IVIG, SCIG - BMC HealthNet Plan

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WELLSENSE.ORG 

CLINICAL COVERAGE GUIDELINES – Immune Globulin Intravenous, 

Subcutaneous (IVIG, SCIG) 

BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense 

Health Plan in New Hampshire. Boston Medical Center HealthNet Plan and Well Sense Health 

Plan are trade names used by Boston Medical Center Health Plan, Inc. 

Policy Applicability 

Boston Medical Center HealthNet Plan Well Sense Health Plan 

MassHealth 

New Hampshire Medicaid 

Commonwealth Care 

Commercial 

Integrated Care Program 

Effective Date: 07/01/2013 

Policy Number: 9.129 

Policy Effective Date: 07/13/2006 

Last Review Date: 03/14/2013 

Approved by: Pharmacy and Therapeutics Committee 

Policy Owner/Title: Pharmacy Services 

Summary: 

BMC HealthNet Plan will authorize coverage of IVIG, SCIG products when appropriate criteria are met. 

This guideline has been adapted from the Express Scripts ® Prior Authorization Policy for Immune Globulin 

Intravenous and Subcutaneous drugs with permission from CuraScript, Inc., An Express Scripts Company. 

Description of Item or Service: 

Immune globulin intravenous (IVIG) products consist of concentrated human immunoglobulins, primarily 

immunoglobulin G (IgG), that is prepared from pooled plasma collected from a large number of human 

donors. 1-11 The donors in a typical pool of plasma have a wide range of antibodies against infectious 

agents. 12 These products have IgG subclasses similar to that found in normal humans. Although the 

products should not be considered equivalent; from the standpoint of efficacy, immune globulin products 

can be used interchangeably. 13 There are immunoglobulin A (IgA) and IgG subclass differences and 

antibody titers also vary from lot-to-lot and among IVIG preparations. There are especially variations in 

This guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. The use of this 

guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement is based on member 

benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Plan policies, clinical coding criteria, 

and the BMC HealthNet Plan agreement with the rendering or dispensing provider. Reimbursement policies may be amended at BMC 

HealthNet Plan’s discretion. BMC HealthNet Plan will always use the most recent CPT and HCPCS coding guidelines. All Plan policies are 

developed in accordance with state, federal and accrediting organization guidelines and requirements, including NCQA. 

This document is subject to further revision in response to additional terms and requirements imposed under the Integrated Care Program, 

including the ICP contract. 

BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire. Boston Medical 

Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan, Inc. 

BMC HealthNet Plan – IVIG, SCIG

IgG4, which is often reduced. 12 Some congenital hypogammaglobulinemias involve IgG subclass 

deficiencies (e.g., deficiencies of IgA or immunoglobulin E [IgE] in association with reduced IgG2 or 

IgG4). However, there is currently no clinical evidence that this is an important issue. In the US, 

manufacturers of IVIG use Cohn-Oncley ethanol fractionation as an initial step in preparation and then 

other manufacturing steps are added by individual manufacturers to remove IgG aggregates and other 

contaminants and to inactivate viruses. Various stabilizing agents are used (e.g., albumin, glycine, 

polyethylene glycol, sugars). Some of these modifications affect the product, but the biologic relevance 

has not been established. Current products contain only trace amounts of immunoglobulin M (IgM). 

All of the US licensed products are Food and Drug Administration (FDA)-indicated for replacement 

therapy in patients with primary immunodeficiencies. Individual products are indicated for use in five 

other conditions detailed below. 

Primary (inherited) immunodeficiencies (e.g., common variable immunodeficiency [CVID], 1-11 severe 

combined immunodeficiency [SCID], 1-11 congenital agammaglobulinemia [X-linked 

agammaglobulinemia], 1-8,10-11 Wiskott-Aldrich Syndrome 2-11 , congenital hypogammaglobulinemia 8 ). 

Gamunex-C, Gammaked and Gammagard Liquid, 10% may be administered via intravenous (IV) or 

subcutaneous (SC) infusion while Hizentra may be administered subcutaneously for primary 

immunodeficiency. 4,8,10 Immune globulin replacement therapy provides IgG antibodies to those who lack 

them. 14 

Patients with primary humoral immunodeficiency are at high risk of developing acute and chronic 

bacterial infections. IVIG provides a broad spectrum of IgG antibodies that help prevent or attenuate 

infectious diseases. The use of IVIG in IgG subclass deficiencies is controversial and is recommended 

only in those patients who also demonstrate a deficiency in the ability to form antibodies against a variety 

of polysaccharide and protein antigens. 14 

Acute and chronic idiopathic [immune] thrombocytopenic purpura (ITP). 1,3-4,7,10-11 IVIG is indicated 

when a rapid rise in the platelet count is needed, such as prior to surgery, to control excessive bleeding, or 

to defer or avoid splenectomy. 15 

ITP can occur in isolation (primary) or in association with other disorders (secondary; e.g., autoimmune 

diseases, viral infections, and certain drugs). 15 An International Working Group (IWG) consensus panel 

defines primary ITP as a platelet count < 100,000/mm 3 in the absence of other causes or disorders 

associated with thrombocytopenia. ITP is also defined by time from diagnosis: newly diagnosed 

(diagnosis to 3 months), persistent (3 months to 12 months from diagnosis), or chronic (lasting for more 

than 12 months). These definitions may not apply to patients with secondary forms of ITP. Refractory 

ITP is defined as the presence of severe ITP occurring after splenectomy. Non-splenectomized patients 

are defined as responders and nonresponders to various drug therapies, but should not be considered 

refractory. 

In pregnant women, corticosteroids and IVIG are considered safe with regard to teratogenicity but may 

have maternal side effects including exacerbation of gestational diabetes and postpartum psychiatric 

disorders. 15 The American Society of Hematology (ASH) recommends IVIG or corticosteroids in 

pregnant patients requiring treatment with no recommendations for specific platelet counts at which 

patients should be treated. During labor and delivery, ITP management is based on assessment of 

maternal bleeding risks associated with delivery and epidural anesthesia, and the minimum platelet counts 












equired to undergo these procedures. 

ITP is usually chronic in adults; however, there is no clear age at which children should be treated in a 

manner more like adults. 15 Although data suggest that adolescents are more likely than younger children 

to develop persistent or chronic disease, there have been no studies investigating a benefit to altered 

treatment in this age group or the age at which this effect is likely to be most present. Therefore the 

management of adolescents should follow the usual management for children. Children with no or mild 

bleeding are managed with observation alone regardless of platelet count. 

Glucocorticoids have been the standard initial therapy for adults with moderate to severe 

thrombocytopenia and symptomatic purpura. 15-17 Evidence for use of glucocorticoids is based on case 

series. In a small randomized trial, glucocorticoid therapy was compared to IVIG and both in 

combination as initial treatment and there was no difference in response. This study was too small to 

make definite conclusions. According to guidelines from ASH, there is limited evidence on which to base 

treatment recommendations on a specific platelet count or age for all patients. Observational data of 

patients with ITP have suggested that bleeding risk is increased with platelet counts < 20,000 or < 

30,000/mm 3 , but it is unclear whether offering treatment to all patients with ITP at these levels will result 

in decreased bleeding. In patients with recurrent or persistent thrombocytopenia associated with bleeding 

after an initial treatment course with corticosteroids (or IVIG or anti-D), there is no evidence to guide a 

sequence of treatments. 

Splenectomy remains the only treatment that provides sustained remission off all treatments at 1 year and 

beyond. 15 ASH recommends splenectomy for patients who have failed corticosteroids. Patients who do 

not achieve spontaneous remission or do not maintain a complete response following cessation of therapy 

are classified as having persistent (3 to 12 months from diagnosis) or chronic (lasting > 12 months) ITP. 

Patients who have failed splenectomy or relapsed thereafter and have severe ITP or have a risk of 

bleeding that requires therapy are classified as having refractory ITP. ASH does not recommend therapy 

in patients with platelet counts > 30,000/mm 3 in the absence of bleeding after splenectomy. 

Studies in children with ITP suggest the majority of children experience no bleeding or mild bleeding 

regardless of whether or not they initially receive drug therapy. 15 ASH notes the decision to manage with 

observation requires a detailed discussion between the healthcare provider, patient and family. Treatment 

may be appropriate if follow-up cannot be assured, if there are other societal concerns (e.g., travel and 

distance from hospital), if there are concerns attributed to activity level or risk of bleeding, or there is a 

need for upcoming procedures associated with a risk of bleeding. A meta-analysis comparing treatment 

with IVIG (dose 0.8 to 1 g/kg) and corticosteroids reported pooled data from six trials. The primary 

outcome was platelet count > 20,000/mm 3 at 48 hours. The relative risk (RR) of achieving a platelet 

count > 20,000/mm 3 at 48 hours was 0.74 (95% confidence interval [CI]: 0.65, 0.85) for corticosteroids 

vs. IVIG indicating children treated with corticosteroids were 26% less likely to achieve the primary 

outcome. For pediatric patients requiring treatment, a single dose of IVIG or a short course of 

corticosteroids are recommended as first-line treatment (long-term use of corticosteroids should be 

avoided). IVIG can be used if a more rapid rise in platelet count is desired. 

