1/2021 Coding information clarified.
12/2020 BCBSA National medical policy review. No changes to policy statements. New references added. 10/2020 Clarified coding information 4/2020 Updated to add Asceniv to the policy. 11/2019 Updated to add Xembify to the policy. 7/2019 Updated to add Cutaquig to the policy. 1/2019 Clarified coding information.

15 8/2018 Updated to include Association coverage statement for Neuromyelitis Optica & Blistering disease. 10/2017 Clarified coding information plus updated to change Walgreens Specialty Name. 7/2017 Updated to add AllCare to Pharmacy Specialty list. 6/2017 Updated address for Pharmacy Operations. 1/2016 Updated to add new HCPCS code J1575. 10/2015 Updated to included revised language for Pharmacy only medications. 7/2015 Update to include Retail billing. 6/2015 Updated to include Bivigam, Cytogam, Gammaplex, Hizentra and HyQvia and to align ICD codes. 2/2015 Updated to include a couple HCPCS codes and one ICD code. 7/2014 Updated Coding section with ICD10 procedure and diagnosis codes, effective 10/2015. 1/2014 Updated ExpressPAth Language. 1/2013 Updated 1/2013 to include new FDA products Gammaked ™ and Gamunex ®-C. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates.
No changes to policy statements.
1/2012 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 11/2011 Reviewed - Medical Policy Group - Plastic Surgery and Dermatology. No changes to policy statements. 10/2011 Reviewed - Medical Policy Group - Gastroenterology, Nutrition and Organ Transplantation. No changes to policy statements. 9/2011 Reviewed - Medical Policy Group - Urology and Obstetrics/Gynecology. No changes to policy statements. 1/2011 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 12/2010 Reviewed - Medical Policy Group - Plastic Surgery and Dermatology. No changes to policy statements. 11/2010 Reviewed - Medical Policy Group - Gastroenterology, Nutrition and Organ Transplantation. No changes to policy statements. 10/2010 Reviewed - Medical Policy Group - Urology and Obstetrics/Gynecology. No changes to policy statements. 9/2010 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements. 1/2010 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 12/2009 Reviewed - Medical Policy Group - Plastic Surgery and Dermatology. No changes to policy statements. 11/2009 Reviewed - Medical Policy Group - Gastroenterology, Nutrition and Organ Transplantation. No changes to policy statements. 10/2009 Reviewed - Medical Policy Group - Urology and Obstetrics/Gynecology. No changes to policy statements. 9/2009 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements. 10/2009 Updated to reflect UM requirements.
1/2009 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 12/2008 Reviewed - Medical Policy Group - Plastic Surgery and Dermatology. No changes to policy statements. 11/2008 Reviewed - Medical Policy Group - Gastroenterology, Nutrition and Organ Transplantation. No changes to policy statements. 10/2008 Reviewed - Medical Policy Group - Urology and Obstetrics/Gynecology. No changes to policy statements.

16 10/2008 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements. 1/2008 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 9/2007 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements. 1/2007 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements.

References

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76. Gajdos P, Tranchant C, Clair B, et al. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol. Nov 2005; 62(11): 1689-93. PMID 16286541

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77. Gajdos P, Chevret S, Clair B, et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol. Jun 1997; 41(6): 789-96. PMID 9189040
78. Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. Jan 22 2002; 58(2): 169-
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82. Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. Apr 2009; 60(4): 595-603. PMID 19293008
83. Huang YC, Chien YN, Chen YT, et al. Intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. G Ital Dermatol Venereol. Oct 2016; 151(5): 515-24. PMID 27248150
84. Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens- Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol. Jan 2015; 54(1): 108-15. PMID 24697283
85. Wang DX, Shu XM, Tian XL, et al. Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol. May 2012; 31(5): 801-
86. PMID 22274797
87. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. Dec 30 1993; 329(27): 1993-2000. PMID 8247075
88. Miyasaka N, Hara M, Koike T, et al. Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double- blind placebo-controlled trial. Mod Rheumatol. Jun 2012; 22(3): 382-93. PMID 21971943
89. Dalakas MC, Sonies B, Dambrosia J, et al. Treatment of inclusion-body myositis with IVIg: a double- blind, placebo-controlled study. Neurology. Mar 1997; 48(3): 712-6. PMID 9065553
90. Walter MC, Lochmuller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. Jan 2000; 247(1): 22-8. PMID 10701893
91. Dalakas MC, Koffman B, Fujii M, et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology. Feb 13 2001; 56(3): 323-7. PMID 11171896
92. Sakthiswary R, D'Cruz D. Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore). Oct 2014; 93(16): e86. PMID 25310743
93. Boletis JN, Ioannidis JP, Boki KA, et al. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet. Aug 14 1999; 354(9178): 569-70. PMID 10470708
94. Orange JS, Hossny EM, Weiler CR, 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. Apr 2006; 117(4 Suppl): S525-
95. PMID 16580469
96. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. Mar 08 2005; 64(5): 804-10. PMID 15753413
97. Noseworthy JH, O'Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. Jun 12 2001; 56(11): 1514-22. PMID 11402108
98. Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn's disease. Autoimmun Rev. Dec 2012; 12(2): 275-80. PMID 22579561
99. Rajagopala S, Singh N. Diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics: systematic review from the Indian subcontinent. Acta Med Acad. 2012; 41(2): 161-74. PMID 23331391