B-cell chronic lymphocytic leukemia (CLL) for prevention of bacterial infections in patients with 

hypogammaglobulinemia and/or recurrent bacterial infections. 3,11 In one placebo-controlled study, IVIG 

significantly reduced bacterial infections and the median time to first bacterial infection for the IVIG 












patients was greater than 365 days compared with 192 days with placebo. The number of viral and fungal 

infections was not different between the two groups. 

Kawasaki disease, for the prevention of coronary artery aneurysm. 3,11 The efficacy of IVIG in reducing 

the prevalence of coronary artery abnormalities is well-established when given in conjunction with aspirin 

in the acute phase of Kawasaki disease. 18 

Chronic inflammatory demyelinating polyneuropathy (CIDP), to improve neuromuscular disability 

and impairment and for maintenance therapy to prevent relapse. 8,19,10 Efficacy of IVIG was established in a 

multi-center, double-blind trial using IVIG caprylate/chromatography purified (Gamunex). Patients 

with CIDP were randomized to IVIG or placebo given as a loading dose at baseline over 2 to 4 

consecutive days and then a maintenance dose every 3 weeks for up to 24 weeks. Patients who did not 

improve and maintain this improvement for 24 weeks were crossed over to the alternate study drug 

(rescue). Significantly more patients responded to IVIG 47.5% vs. 22.4% with placebo (25% difference; 

95% CI: 7%, 43%; P = 0.006). This study included patients who were IVIG-naïve and subjects who had 

previously received IVIG. See Table 1. In an extension phase, time to relapse was evaluated in the 

subset of patients who previously responded to IVIG (i.e., patients who completed the efficacy phase or 

rescue phase for 24 weeks). Thirty-one patients were randomly reassigned to continue with IVIG and 26 

patients were reassigned to placebo (withdrawal period) for 24 weeks. Patients who continued on IVIG 

had a significantly longer time to relapse vs. patients on placebo (P = 0.011). The probability of relapse 

was 13% with IVIG vs. 45% with placebo (hazard ratio [HR]: 0.19 [95% CI: 0.05, 0.70]). 

Table 1. CIDP: Outcomes in Intent-to-Treat Population Efficacy Period (24 weeks). 4 

IVIG Placebo 

Efficacy Period 

Responder* Non-Responder Responder* Non-Responder P-Value** 

All subjects 28/59 (47.5%) 31/59 (52.5%) 13/58 (22.4%) 45/58 (77.6%) 0.006 

IVIG naïve subjects 17/39 (43/6%) 22/39 (56.4%) 13/46 (28.3%) 33/46 (71.7%) 0.174 

IVIG experienced subjects 11/20 (55.0%) 9.20 (45.0%) 0/12 (0%) 12/12 (100%) 0.002 

CIDP – Chronic inflammatory demyelinating polyneuropathy; IVIG – Intravenous immunoglobulin; * Responder was 

defined as at least 1-point improvement from baseline in the adjusted Inflammatory Neuropathy Cause and Treatment 

(INCAT) score that was maintained for 24 weeks. ** P-value based on Fisher’s exact method. 












IVIG is recommended as an equivalent alternative to plasma exchange in children and adults with 

CIDP. 20-21 In short-term, controlled trials, IVIG improved disability more than prednisolone and the 

quality of life was better with IVIG because adverse effects were less. 21-22 Neurological disability score 

improved similarly with IVIG and plasma exchange. 23 IVIG was also significantly more effective than 

placebo in improving muscle strength. About two-thirds of patients responded to IVIG and about onethird 

of these need no further treatment and two-thirds required repeated courses of IVIG. 21 Benefit from 

IVIG lasts for 2 to 12 weeks, so treatment may need to be repeated. 

IVIG also is used for many off-label indications. 12 Most evidence for clinical effectiveness of IVIG is 

anecdotal (i.e., case reports, open series, or cohort studies). 23 Some conditions, however, have been 

studied in controlled trials. Usually IVIG is indicated only if standard approaches have failed, become 

intolerable, or are contraindicated. 

Clinical Guideline Statement 

BMC HealthNet Plan may authorize coverage of IVIG, SCIG products for members meeting the following 

criteria: 

Prior Authorization – (Duration of Approval – see specific indications for details) 

A prior authorization request will be required for all prescriptions for IVIG, SCIG. These requests will be 

approved when indication-specific criteria below are met: Note: Hizentra will only be approved for the 

treatment of primary humoral immunodeficiency when the specified criteria below are met. 

FDA-Approved Indications 

1. Immunodeficiency, primary humoral (treatment) (e.g., X-linked agammaglobulinemia [Bruton’s 

agammaglobulinemia, congenital agammaglobulinemia), CVID, SCID, Wiskott-Aldrich 

syndrome). 1,3-10,22-26 Approve for 12 months if IVIG is prescribed by an allergist/immunologist, 

immunologist, otolaryngologist (ear nose and throat [ENT] physician) or an infectious diseases 

physician who treats patients with primary immune deficiencies, or in consultation with one of these 

physician specialists. Note: Document primary humoral immune deficiency disorder. Treatment is 

lifelong. 

IVIG is used for replacement in primary immunodeficiency disorders where antibody production is 

significantly impaired to increase IgG levels and to prevent or control recurrent and chronic bacterial 

infections and to control symptoms. 24,26 

Notes: Also see Hyperimmunoglobulinemia E syndrome (Job’s syndrome). 22 

2. Idiopathic thrombocytopenic purpura (ITP) or immune thrombocytopenia (IT) acute and 












chronic (treatment). 1,3-4,7,10 

a. Children and adolescents (age ≤ 17 years) with ITP. Approve for one of the following (i, ii, iii, or 

iv) when IVIG is prescribed by or in consultation with a hematologist. In children and 

adolescents ≤ 17 years of age, use of IVIG is based on risk of bleeding and not on platelet counts. 

i) If there is significant acute (newly diagnosed or requiring therapy for the first time) mucous 

membrane or other noncutaneous bleeding, then approve for 1 month. 17 In clinical trials 

IVIG shortened the duration of severe thrombocytopenia, OR 

ii) If IVIG is required to prevent bleeding in a child or adolescent with persistent (3 to 12 

months) or chronic (≥ 12 months) ITP/IT, approve for 12 months, OR 

iii) If inaccessibility or noncompliance is a concern and the child or adolescent is at risk of 

bleeding, approve for 12 months, 15 OR 

iv) If splenectomy, other surgery, dental extractions, or other procedures likely to cause blood 

loss are needed, then approve for 1 month. 17 

Most children do not require therapy with IVIG. 27 In emergency situations, platelet transfusions 

given with IV corticosteroids and IVIG should be given for intracranial hemorrhaging or other lifethreatening 

or serious bleeding. 28 

b. Adults (> 17 years) with ITP. Approve for one of the following (i, ii, or iii) when IVIG is 

prescribed by or in consultation with a hematologist. 

i) If there is acute bleeding (newly diagnosed or requiring therapy for the first time) in a patient 

with platelet count < 30,000 mm 3 who has tried a corticosteroid (e.g., prednisone). Approve 

IVIG for 1 month. 

An exception can be made for trying a corticosteroid, if a corticosteroid has been tried in the 

past for ITP/IT, there is a contraindication to corticosteroid therapy, or corticosteroids should 

be avoided (such as in patients with diabetes, advanced osteoporosis, severe infections, 

psychological changes, or prior gastrointestinal bleeding or when ITP is associated with 

interferon therapy [such as peginterferon alfa-2a {Pegasys ® } or alfa-2b {PEG-Intron ® } for 

hepatitis C virus {HCV} infection]). 15 

IVIG may be added to corticosteroid therapy if thrombocytopenia persists or worsens after 

about 3 days of corticosteroid therapy. 15,28 If there is an urgent need to increase the platelet 

count quickly, IVIG can be started with a corticosteroid 15 

According to ASH guidelines if platelet count is < 30,000 mm 3 initial therapy is corticosteroids. 15,27 

Longer courses of steroids over shorter courses of steroids or IVIG are preferred as first-line 

treatment in adults because they are associated with a longer time-to-loss of response. 15 IVIG may be 

used with corticosteroid when a more rapid increase in platelet count is required. ASH guidelines 

state that splenectomy remains the only treatment that provides sustained remission off all treatments 

at 1 year and beyond. Splenectomy is recommended in patients who have failed corticosteroid 

therapy. 

OR 












ii) To increase platelet counts before surgical procedures (e.g., splenectomy) or dental 

procedures. Approve for 1 month, in a patient with platelet count < 50,000 mm 3 . If the 

patient is undergoing major surgery (e.g., central nervous system or cardiac surgery) approve 

if the platelet count is < 75, 000 mm 3 , OR 

iii) Patient with persistent (3 to 12 months duration) or chronic (≥ 12 months duration) 

ITP/IT, who has tried a corticosteroid, where IVIG is needed to prevent bleeding. Approve 

for 12 months. 