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97. Hot A, Madoux MH, Viard JP, et al. Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins. Am J Hematol. Feb 2008; 83(2): 159-62. PMID 17849465
98. Ostronoff M, Ostronoff F, Coutinho M, et al. Hemophagocytic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma; successful treatment with high-dose intravenous immunoglobulin. Bone Marrow Transplant. Apr 2006; 37(8): 797-8. PMID 16518425
99. Arlet JB, Le TH, Marinho A, et al. Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis. Dec 2006; 65(12): 1596-601. PMID 16540551
100. Flores G, Cunningham-Rundles C, Newland AC, et al. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. Dec 1993; 44(4): 237-42. PMID 8237993
101. Macintyre EA, Linch DC, Macey MG, et al. Successful response to intravenous immunoglobulin in autoimmune haemolytic anaemia. Br J Haematol. Jun 1985; 60(2): 387-8. PMID 4005186
102. Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. Aug 2006; 54(8): 2568-76. PMID 16868979
103. Rayment R, Brunskill SJ, Soothill PW, et al. Antenatal interventions for fetomaternal alloimmune thrombocytopenia. Cochrane Database Syst Rev. May 11 2011; (5): CD004226. PMID 21563140
104. Paridaans NP, Kamphuis MM, Taune Wikman A, et al. Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial. Fetal Diagn Ther. 2015; 38(2): 147-53. PMID 25896635
105. Berkowitz RL, Lesser ML, McFarland JG, et al. Antepartum treatment without early cordocentesis for standard-risk alloimmune thrombocytopenia: a randomized controlled trial. Obstet Gynecol. Aug 2007; 110(2 Pt 1): 249-55. PMID 17666597
106. Berkowitz RL, Kolb EA, McFarland JG, et al. Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet Gynecol. Jan 2006; 107(1): 91-6. PMID 16394045
107. Bussel JB, Berkowitz RL, Lynch L, et al. Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol. May 1996; 174(5): 1414-23. PMID 9065105
108. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. Apr 19 2006; (2): CD000112. PMID 16625529
109. Egerup P, Lindschou J, Gluud C, et al. The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data. PLoS One. 2015; 10(10): e0141588. PMID 26517123
110. Wang SW, Zhong SY, Lou LJ, et al. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. Dec 2016; 33(6): 720-736. PMID 27720163
111. Christiansen OB, Pedersen B, Rosgaard A, et al. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. Mar 2002; 17(3): 809-16. PMID 11870141
112. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. Jan 2000; 182(1 Pt 1): 122-7. PMID 10649166
113. Jablonowska B, Selbing A, Palfi M, et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. Mar 1999; 14(3): 838-41. PMID 10221723
114. 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. Oct 2016; 55(10): 860-867.e2. PMID 27663941