An exception can be made for trying a corticosteroid, if a corticosteroid has been tried in the 

past for ITP/IT, there is a contraindication to corticosteroid therapy, or corticosteroids should 

be avoided (such as in patients with diabetes, advanced osteoporosis, severe infections, 

psychological changes, or prior gastrointestinal bleeding or when ITP is associated with 

interferon therapy [such as peginterferon alfa-2a {Pegasys ® } or alfa-2b {PEG-Intron ® } for 

HCV infection]). 

IVIG may be added to corticosteroid therapy if thrombocytopenia persists or worsens after 

about 3 days of corticosteroid therapy. 28 If there is an urgent need to increase the 

platelet count quickly, IVIG can be started with a corticosteroid. 15 

Patients who are at risk for intracerebral bleeding will be hospitalized and treated with a highdose 

corticosteroid, IVIG, and platelet transfusions or other modalities. 15 

c. Pregnant women with ITP. Approve for one of the following (i or ii) when IVIG is prescribed by 

or in consultation with a hematologist. 

i) Pregnant woman in any trimester. Approve for 3 months. ASH recommends pregnant 

patients requiring treatment for ITP receive either a corticosteroids or IVIG, 15 OR 

ii) Before normal vaginal delivery, cesarean section, or spinal or epidural anesthesia. Approve 

IVIG for 2 weeks. 17,27 

Newborns of mothers with ITP: Infants are hospitalized. 

3. Kawasaki disease (treatment adjunct). 3,29 Approve one dose of IVIG in the acute phase, if 

prescribed by or in consultation with a pediatric cardiologist or pediatric infectious diseases physician 

[Note: patients are generally hospitalized for initial therapy]. A second dose may be given in patients 

who fail to respond to the initial therapy (e.g., persistent or recrudescent [recurring] fever or signs of 

inflammation 24 to 48 hours after completing the initial IVIG infusion 30 ). 

Patients should receive a single dose of IVIG together with aspirin within the first 10 days of illness, 

and if possible, within 7 days of illness. 18,30 IVIG can also be given in children presenting after the 

10 th day of illness (i.e., the diagnosis was missed earlier) if they have persistent fever without other 

explanation or aneurysms and ongoing systemic inflammation. Efficacy of IVIG with aspirin in the 

acute phase of illness is well established. Treatment with IVIG during the acute phase reduces the 












isk of coronary artery aneurysms from 17% to 4%. 30 

4. B-cell chronic lymphocytic leukemia (CLL) in patients with hypogammaglobulinemia and with 

a previous history of a serious bacterial infection. 3,31-34 Approve for 12 months in patients with 

hypogammaglobulinemia and a previous history of a serious bacterial infection, when IVIG is 

prescribed by or in consultation with an oncologist, hematologist, or infectious diseases specialist. 

Hypogammaglobulinemia for these patients is IgG < 500 mg/dL (5.0 g/L). 35 A serious bacterial 

infection is one requiring an IV antibiotic for treatment. 30,33 

In placebo-controlled trials, IVIG significantly reduced bacterial infections. 32 According to a 

Canadian expert panel of hematologists, IVIG is recommended for infection prophylaxis in these 

adults who have either a recent episode of a life-threatening infection thought to be caused by low 

levels of polyclonal immunoglobulins or recurrent episodes of clinically significant infections (e.g., 

pneumonia) that are caused by low levels of polyclonal immunoglobulins. 31 IVIG is an option 

for acute life-threatening infections in these patients. This panel of hematologists recommended 

re- evaluation every 4 to 6 months when used for prophylaxis but there was no consensus on 

specific criteria to use for duration of treatment with IVIG. 

5. Chronic inflammatory demyelinating polyneuropathy (or polyradiculoneuropathy) (CIDP). 

Approve for 12 months if IVIG is prescribed by a neurologist who is specialized or experienced in the 

treatment of neuromuscular diseases. 

IVIG is FDA-approved to improve neuromuscular disability and impairment and for maintenance 

therapy to prevent relapse. 4,10 IVIG is recommended as an equivalent alternative to plasma exchange 

in children and adults. 20-21,35 In the pivotal trial for CIDP, IVIG was effective at improving certain 

motor functions for up to 48 weeks after initial therapy. 19,36 In previous short-term, controlled trials, 

IVIG improved disability more than prednisolone and the quality of life was better with IVIG because 

adverse effects were less. ,22 Neurological disability score improved similarly with IVIG and plasma 

exchange. 23 IVIG was also significantly more effective than placebo in improving muscle strength. 

About two-thirds of patients responded to IVIG and about one-third of these need no further treatment 

and two-thirds required repeated courses of IVIG. 21 Benefit from IVIG lasts for 2 to 12 weeks, 

so treatment may need to be repeated. 

Note: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) or Lewis 

Sumner Syndrome are rare variants of CIDP. IVIG is not FDA-indicated for the treatment of 

MADSAM or Lewis Sumner Syndrome; however, these rare variants of CIDP are treated the same as 

CIDP (above). 31,37 

Other Uses with Supportive Evidence 

6. Allogeneic bone marrow transplantation 1 (BMT) or hematopoietic stem cell transplantation 

(HSCT) 22,38 (i.e., blood or marrow HSCT). Approve IVIG for 6 months in patients who meet the 

following criteria (a, b, and c): 

a) IVIG is prescribed by or in consultation with a hematologist or oncologist, AND 

b) The patient has had an allogeneic HSCT or BMT within the previous year, AND 

c) The patient has an IgG level < 500 mg/dL. 












The requirement for IgG < 500 mg/dL does not apply to patients who underwent transplantation 

for multiple myeloma or malignant macroglobulinemia because their total IgG concentration is 

affected by their underlying paraproteinemia. 

In the absence of hypogammaglobulinemia, routine monthly administration of IVIG to HSCT 

recipients > 100 days after allogeneic or autologous HCT is not recommended as a means of 

preventing bacterial infections. 39 

Although IVIG has been recommended for use in producing immune system modulation for the 

prevention of graft-versus-host disease (GVHD); routine administration of IVIG to HSCT recipients 

for prophylaxis of bacterial infection within the first 100 days after transplantation is not 

recommended. 38 Some centers check total IgG levels in high-risk HCT recipients (e.g., those 

with unrelated marrow grafts). For patients with severe hypogammaglobulinemia (i.e., IgG < 500 

mg/dL) IVIG prophylaxis may be considered to maintain a trough serum IgG concentration > 400 

mg/dL. 

In a randomized trial where IVIG or no IVIG prophylaxis were given from Day 90 to Day 360 post 

bone marrow transplantation (patients received methotrexate plus cyclosporine for graft-versus-host 

disease [GVHD] prophylaxis), the incidence of bacteremia, sepsis, localized infection, survival, 

obliterative bronchiolitis, or the incidence or mortality of chronic GVHD were not reduced with 

IVIG. 40 Patients with severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dL) 

can continue receiving IVIG. 38,40-41 IVIG supplementation is often used in patients with 

severe infections and IgG levels < 400 mg/dL to maintain levels until infections resolve. 41 

Gamimune ® N, a brand of IVIG that has been discontinued, was FDA-approved for the treatment of 

bone marrow transplant patients ≥ 20 years of age to decrease the risk of septicemia and other 

infections, interstitial pneumonia of infectious or idiopathic etiologies, and acute GVHD in the first 

100 days posttransplant. 42 Currently marketed IVIG products do not carry this indication. 

GVHD, acute (within the first 100 days after transplantation). Not recommended unless the 

patient has severe hypogammaglobulinemia. (See Exclusions.) 

GVHD, chronic, prevention. Not recommended unless the patient has severe 

hypogammaglobulinemia. (See Exclusions.) 

HSCT in allogeneic recipients from human leukocyte antigen (HLA)-identical sibling donors. 

Not recommended. (See Exclusions.) 

Autologous bone marrow transplantation or HSCT. 

transplants. 38 (See Exclusions.) 

Not recommended in autologous 

Although IVIG is used for immune system modulation, IVIG is not recommended for 

cytomegalovirus (CMV) disease prophylaxis in HSCT recipients. 38 (See Exclusions.) 

7. Human immunodeficiency virus (HIV)-infected infants and children < 13 years of age. HIVinfected 

infants and children are divided into category a (prevention of recurrent bacterial infections) 












and category b (passive immunization for Varicella) below. 

a. For prevention of recurrent bacterial infections in HIV-infected infants and children < 13 

years of age. Approve for 12 months for patients who meet all of the following criteria (i, ii, and 

iii). 

i) IVIG is prescribed by an infectious diseases specialist or an immunologist, AND 

ii) The patient is receiving highly active antiretroviral therapy (HAART) (Note: HAART is a 

combination of three or more anti-HIV drugs from at least two classes taken at the same time), 

AND 

iii) The patient has one of the following (1, 2, or 3) 

1) functional antibody deficiency as demonstrated by recurrent, serious bacterial infections, 

defined as two or more serious bacterial infections, such as bacteremia, meningitis, or 

pneumonia during a 1-year period despite administration of HAART and prophylactic 

antimicrobials (e.g., trimethoprim and sulfamethoxazole [TMP-SMZ]) 43-47 OR 

2) functional antibody deficiency as demonstrated by the absence of detectable antibody 

response against protein and polysaccharide antigens, 46 OR 

3) hypogammaglobulinemia (IgG < 400 mg/dL [4.0 g/L]). 46 

IVIG is no longer recommended for primary prevention of serious bacterial infections in HIVinfected 

children unless hypogammaglobulinemia is present or functional antibody deficiency is 

demonstrated by either poor specific antibody titers or recurrent bacterial infections. 46 












. Passive immunization for Varicella (chickenpox) in HIV-infected infants and children < 13 

years of age. Approve a single dose of IVIG if varicella zoster immune globulin (VariZIG ® ) is 

not available (or cannot be obtained) 47 for patients who meet the following criteria (i, ii, and iii). 

i) IVIG is prescribed by an infectious diseases specialist or an immunologist, AND 

ii) The patient meets one of the following criteria (1, 2, 3, or 4), AND 

1) has no history of varicella infection, OR 

2) has seronegative status for varicella-zoster virus (VZV), OR 

3) has lack of evidence of age appropriate vaccination (child has not received two doses of 

varicella vaccine), OR 

4) the child has been immunized but is moderately to severely immune compromised. 45 

iii)The patient has not received a dose of IVIG within 2 to 3 weeks of exposure to varicella. 45-46 

Children with moderate to severe immune compromise should receive VariZIG or, if not available, 

IVIG within 96 hours after close contact with a person who has chickenpox or shingles. 45 Post 

exposure prophylaxis with acyclovir, VariZIG, or if VariZIG is not available, IVIG should be 

considered for HIV-infected children with moderate-to-severe immune compromise even if they have 

been immunized. Children who have received IVIG within 2 weeks of exposure do not require 

additional passive immunization. Also see, Varicella, postexposure prophylaxis. 

Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and the 

Infectious Diseases Society of America (IDSA) guidelines do not include recommendations for use of 

IVIG in treatment of serious or recurrent bacterial infections. 46 Studies that showed IVIG was 

beneficial for prevention of bacterial infections in HIV-infected children were done before HAART 

was available. 41 HAART that suppresses HIV replication to undetectable levels has decreased the 

incidence of opportunistic infections (Pneumocystis pneumonia [PCP], CMV retinitis, mycobacterium 

avium complex [MAC] infection, toxoplasmosis) dramatically. US Public Health Service (USPHS) 

and IDSA guidelines for preventing opportunistic infections in HIV-infected persons recommend that 

infants and children with hypogammaglobulinemia (IgG < 400 mg/dL) receive IVIG to prevent 

serious bacterial infections. 44 IVIG should also be considered for HIV-infected children who 

have recurrent serious bacterial infections even though such treatment might not provide additional 

benefit to children who are receiving daily TMP-SMZ for PCP prophylaxis. 44-45,48 Also see HIVassociated 

thrombocytopenia, children. 

Gamimune N, a brand of IVIG that has been discontinued, was FDA-approved for pediatric HIV 

infection to decrease the frequency of serious and minor bacterial infections and the frequency of 

hospitalization and to increase the time free of serious bacterial infection. 42 Currently marketed IVIG 

products do not carry this indication. 

8. Adult Still’s disease. Approve for 12 months if the patient has tried a corticosteroid and 

methotrexate and a biologic agent (e.g., etanercept, infliximab, anakinra) or if these therapies are 

contraindicated. An exception can be made for trying a corticosteroid if corticosteroids should be 

avoided (such as in patients with diabetes, advanced osteoporosis, severe infections, psychological 

changes, or prior gastrointestinal bleeding). No controlled trials are available using IVIG. 31,49 Case 

reports indicate IVIG may be effective in some patients who do not respond to nonsteroidal antiinflammatory 

drugs and in the treatment of flares in recent onset of disease. 












9. Autoimmune hemolytic anemia (AIHA). Approve for 12 months in patients with warm-antibody 

AIHA who have tried corticosteroids or had a splenectomy or if these treatments are contraindicated 

(or if corticosteroids should be avoided [such as in patients with diabetes, advanced osteoporosis, 

severe infections, psychological changes, or prior gastrointestinal bleeding]). Evidence does not 












support routine use of IVIG, but IVIG may have a role in patients with warm-type AIHA that does 

not respond to corticosteroids or splenectomy. 38,50 

10. Autoimmune mucocutaneous blistering diseases (pemphigus vulgaris, pemphigus foliaceus, 

bullous pemphigoid, mucous membrane pemphigoid [cicatricial pemphigoid], and 

epidermolysis bullosa acquisita). Approve for 12 months in patients who meet one of the following 

criteria (a, b, or c): 

a) Patient has tried conventional therapy (systemic corticosteroids [e.g., prednisone] AND an 

immunosuppressive agent [e.g., azathioprine, cyclophosphamide, dapsone, methotrexate, 

cyclosporine, mycophenolate mofetil (Cellcept ® )], tacrolimus), 

Exceptions to trying conventional therapy can be made for patients with contraindications to 

treatment with a corticosteroid (or a corticosteroid should be avoided [e.g., diabetes, advanced 

osteoporosis, severe infections, psychological changes, or prior gastrointestinal bleeding]) and an 

immunosuppressive agent (examples differ among the immunosuppressives but may include 

infections, bone marrow suppression) 51 or has had significant adverse effects from conventional 

therapy. 51 

OR 

b) The disease is rapidly progressive, extensive, or debilitating (cannot be controlled with 

conventional therapy), 51-54 OR 

c) The disease is rapidly progressive or debilitating diseases such that there is inadequate time for 

conventional therapy to have rapid enough effect. 

Conventional therapy is started at the same time or before IVIG. Many case reports and uncontrolled 

case series suggest benefit of IVIG in patients with recalcitrant disease or in those with 

contraindications to conventional therapy. 31,52-54 The total duration of treatment with IVIG can be at 

least 2 years or longer. 54 The interval between infusions is increased gradually and prolonged clinical 

remission has been reported with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, and 

mucous membrane pemphigoid [cicatricial pemphigoid]. In a randomized, double-blind, placebocontrolled 

trial, the therapeutic efficacy of single-cycle, high-dose IVIG administered over 5 

consecutive days was assessed in patients (n = 61) with pemphigus vulgaris and pemphigus foliaceus, 

who were relatively refractory to systemic corticosteroids. Time to escape from the protocol (TEP) 

was used as the primary efficacy endpoint; defined as the length of the period until a patient stayed on 

the protocol without any additional treatment. The TEP was significantly longer in patients 

randomized to receive high dose (400 mg) IVIG compared to placebo (P < 0.001). Pemphigus 

activity score was also significantly decreased from baseline in patients who received IVIG compared 

to placebo. 55 

11. Churg-Strauss syndrome (allergic granulomatosis and angiitis). Approve for 12 months in 

patients who have tried corticosteroids and cyclophosphamide. In case series and case reports, IVIG 

has been effective when used in addition to corticosteroids and cyclophosphamide. 29,56-57 

12. CMV interstitial pneumonia in allogeneic bone marrow transplant or HSCT patients. Approve 

for 2 months. For CMV disease, especially CMV pneumonia, therapy consists of IV ganciclovir and 

IVIG in combination. 36,40 Whether adding IVIG adds efficacy is controversial, 58,147 and there is no 












data to support adding IVIG for the treatment of any manifestation of CMV disease other than 

pneumonia. 58 CMV immune globulin (Cytogam ® ) may be preferred instead of IVIG for interstitial 

pneumonia. The Infectious Diseases Working Party of the European Group for Blood and Marrow 

Transplantation (EBMT) recommends the combination of ganciclovir and IVIG for the therapy of 

CMV pneumonia. 58 For other types of CMV disease, the EBMT recommends ganciclovir or 

foscarnet without IVIG. 58 These recommendations are consistent with those from the National 

Comprehensive Cancer Network (NCCN). 36 

CMV prophylaxis and preemptive therapy. (see Exclusions.) 

13. Dermatomyositis and Polymyositis. Approve for 12 months in patients who meet the following 

criteria (a and b). 

a) IVIG is prescribed by or in consultation with a neurologist who is specialized in the treatment of 

neuromuscular diseases or by a rheumatologist, AND 

b) The patient has tried conventional therapy with BOTH a systemic corticosteroid AND an 

immunosuppressant agent (e.g., azathioprine, methotrexate, cyclosporine, cyclophosphamide, 

mycophenolate mofetil), 20,31,59 

Exceptions to trying conventional therapies (systemic corticosteroid and immunosuppressants) can 

be made for patients with contraindications to a corticosteroid (or if a corticosteroid should be 

avoided [e.g., diabetes, advanced osteoporosis, severe infections, psychological changes, or prior 

gastrointestinal bleeding]) and an immunosuppressant agent (examples differ among the 

immunosuppressive agents but may include infections, bone marrow suppression) or the patient 

cannot tolerate adverse effects from corticosteroids or immunosuppressant agents. 