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115. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. Oct 02 1999; 354(9185): 1153-8. PMID 10513708
116. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. Aug 1996; 26(4): 439-52. PMID 8863094
117. Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. Feb 1998; 13(2): 79-82. PMID 9512308
118. DelGiudice-Asch G, Simon L, Schmeidler J, et al. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord. Apr 1999; 29(2): 157-60. PMID 10382136
119. Goebel A, Bisla J, Carganillo R, et al. Low-Dose Intravenous Immunoglobulin Treatment for Long- Standing Complex Regional Pain Syndrome: A Randomized Trial. Ann Intern Med. Oct 03 2017; 167(7): 476-483. PMID 28973211
120. Goebel A, Baranowski A, Maurer K, et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. Feb 02 2010; 152(3): 152-8. PMID 20124231
121. Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. May 02 2017; 88(18): 1768-1775. PMID 28381506
122. Kile S, Au W, Parise C, et al. IVIG treatment of mild cognitive impairment due to Alzheimer's disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry. Feb 2017; 88(2): 106-112. PMID 26420886
123. Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to- moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose- finding trial. Lancet Neurol. Mar 2013; 12(3): 233-43. PMID 23375965
124. Comi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol. Oct 2002; 249(10): 1370-7. PMID 12382151
125. Dalakas MC, Quarles RH, Farrer RG, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. Nov 1996; 40(5): 792-5. PMID 8957021
126. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med. Jul 1997; 103(1): 38-43. PMID 9236484
127. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. May 20 2015; (5): CD004370. PMID 25992494
128. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. Aug 19 2020; 8: CD004370. PMID 32835416
129. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. May 08 2001; 103(18): 2254-9. PMID 11342473
130. Kishimoto C, Shioji K, Hashimoto T, et al. Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance. Heart Vessels. May 2014; 29(3): 336-42. PMID 23702697
131. El-Saiedi SA. Randomized controlled trial on the use of intravenous immune globulin in acute pediatric myocarditis. J Clin Res Bioethics. 2013;5(1):1-5. https://www.longdom.org/open- access/randomized-controlled-trial-on-the-use-of-intravenous-immune-globulin-2155-9627-5- 170.pdf. Accessed September 2, 2021
132. Huang X, Sun Y, Su G, et al. Intravenous Immunoglobulin Therapy for Acute Myocarditis in Children and Adults. Int Heart J. Mar 20 2019; 60(2): 359-365. PMID 30745539
133. Heidendael JF, Den Boer SL, Wildenbeest JG, et al. Intravenous immunoglobulins in children with new onset dilated cardiomyopathy. Cardiol Young. Jan 2018; 28(1): 46-54. PMID 28797313
134. Imazio M, Lazaros G, Picardi E, et al. Intravenous human immunoglobulins for refractory recurrent pericarditis: a systematic review of all published cases. J Cardiovasc Med (Hagerstown). Apr 2016; 17(4): 263-9. PMID 26090917

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135. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. Dec 27 2001; 345(26): 1870-6. PMID 11756577
136. LeHoang P, Cassoux N, George F, et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. Mar 2000; 8(1): 49-57. PMID 10806434
137. Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol. May 1999; 127(5): 545-9. PMID 10334347
138. Huang YH, Chen HC, Huang KW, et al. Intravenous immunoglobulin for postpolio syndrome: a systematic review and meta-analysis. BMC Neurol. Mar 22 2015; 15: 39. PMID 25886512
139. Madsen MB, Hjortrup PB, Hansen MB, et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. Nov 2017; 43(11): 1585-1593. PMID 28421246
140. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. Mar 2017; 139(3S): S1-S46. PMID 28041678
141. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. Nov 2015; 136(5): 1186-205.e1-78. PMID 26371839
142. 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. Jan 2010; 24 Suppl 1: S7-S27. PMID 19962580
143. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 4.2021. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed August 31, 2021
144. Centers for Disease Control (CDC). Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: bacterial infections. 2013; https://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf. Accessed August 31, 2021
145. Polin RA, Committee on Fetus Newborn. Management of neonates with suspected or proven early- onset bacterial sepsis. Pediatrics. https://pediatrics.aappublications.org/content/pediatrics/142/6/e20182894.full.pdf. Accessed August 31, 2021
146. Patwa HS, Chaudhry V, Katzberg H, et al. 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. Mar 27 2012; 78(13): 1009-15. PMID 22454268
147. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. Mar 15 2015; 91(6): 365-71. PMID 25822554
148. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. Apr 25 2017; 135(17): e927-e999. PMID 28356445
149. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force - second revision. J Peripher Nerv Syst. 2021;1-27. https://onlinelibrary.wiley.com/doi/10.1111/jns.12455. Accessed September 1, 2021
150. Trebst C, Jarius S, Berthele A, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. Jan 2014; 261(1): 1-16. PMID 24272588
151. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. Jul 26 2016; 87(4): 419-25. PMID 27358333
152. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. Aug 2003; 139(8): 1051-9. PMID 12925395
153. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. Jun 2016; 174(6): 1194-227. PMID 27317286
154. McPherson T, Exton LS, Biswas S, et al. British Association of Dermatologists' guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in children and young