In a double-blind, placebo-controlled crossover trial, patients with treatment resistant 

dermatomyositis who received IVIG for 3 months had significant improvement in muscle strength, 

neuromuscular symptoms, and rash. IVIG may be used in dermatomyositis patients with severe 

active illness for whom other interventions have been unsuccessful or intolerable. IVIG has been 

used to maintain response in dermatomyositis. 59 

IVIG may be considered amongst the treatment options for patients with polymyositis not responding 

to first line immunosuppressive treatment. 60 In uncontrolled series, IVIG has been effective in 

polymyositis. 60 

14. End stage heart failure awaiting transplant, to lower allosensitization (may or may not be on a 

left ventricular assist device [LVAD]) or post-transplant. Approve for 12 months in patients with 

high levels of preformed anti-human leukocyte antigen (HLA) antibodies (high panel peak reactive 

antibody [PRA] levels 

> 20%) who are being managed by a transplant center. In a study in sensitized LVAD recipients who 

were awaiting cardiac transplant, treatment with IVIG reduced serum reactivity to HLA class I 

antigens, decreased the risk of positive cross-match reactions, and shortened the waiting time for 

cardiac transplantation. 61 In another study, in 35 sensitized patients who had orthotopic heart 

transplantation, IVIG was used with plasmapheresis pre-transplant to allow successful cardiac 

transplantation and to improve survival. 62 There were various causes for sensitization in these 

patients. 












15. End stage renal disease (ESRD) awaiting transplant, to lower allosensitization (preparation for 

renal transplant) or post renal transplant to treat rejection. Approve for 12 months in patients 

with high levels of preformed anti-HLA antibodies (high panel PRA levels > 20%) who are being 

managed by a transplant center. IVIG has been used in highly sensitized patients to reduce 

allosensitization, ischemia-reperfusion injuries, and acute rejections episodes in renal and cardiac 

allograft recipients. 63-65 In a double-blind trial in patients with ESRD, IVIG was better than placebo 

in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized 

patients; waiting time for transplant was decreased. 63 

16. End stage lung or liver disease awaiting transplant, to lower allosensitization (preparation for 

lung or liver transplant). Approve for 12 months in patients with high levels of preformed anti- 

HLA antibodies (high panel PRA levels > 20%) who are being managed by a transplant center. (In 

the professional opinion of specialist physicians reviewing the data, we have adopted this criterion.) 

IVIG has been used in highly sensitized patients to reduce allosensitization, ischemia-reperfusion 

injuries, and acute rejections episodes in renal and cardiac allograft recipients. 63 Limited information 

is available in lung transplant patients. 

17. Epilepsy, pediatric intractable. Approve for 12 months of therapy in children with seizures that are 

refractory to at least two drugs for seizures and a corticosteroid. Exceptions are not recommended for 

West syndrome (infantile spasms). Exceptions are not recommended in adults. Evidence does not 

support routine use of IVIG but IVIG may have a role in certain syndromes (e.g., Lennox-Gastaut 

syndrome [LGS], Rasmussen syndrome, Landau-Kleffner syndrome, mixed seizures of early onset 

with immune deficiency [IgA or IgG subclass deficiency]) 22,31,146 as a last resort, in patients who may 

be candidates for surgical resection. 22,60,143 Only one randomized controlled trial is available in a 

small (n = 61) number of patients (n = 4 with LGS, n = 49 with partial epilepsy, and n = 8 with 

generalized epilepsy) . 154,144 In this study, there was no statistically significant difference between 

IVIG and placebo for the primary endpoint (a 50% or greater reduction in seizure frequency). All 

patients were treated with AEDs [not specified]. 154 Additional controlled trials are needed on welldefined 

populations. The Canadian expert panel of neurologists does not recommend IVIG for 

pediatric intractable epilepsy. 20 The European Federation of Neurological Societies (EFNS) 

recognizes IVIG may have a favorable effect in childhood refractory epilepsy (good practice point). 60 

IVIG is considered a last resort effort in the treatment of intractable pediatric epilepsy. 155 

18. Evans syndrome. Refer to ITP or to warm AIHA criteria depending on which symptoms are 

predominant. Patients are initially treated as having either ITP or warm AIHA depending on 

presentation and the diagnosis is often made retrospectively. 28 

19. Guillain-Barré syndrome (GBS). Approve for 12 months when IVIG is prescribed by a neurologist 

or specialist with experience in diagnosing and treating patients with GBS, in patients who meet 

following criteria a or b. 

a) IVIG is initiated within 2 weeks and no longer than 4 weeks of onset of neuropathic symptoms 

(weakness, inability to stand or walk without assistance, respiratory or bulbar weakness; patients 

are hospitalized), OR 

b) The patient has had a relapse, but had an initial response to IVIG. 












Treatment with IVIG after 4 weeks from onset is indicated since some patients may relapse and the 

relapse may be severe enough to warrant a repeat course of IVIG. 20-21 IVIG is recommended as an 

equivalent alternative to plasma exchange in children and adults. 20,22 IVIG is the treatment of choice, 

since plasma exchange (which is equivalent to treatment with IVIG) is not always readily 

available. 22,66 In controlled trials, IVIG was as effective or more effective than plasma exchange in 

improving strength, time to unaided walking, or discontinuation of ventilation. 20 The American 

Academy of Neurology (AAN) recommends IVIG in patients who require aid to walk within 2 or 4 

weeks from the onset of neuropathic symptoms. 66 A report of the Therapeutics and Technology 

Assessment Subcommittee of the AAN note there is insufficient evidence to demonstrate the 

superiority of one treatment (IVIG or plasmapheresis) over the other. 67 The effects of IVIG and 

plasma exchange are equivalent in hastening recovery, and multiple complications were less frequent 

with IVIG than with plasma exchange. In a retrospective review of 92 patients with Miller Fisher 

syndrome (a variant of GBS), the authors concluded that IVIG and plasmapheresis did not seem to 

have influenced patients’ outcomes. 60 

The effect of IVIG in GBS has only been investigated in randomized controlled trials in patients who 

are unable to walk at nadir (i.e., severely affected patients), not in mildly affected patients who are 

able to walk unaided at nadir. 68 IVIG is not indicated or proven to be effective in mildly 

affected GBS patients. The EFNS task force on the use of IVIG in the treatment of neurological 

diseases states that no recommendation can be made as to whether mildly affected GBS patients or 

patients with Miller Fisher syndrome (a variant of GBS) should be treated with IVIG, because this 

has not been well studied. 60 Another consensus statement from the American Association of 

Neuromuscular and Electrodiagnositc Medicine (AANEM) on the use of IVIG in neuromuscular 

conditions notes, on the basis of a single retrospective analysis and case reports, it is difficult to 

clearly define the role of IVIG in treating Miller Fischer syndrome. 69 Further, the literature 

suggests that best medical management may suffice for many patients. 

20. HIV-associated thrombocytopenia, adults. Approve for 1 month in patients who meet the 

following criteria a and b. 

a) IVIG is prescribed by or in consultation with an infectious diseases specialist 15 or a physician 

who specializes in the treatment of HIV, and 

b) The patient is receiving HAART for their HIV, exceptions can be made for patients with 

clinically significant bleeding complications. 15 

Effective viral suppression using antiretroviral therapy improves HIV-associated cytopenias, 

including thrombocytopenia. 15 Treatment of secondary ITP (HIV-associated) with short-term 

corticosteroid increases the platelet count in a similar manner as in non-HIV infected individuals and 

does not appear to be associated with AEs. 15 IVIG and Rh 0 [D] immune globulin have similarly 

been reported to increase the platelet count with one small randomized crossover study 

demonstrating higher peak platelet counts and longer duration of response with Rh 0 [D] 

immune globulin. 70 

Splenectomy is an effective option for patients failing to respond to corticosteroids or IVIG. 15 The 

risk of HIV progression occurring with other immunosuppressive agents and the newer therapies 

remains undefined. 

Evidence for IVIG is mostly based on case reports and cohort studies and most studies predate the 












current standard practices for treatment of HIV. 31,70,71 In one small study, nine Rh 0 [D] positive 

nonsplenectomized adults and children with HIV infection with platelet counts

treatment of neuromuscular diseases, AND 

b) The patient (non-paraneoplastic diagnosis) has tried a corticosteroid, azathioprine or another 

immonosupressive agent (e.g., cyclosporine, mycophenolate mofetil) or has a contraindication to 

BOTH a corticosteroid (or a corticosteroid should be avoided [e.g., diabetes, advanced 

osteoporosis, severe infections, psychological changes, or prior gastrointestinal bleeding]) and 

azathioprine (e.g., bone marrow suppression). 20 

Patients with paraneoplastic LEMS do not have to try any of these other therapies. 

In a placebo-controlled crossover trial, a single dose of IVIG produced significant improvement in 

muscle strength and reduced serum calcium channel antibody titers. There have been only five 

randomized controlled trials of treatment for LEMS; four with 3,4 diaminopyridine and one with 

IVIG. 75 Plasma exchange, steroids, and immunosuppressive agents have not been studied in 

randomized controlled trials. 75 IVIG may be useful as adjunctive therapy in difficult to treat 

patients. 20,31 

25. Leukemia, acute lymphoblastic. Approve for 12 months in children with hypogammaglobulinemia 

and either a history of severe invasive infection or with recurrent sinopulmonary infections. 

According to a Canadian expert panel of hematologists, IVIG is not recommended for routine use in 

children with hematologic malignancies with or without hypogammaglobulinemia. 28 Two exceptions 

are recommended by the expert panel. In children with hematologic malignancies with acquired 

hypogammaglobulinemias and either a history of severe invasive infection or recurrent 

sinopulmonary infections, IVIG may be an option. The second exception is children registered in 

clinical trials that include IVIG in the protocol for treatment of hematologic malignancies (and/or 

hematopoietic stem cell transplantation) even without severe or recurrent infection. 

26. Marburg disease (a variant of multiple sclerosis). Approve for 12 months. The Canadian panel of 

expert neurologists agreed IVIG may be considered among the treatment options considering the lifethreatening 

nature of this condition. 20 

27. Multifocal motor neuropathy (MMN) (treatment). Approve for 12 months, when IVIG is 

prescribed by or in consultation with a neurologist who is specialized or experienced in the treatment 

of neuromuscular diseases. In several placebo-controlled trials, IVIG improved muscle strength and 

neurological disability scores. 20-22,31,76 IVIG is the only proven effective treatment (plasma exchange 

and corticosteroids are not effective) and is considered first-line treatment. IVIG is beneficial in 

maintenance treatment but the disease continues to progress over many years. Some patients with 

MMN do not respond to IVIG and should not be retreated with IVIG. 20 

28. Multiple myeloma. Approve for 12 months in patients with stable (plateau phase) disease (> 3 

months from diagnosis) and who have severe recurrent bacterial infections. These patients usually 

have hypogammaglobulinemia and IVIG is used as prophylaxis. 31,34 In a randomized placebocontrolled 

trial, prophylactic use of IVIG reduced serious and life-threatening infections in 

immunosuppressed patients with multiple myeloma. 28 According to a Canadian expert panel of 

hematologists, IVIG is recommended for infection prophylaxis in these adults who have either a 

recent episode of a life-threatening infection thought to be caused by low levels of polyclonal 












immunoglobulins or recurrent episodes of clinically significant infections (e.g., pneumonia) that are 

caused by low levels of polyclonal immunoglobulins. 28 IVIG is an option for acute life-threatening 

infections in these patients. This panel of hematologists recommended re-evaluation every 4 to 6 

months when used for prophylaxis but there was no consensus on specific criteria to use for duration 

of treatment with IVIG. NCCN guidelines note that IVIG prophylaxis should be considered in the 

setting of recurrent, life-threatening infections in patients with multiple myeloma. 77 

29. Multiple sclerosis, acute severe exacerbation. Approve 1 course of IVIG treatment (up to 5 days) 

in patients who meet the following criteria (a and b). 

a) IVIG is prescribed by an MS specialist, AND 

b) The patient has not responded to or has had a significant adverse reaction from therapy with oral or 

IV corticosteroids (e.g., methylprednisolone sodium succinate [Solu-Medrol ® ]), plasma exchange, 

or adrenocorticotropic hormone (ACTH, H.P ®. Acthar gel) and is continuing to deteriorate. In the 

professional opinion of a specialist physician, we have adopted this criterion. 

Exceptions to trying a corticosteroid or ACTH can be made in patients who have had severe 

reactions to these medications. Exceptions to trying a corticosteroid can be made if the patient has 

a contraindication to treatment with a corticosteroid or if a corticosteroid should be avoided (e.g., 

diabetes, advanced osteoporosis, severe infections, psychological changes, or prior gastrointestinal 

bleeding). Some patients may not be candidates for plasma exchange. 

31. Multiple Sclerosis, post-partum to prevent relapses. Approve IVIG for 6 months for women in the 

post partum period who meet the following criteria a and b. 

a) IVIG is prescribed by an MS specialist, AND 

b) the patient is not currently receiving therapy with disease modifying treatments ([DMT]; e.g., 

interferon beta-1a injection, intramuscular [Avonex ], interferon beta-1a injection, subcutaneous 

[Rebif ], interferon beta-1b injection [Betaseron , Extavia ], glatiramer acetate injection 

[Copaxone ], fingolimod capsules [Gilenya ], natalizumab injection [Tysabri ® ], mitoxantrone 

injection [Novantrone ® ]) to prevent relapses of MS. 

None of the DMTs have been approved for use in women who are nursing; IVIG is safe for use in 

nursing mothers. 78 

It has been documented that there is an increase in relapse during the initial three months after birth 

which may continue for up to 6 months (in patients not receiving therapy). 79-81 In a randomized, 

confirmatory, multicenter, double-blinded-placebo-period (Days 1 through 3 post-partum) trial, 

women with clinically confirmed relapsing remitting MS and at least one relapse within the 2 years 

prior to pregnancy received treatment with IVIG (IVIG 150 mg/kg Day 1 post-partum followed by 

placebo injections on Days 2 and 3 [Group I], or IVIG 900 mg/kg over a 3 day period [Group II]). 81 

Initial IVIG treatment was followed by an open phase in which both groups received five doses of 

IVIG (150 mg/kg) at monthly (every 4 week) intervals. Prior to pregnancy the number of relapses per 

women per year in the 2 years prior to pregnancy was 1.0 ± 0.7 and 1.0 ± 0.6 in Group I and Group II, 

respectively. In Groups I and II, 75.6% and 81.5% of patients respectively, remained relapse-free 

during the 3 month post-partum period (primary efficacy endpoint). The difference between the 

groups (6%) at 3 months was not statistically significant (P = 0.2353). Numerically more patients in 












Group II remained relapse-free compared with Group I between Months 4 to 6 (82.3% vs. 70.9%) and 

within the total observation period of 6 months (69.1% vs. 57.5%); none of these differences reached 

statistical significance between groups. 

Steroids may be used to treat acute relapses during pregnancy and in the post-partum period in 

nursing women (see Multiple Sclerosis, acute severe exacerbation). 

IVIG is not recommended for maintenance treatment to prevent relapses (see Exclusions). 

31. Myasthenia gravis. Approve IVIG for 1 course of treatment (up to 5 days) in patients who meet the 

following criteria (a and b). Note: IVIG is used for severe exacerbations and as a short-term 

measure. Some patients may require additional courses of therapy, but IVIG is not appropriate for 

maintenance therapy in myasthenia gravis. 

a) IVIG is prescribed by or in consultation with a neurologist who is specialized or experienced in the 

treatment of neuromuscular diseases, 82 AND 

b) The patient meets one of the following criteria (i, ii, iii, or iv). 

i) The patient has an exacerbation of myasthenia gravis 20 , OR 

ii) The patient requires stabilization of myasthenia gravis before surgery 19 , OR 

iii)The patient has been started on an immunosuppressive drug (e.g., azathioprine, cyclosporine, 

cyclophosphamide, mycophenolate mofetil) 31 and is waiting for full effect, OR 

iv) The patient has responded to a previous course of IVIG therapy, but weakens (relapses) and has 

no response to other medications. (In the professional opinion of a specialist physician 

reviewing the data, we have adopted this criterion) 

Mild to moderate myasthenia gravis can be successfully managed with symptomatic and 

immunosuppressive medications. 20 IVIG should be reserved for the treatment of severe exacerbations 

or myasthenia crises. Patients with myasthenia gravis crisis are hospitalized. 68 Crisis is defined by 

respiratory failure necessitating ventilation resulting from myasthenic weakness. 












IVIG is used in clinical practice as short-term therapy until more effective long-term 

immunosuppression can be achieved for patients with severe myasthenic exacerbations or in 

preparation for surgery. 20 In one randomized study, IVIG for either 3 or 5 days was similar in 

efficacy to plasma exchange in patients with severe exacerbations of myasthenia gravis. 146 Evidence 

does not support routine use of IVIG. IVIG may be considered in patients with severe myasthenia 

gravis to treat acute severe decompensation when other treatments have been unsuccessful or are 

contraindicated. 20-22,146 Maintenance therapy with IVIG in chronic myasthenia gravis is not 

recommended. 20 

In a randomized, double-blind, placebo-controlled trial in 51 patients (not hospitalized) with 

myasthenia gravis and worsening weakness, IVIG-treated patients had a clinically meaningful 

improvement in the Quantitative Myasthenia Gravis (QMG) Score for Disease Severity at Day 14 and 

Day 28. 82 The greatest improvement occurred in patients with more severe disease (QMG Score for 

Disease Severity > 10.5). 

32. Neutropenia, immune-mediated (autoimmune). Approve for one month of therapy if patient has 

tried two other therapies (a corticosteroid, antibiotics, filgrastim [Neupogen ® ] or pegfilgrastim 

[Neulasta ® ]). Evidence does not support routine use of IVIG, but IVIG may have a role in severe 

illness that does not respond to other modalities or when the latter are contraindicated. 22,28,21,83 

Symptomatic treatment with antibiotics is usually adequate, but for severe infections due to 

neutropenia or for surgical preparation, filgrastim, corticosteroids, and IVIG have been effective. 83 

Primary autoimmune neutropenia is usually benign and self-limiting. Secondary autoimmune 

neutropenia is often due to an underlying malignancy. 28 Limited information is available on the use 

of IVIG. 