24 people, 2018. Br J Dermatol. 2019;181:37-54. doi: 10.1111/bjd.17841. https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.17841. Accessed September 1, 2021

155. Cervera R, Rodriguez-Pinto I, Cervera R, et al. Catastrophic antiphospholipid syndrome: task force report summary. Lupus. Oct 2014; 23(12): 1283-5. PMID 25228727
156. Royal College of Obstetricians and Gynecologists. The Investigation and Treatment of Couples with Recurrent Firsttrimester and Second-trimester Miscarriage. Royal Colleg of Obstetricians and Gynecologists Green-Top Guidelines No. 17. 2011; https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf. Accessed September 1, 2021
157. Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. Apr 2007; 21(2 Suppl 1): S57-107. PMID 17397768
158. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. Feb 2014; 53(2): 237-57. PMID 24472258
159. National Institute for Health and Care Excellence (NICE). Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management [CG53]. 2007; https://www.nice.org.uk/guidance/cg53. Accessed September 1, 2021
160. Writing Committee Members, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. https://www.jacc.org/doi/full/10.1016/j.jacc.2013.05.019?_ga=2.248107975.1773510622.163053172 9-1275499959.1630531729 Accessed September 1, 2021
161. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination for intravenous immune globulin for the treatment of autoimmune mucocutaneous blistering diseases (250.3). 2002; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=158. Accessed August 31, 2021

162. Yimmugo [package insert]. Dreieich, Germany: Biotest AG.: July 2024.

     Endnotes

163. Revised 9/95 based on TEC (Technology Evaluation Center) 6/95 assessment of medical literature from 1991 to 1995 addressing IVIg for SLE-related cytopenia, vasculitis, pericarditis, and pleural effusions in patients who were not controlled by immunosuppressives or cytotoxic agents.
164. Revised 9/95 to include the 2/95 TEC evaluation of medical literature from 1991-4/95 assessing IVIg to improve the functional status of patients with inclusion body myositis who have not responded to prednisone or other immunosuppressives.
165. Revised 10/95 based on 1994 TEC evaluation of medical literature from 1991-1994 assessing IVIG to stop progression of muscle weakness or to decrease frequency or severity of relapses in MS..
166. Revised 10/95 based on a 1994 TEC evaluation of medical literature from 1991-1994 assessing IVIg to improve functional capacity or to reduce pain in patients with RA refractory to NSAIDS and either cytotoxic or disease-modifying antirheumatic drugs.
167. Revised 10/95 based on a 1994 TEC evaluation of medical literature from 1991-1994 assessing IVIG to improve neurologic function in CIDP, either as first-line therapy, or for acute exacerbations in patients refractory or intolerant of prednisone or azathioprine.
168. Revised 10/95 based on a 1994 TEC evaluation of medical literature assessing IVIG to reduce fetal loss in women with recurrent fetal loss (sequence of 3 or more miscarriages), with or without antiphospholipid antibodies.
169. Revised 3/96 to include CMS (Centers for Medicare and Medicaid services) regulations published in the February/March 1996 issue of the Medicare Health Resources.
170. Revised 2/97 to include CMS (Centers for Medicare and Medicaid services) regulations published in the February/March 1997 issue of the Medicare Health Resources.
171. Revised 9/97 to include CMS regulations (Centers for Medicare and Medicaid services) published in the June/July 1997 Medicare B Health Resources.
172. Added based on recommendations made by the Massachusetts Neurological Society.
173. Based on the July 1998 TEC (Technology Evaluation Center) analysis of the literature on IVIg for MS. Health outcomes considered by TEC included prevention of disease progress and disability, improving baseline neuro disability, and reducing acute relapse.

25 Also see the July/August 1997 ACP Journal Club commentary: http://www.acponline.org/journals/acpjc/julaug97 Regarding the article: Fazekas F et al., Austrian Immunoglobulin in Multiple Sclerosis Study Group. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing- remitting multiple sclerosis. Lancet. 1997 Mar 1;349:589-93.