33. Opsoclonus myoclonus (infantile polymyoclonia, acute cerebellar encephalopathy, 

oculocerebellomyoclonic syndrome, dancing eyes-dancing feet syndrome). Approve for 12 

months. Symptoms have improved with ACTH, corticosteroids, IVIG or plasma exchange. 31,84 

Corticosteroids are usually slowly tapered. Both corticosteroids and ACTH appear to be effective in 

the majority of patients for improving acute symptoms of opsoclonus myoclonus syndrome). 84 There 

are no controlled trials (rare condition). ACTH is usually the initial therapy but is not used long-term 

due to adverse effects. 31 IVIG is usually used before plasma exchange due to the difficulty of 

obtaining venous access for plasma exchange in children. Maintenance therapy is usually required. 

In case reports treatment with IVIG has continued for about 1 year. A clinical trial in which patients 

neuroblastoma associated opsoclonus-myoclonus-ataxia syndrome are treated with prednisolone and 

cyclphosphamide with or without IVIG is ongoing to assess the role of IVIG in the treatment of 

opsoclonus-myoclonus syndrome. 85 Objective evidence of clinical improvement should be required 

for sustained use of IVIG. 20 

Pemphigus. See autoimmune mucocutaneous blistering diseases. 

34. Pure red blood cell aplasia (PRCA) secondary to chronic (persistent) parvovirus B19 infection. 

Approve for 3 months in patients who meet the following criteria (a, b, and c). 

a) IVIG is prescribed by or in consultation with an infectious diseases specialist, immunologist, 












hematologist, or transplant specialist, AND 

b) The patient has a chronic immunodeficient condition (e.g., patients with HIV infection, solid 

organ transplants [e.g., renal, liver], chemotherapy for hematologic malignancy), 31,86 AND 

c) The patient has clinically significant anemia as determined by the prescribing physician OR the 

patient is transfusion dependent. 31 

In immunosuppressed patients lacking neutralizing antibodies, IVIG has been useful for the treatment 

of persistent B19 infection. 87 IVIG has been used to treat severe anemia secondary to chronic B19 

infection in the context of solid-organ transplantation, HIV infection, or primary antibody 

deficiency. 87 Three to five days of IVIG induces an increase in reticulocyte count with an 

accompanied rise in the hemoglobin level, and is often curative in that B19 is cleared from the 

body. 31,87 Persistent B19 infection in apparently immunocompetent individuals who possess 

neutralizing antibodies does not respond well to IVIG. 87 In immunocompetent children, adolescents 

and adults, parvovirus B19 is self limiting and does not require treatment with IVIG. 86 Pure red cell 

aplasia and the underlying persistent parvovirus B19 infection may be terminated rapidly by 

discontinuing immunosuppressive therapy or by instituting antiretroviral therapy in patients with 

AIDS. Immune globulin has been curative in patients with congenital immunodeficiency, but in 

patients with AIDS, parvovirus often persists at lower levels; relapses of anemia may require repeated 

administration of immunoglobulin. Maintenance therapy has been used in patients who relapse. 31 

35. Pure red cell aplasia (PRCA), immunologic subtype. Approve for 12 months if patient has tried 

prednisone and either cyclophosphamide or cyclosporine. 28 Based on case reports about 50% of 

patients benefit with IVIG therapy. The immunologic subtype mechanism may be humoral or cellular 

and can be caused by tumors, certain drugs (e.g., azathioprine, carbamazepine), connective tissue 

disorders, and incompatible bone marrow transplant. 

Pure red cell aplasia due to myelodysplastic syndrome. See Exclusions 

36. Pyoderma gangrenosum. Approve for 6 months if patient has tried two other systemic therapies 

(e.g., intralesional injections of corticosteroids or cyclosporine [for localized pyoderma 

gangrenosum]; systemic corticosteroids, immunosuppressants such as azathioprine/6-mercaptopurine, 

mycophenolate mofetil, cyclosporine, cyclophosphamide, chlorambucil; or dapsone, or infliximab). 

IVIG has been effective in a few cases where other therapies had failed. 88-90 

37. Scleromyxedema. Approve for 12 months if patient has tried one other therapy (e.g., corticosteroids, 

thalidomide, cytotoxic agent [e.g., cyclophosphamide, melphalan], psoralen plus UVA [PUVA], 

extracorporeal photopheresis, retinoids, plasmapheresis, interferon-α, cyclosporine). In case reports, 

patients who received IVIG had improvement in cutaneous and systemic manifestations of the 

disease. 88,91-94,, IVIG was continued to maintain remission. This is a rare disorder and no randomized 

controlled studies are available for any treatment. 

38. Small bowel transplant to lower allosensitization (preparation for small bowel transplant) or 

post small bowel transplant to treat rejection. Approve for 12 months in patients with high levels 

of preformed anti-HLA antibodies (high panel PRA levels > 20%) who are being managed by a 

transplant center. Very limited information is available. In a pilot study, highly sensitized patients (n 

= 6) with intestinal failure (short gut syndrome) who were awaiting isolated small bowel transplant 












eceived IVIG and immunosuppressive therapy pre-transplant. 95 Four of the six patients had PRA 

reduction and received intestinal transplantation. Patients continued on IVIG post-transplant at Days 

1, 7 and 21. The waiting time for transplant and mortality was similar to non-sensitized patients. 

39. Stiff-person syndrome (Moersch-Woltman syndrome). Approve for 12 months if IVIG is 

prescribed by a neurologist AND the patient has tried a benzodiazepine (e.g., diazepam) or baclofen. 

Exceptions can be made for patients who have contraindications to both a benzodiazepine AND 

baclofen. In a small double-blind, placebo-controlled crossover trial, IVIG decreased stiffness scores 

significantly and decreased heightened sensitivity scores. 20,60,82,96 

40. Systemic lupus erythematosus (SLE). Approve for 12 months if patient has tried azathioprine, 

cyclophosphamide, methotrexate, mycophenolate mofetil, rituximab or a corticosteroid. IVIG has 

been used for severe of unstable thrombocytopenia that has been refractory to corticosteroids. 97-98 

There is no role for IVIG as a first-line treatment in patients with SLE, but it may be an alternative 

treatment in difficult-to-treat cases. 99 Well-controlled trials are needed to determine which subsets of 

patients will benefit the most from IVIG. 22,99 The role of IVIG in non-hematologic manifestations of 

lupus is less clear. It has been used effectively to treat lupus nephritis. 97-100 First line therapy for 

active SLE is corticosteroids and antimalarial drugs (hydroxychloroquine). Second-line drugs are 

azathioprine, methotrexate, cyclophosphamide, or rituximab. 

41. Thrombocytopenia refractory to platelet transfusions. Approve for 12 months. Evidence does 

not support routine use of IVIG but IVIG may have a role in patients with severe thrombocytopenia 

of documented immune basis for whom other modalities are unsuccessful or contraindicated. 22 

42. Thrombocytopenia, fetal alloimmune. Approve maternal antenatal infusion of IVIG for 6 

months. 22,28,101 Antenatal therapy with IVIG is effective in increasing fetal platelet counts in neonatal 

alloimmune thrombocytopenia. 101-102 IVIG reduces the risk of intracranial hemorrhage and increases 

the fetal platelet count. In newborns with fetal/neonatal alloimmune thrombocytopenia, first-line 

therapy is antigen-negative compatible platelets and IVIG is adjunctive. 28 

Transplantation. See End stage heart failure, renal disease, lung or liver disease. See Small bowel 

transplant. 

43. Urticaria, chronic autoimmune. Approve for 6 months of therapy in patients with chronic 

autoimmune urticaria who have tried all of the following medications: 

a) a first generation antihistamine (e.g., chlorpheniramine, diphenhydramine, hydroxyzine), 

b) a second generation antihistamine (e.g., loratadine, cetirizine, fexofenadine, desloratadine 

[Clarinex ® ]), 

c) an H2-receptor antagonist (e.g., ranitidine, cimetidine, doxepine), 

d) a corticosteroid and 

e) at least one of the following: cyclosporine, montelukast (Singulair ). 

After initial 6 months approve for another 6 months if patient is improved. Further authorization after 

12 months total is not recommended. 












One cycle (5 days) of IVIG was beneficial in nine of ten patients with chronic autoimmune urticaria 

who had poor responses to antihistamines with three of the patients having prolonged remission. 103 In 

a single center open-label study, 29 patients with autoimmune urticaria received 0.15 mg/kg of IVIG 

every 4 weeks for a minimum of 6 months and a maximum of 51 months. 104 There was clinical 

improvement in 26 patients with reduced urticaria or angioedema and decreased use of 

antihistamines. The onset of clinical benefit ranged from 1 to 13 months (mean 4.5 months) and was 

gradual and progressive. Nineteen of 26 patients had complete remission of symptoms. Efficacy 

persisted for at least 12 months after treatment. In other cases IVIG was not effective. 105 IVIG also 

induced remission or improved symptoms in five of eight patients with severe unremitting delayed 

pressure urticaria (some with autoimmune urticaria) who had not responded to other therapies or were 

controlled only with systemic corticosteroids. 106 None of these reports were controlled trials. 