12. FDA-approved uses as of July, 1998.
13. Off-label use in the treatment of AIDS and HIV as required by law.
14. Label use based on National Blue Cross Blue Shield policy 8.01.05, issued 12/15/98.
15. Off-label use based on National Blue Cross Blue Shield policy 8.01.05, issued 12/15/98.
16. Investigational use based on National Blue Cross Blue Shield policy 8.01.05, issued 12/15/98.
17. Based on recommendations from Walt Kagan, MD, Massachusetts Society of Clinical Oncologists.
18. Based upon a September 1999 Medicare B HealthResource Newsletter.
19. Medicare policy is developed separately from BCBSMA policy. While BCBSMA policy is based upon scientific evidence, Medicare policy incorporates scientific evidence with local expert opinion, and governmental regulations from CMS (Centers for Medicare and Medicaid Services) and the U.S Congress. While BCBSMA and Medicare policies may differ, our Medicare HMO Blue and Medicare PPO Blue members must be offered the same services as Medicare offers. In many instances, BCBSMA policies offer more benefits than does Medicare policy.
20. Based on recommendations from David Weinberg, MD, Massachusetts Neurologic Association, 1/2000 MPG Neurology meeting.
21. Medical Policy Group, August 2000.
22. Previous criteria summarized in the current form: vital capacity less than 1L; dysphagia associated with aspiration; inability to ambulate 100 feet without assistance.
23. Medical Policy Group, January 2000.
24. Idiopathic Thrombocytopenic Purpura: A Practice Guideline Developed by Explicit Methods for the American Society of Hematology
25. See the 1998 ASRM (American Society of Reproductive Medicine) Practice Committee Report on Intravenous Immunoglobulin and Spontaneous Pregnancy Loss.
26. Based on the June 2002 Medicare B Resource Newsletter. See also the CMS /Medicare websites at
    www.cms.gov and www medicare.gov.
27. Based upon the 2002 Blue Cross Blue Shield Association policy 8.01.05. IVIG for myasthenic crisis is considered medically necessary. Myasthenic crisis is an off-label indication.
28. Based upon the 2002 Blue Cross Blue Shield Association National policy 8.01.05.
29. Based upon the 2004 Blue Cross Blue Shield Association policy 2.01.01.
30. Based upon the 2004 Blue Cross Blue Shield Association National policy 8.01.05.
31. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol.2003;139:1051-1059.
32. Based upon the 2004 BCBSA National Policy 8.01.05. Bone marrow transplant patients (for prevention of infection or GVH prevention.) • 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.
33. Based upon the 2004 BCBSA National Policy 8.01.05. Recurrent Spontanous Abortion.

34. Based on Blue Cross Blue Shield National policy 8.01.05 Intravenous Immune Globulin Therapy issued 4/06.

    To request prior authorization using the Massachusetts Standard Form for Medication Prior Authorization Requests (eForm), click the link below: http://www.bluecrossma.org/medical-policies/sites/g/files/csphws2091/files/acquiadam- assets/023%20E%20Form%20medication%2 prior%20auth%20instruction%20prn.pdf

26

Home Infusion Therapy
Prior Authorization Form Please complete and fax with the physician's prescription to: (888) 641-5355. If the patient is a BCBSMA employee, please fax the form to: (617)246-4013. Company name:

Contact Name:

Phone #:

Provider #:

Fax#

Address:

Patient name:

Address:

Patient_ID#:

DOB://____ Diagnosis:

Prescribing Physician/addr:
____ Telephone:

PCP name/address: ____ Telephone:

Is this fax number ‘secure’ for PHI receipt/transmission per HIPAA requirements? (circle one) Yes No

Place of Service  Home  SNF  MD office  other (specify)_ Primary Therapy Primary drug name:

Approximate duration: // to // Dose:

Frequency:

Route of Administration: pump: Y N Other Therapy Other drug name:

Approximate duration: // to // Dose:

Frequency

Route of Administration: pump: Y N

 If this is a “drug only” authorization request, indicate other services the nursing agency is providing: __ Nursing provided by: ____ Contact: _ Phone: __ Fax: ___ Request for 7 Day Coverage : Date of occurrence: ___ request dates:___ Occurrence type:  Hospitalization  Death  Change of Therapy
Physician signature:___ Date:____