Practice guidelines state that alternative regimens may be necessary in refractory forms of chronic 

urticaria and mention IVIG in this list of alternatives. 107-108 












44. Uveitis, noninfectious. Approve for 6 months in patients who have tried corticosteroids and at least 

one immunosuppressive drug (methotrexate, cyclosporine, mycophenolate mofetil, azathioprine). For 

acute uveitis, corticosteroids are used. 109 For chronic uveitis, long term immunosuppressive therapy, 

often with two or three drugs, is used. There are no controlled trials using IVIG to treat uveitis, and 

IVIG is considered an alternative when almost all other therapies have failed. 109-110 In one report 

IVIG for 6 months was effective in increasing visual acuity in patients with birdshot 

retinochoroidopathy (an autoimmune posterior uveitis). 111 

After 6 months approve for another 6 months if there is improvement and/or reduction in dose of 

corticosteroid and/or immunosuppressive drug. Further authorization after 12 months total is not 

recommended. 

45. Varicella (chickenpox), postexposure prophylaxis (passive immunization). Approve a single dose 

of IVIG in the following patients (a, b, c, d, or e) who are without evidence of immunity to varicella 

(i.e., with history of disease or age-appropriate vaccination) and if VariZIG is not available or cannot 

be obtained): 

a) Immunocompromised patients, OR 

b) Neonates whose mothers have signs and symptoms of varicella around the time of delivery (i.e., 5 

days before to 2 days after) (these babies are probably hospitalized), OR 

c) Premature infants born at ≥ 28 weeks of gestation who are exposed during the neonatal period 

and whose mothers do not have evidence of immunity, OR 

d) Premature infants born at < 28 weeks gestation or who weigh ≤ 1,000 g at birth and were exposed 

during the neonatal period, regardless of maternal history of varicella disease or vaccination OR 

e) Pregnant women. 

VariZIG is indicated for postexposure prophylaxis in these patients and is given as soon as possible 

after exposure and as late as 96 hours after exposure. 112 The patient groups listed are recommended 

by the Advisory Committee on Immunization Practices (ACIP). In situations where administration of 

VariZIG does not appear possible within 96 hours of exposure, IVIG is considered an alternative and 

should be given within 96 hours of exposure. The dose is 400 mg/kg given once. For pregnant 

women who cannot receive VariZIG, clinicians can choose either IVIG or closely monitor the women 

for signs or symptoms of varicella and institute acyclovir therapy if illness occurs. 

46. Vasculitic syndromes, systemic (Wegener’s granulomatosis or microscopic polyangiitis). 

Approve for 12 months in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated 

systemic vasculitis (Wegener’s granulomatosis or microscopic polyangiitis) if patient has tried a 

corticosteroid and either cyclophosphamide or azathioprine. Evidence does not support routine use of 

IVIG but IVIG may be used in patients with severe active illness for whom other interventions have 

been unsuccessful or intolerable. 29 In a double-blind placebo controlled trial in 34 patients, IVIG for 

5 days was effective in reducing disease activity in patients with ANCA-associated systemic 

vasculitis (Wegener’s granulomatosis, microscopic polyangiitis) who were refractory to conventional 

therapy. 29,113 The effect lasted for 3 months. In a prospective, open-label study 22 patients with 

systemic vasculitides with relapses during therapy with corticosteroids and/or immunosuppressants, 

were given IVIG for 4 days every month for 6 months. 114 IVIG was effective in inducing complete 












emission in 16 of 22 patients at Month 6 and in 13 of 22 patients at Month 9. ANCA is a serological 

marker for disease activity in patients with ANCA+ systemic vasculitis. In one report in patients with 

severe IgA nephropathy, proteinuria, hematuria and renal function improved with IVIG therapy. 31 












Minimal information is available on the effect of IVIG on glomerulonephritis in patients with ANCAassociated 

systemic vasculitis. 29 

Churg-Strauss syndrome and Kawasaki disease are also systemic vasculitic diseases. See other 

applicable criteria (above) for these diseases. 

47. Other Indications. IVIG has been used in many conditions when multiple other therapies have failed 

or are not tolerated. Indications not addressed in this policy will be reviewed by a pharmacist and/or 

physician and coverage will be determined on a case-by-case basis. 

EXCLUSIONS 

Coverage of IVIG is not recommended in the following circumstances: 

1. Adrenoleukodystrophy. Evidence does not support IVIG use. 20,31 Only one small study(n = 12) is 

available; IVIG did not arrest disease progression. 115 

2. Alzheimer’s disease (AD). Further studies are needed. 116-117 A small (n = 8) study originally 

designed as an open label, dose finding, Phase I trial of IVIG in patients with mild AD was extended 

due to unexpectedly positive therapeutic response at 6 months. 118 IVIG was added to stable (3 

months) doses of cholinesterase inhibitor and/or memantine for 6 months, discontinued for 3 months, 

and resumed for 9 months (open-label extension). The primary goal of the trial was to evaluate the 

safety of repeated IVIG infusions in elderly AD patients and to examine the anti-amyloid beta levels 

in blood and CSF as a function of IVIG dose. The study was not designed or powered to fully 

evaluate changes in cognition associated with IVIG treatment; the mini-mental state exam (MMSE) 

was administered throughout the trial to identify any decline in cognitive function. Infusions were 

well tolerated, and anti-amyloid beta antibodies in serum increased in a dose dependent manner. 

Plasma amyloid beta levels increased following each IVIG infusion and CSF amyloid beta decreased 

significantly at 6 months, returned to baseline after washout and decreased again after IVIG was readministered 

for 9 months. MMSE increased on average 2.5 points after the initial 6 months of IVIG 

treatment, returned to baseline during washout, and remained stable during subsequent IVIG 

treatment. The authors concluded that although the results are promising, the findings should not be 

taken as sufficient justification to use IVIG to treat AD patients at this time. A Phase II study has 

been completed; however full results are not published. 119-120 A large retrospective case-control 

analysis found a significant association between IVIG use and Alzheimer’s disease diagnosis. 121 

Patients who received IVIG (mainly for cancers) were less likely to be diagnosed with AD (or 

Alzheimer’s related diseases) than those who did not receive IVIG. Large placebo-controlled trials 

with a longer observation period are needed to establish efficacy, determine the optimal dosing 

regimen, and to confirm the safety of IVIG in the general AD population. 

3. Amyotrophic lateral sclerosis. There is insufficient evidence to recommend IVIG. 20,122-123 Only 

case series are available; no improvement in muscle strength was observed. 122-123 

4. Anemia, aplastic. Evidence does not support IVIG use. 28,31 












5. Anemia, Diamond-Blackfan. Evidence does not support IVIG use. 31 

6. Asthma. Evidence does not support IVIG use. 124-125 Data showing the beneficial effects of IVIG are 

limited. 22,124-125 Further randomized controlled trials are needed in carefully defined groups with 

persistent requirements for high doses of systemic corticosteroids. Uncontrolled studies suggest 

efficacy, but two of three randomized controlled trials showed no significant effect. Some patients 

with hypogammaglobulinemia and recurrent infections also may have asthma and can be evaluated by 

a pharmacist and/or a physician on a case-by-case basis to determine a coverage recommendation for 

the client. 

7. Atopic dermatitis. Evidence does not support IVIG use. IVIG has been reported to be effective in 

severe therapy-resistant atopic dermatitis. 126-131 Most guidelines for the treatment of atopic dermatitis 

do not list IVIG as a treatment. Guidelines from the American Academy of Dermatology state that 

data about the efficacy of IVIG for atopic dermatitis is conflicting and definitive conclusions about its 

role in the treatment of atopic dermatitis cannot be made. 132 Double-blind, placebo-controlled trials 

that are at least 4 months long are needed. 

8. Autism. Evidence does not support IVIG use. 20,31 In case series, IVIG has not demonstrated 

consistent or efficacy in the majority of patients. 20 

9. Autologous bone marrow transplantation or HSCT. Evidence does not support use. 38,133 Routine 

use of IVIG among autologous recipients > 100 days after transplantation is not recommended in the 

absence of severe hypogammaglobulinemia (i.e., IgG levels < 500 mg/dL) as a means of preventing 

bacterial infections. 38,133 IVIG should not be routinely administered to HCT recipients for 

prophylaxis of bacterial infection within the first 100 days after transplantation. For patients with 

severe hypogammaglobulinemia (i.e., IgG < 500 mg/dL), IVIG prophylaxis may be considered. 38 

10. Behcet’s syndrome, ocular manifestations. Evidence does not support IVIG use. There is one 

uncontrolled case series with IVIG. 134 IVIG was effective in controlling the acute ocular 

inflammation in patients with Behcet’s syndrome who were refractory to corticosteroids and 

cyclosporine. 134 A controlled trial is needed. 

11. BK virus associated nephropathy (BKVAN) in kidney transplant patient. Limited information is 

available. 135-136 Standard treatment is to reduce the dose of immunosuppressive therapy and therapy 

with cidofovir (Vistide ® ) or leflunomide. 137 In a report from one center, eight patients with BKVAN 

were treated with IVIG (and reduction of immunosuppressive therapy); 88% of patients still had 

functioning allografts after a mean of 15 months. 136 Prospective randomized, multi-center trials are 

needed to validate these results. 

12. Chronic fatigue syndrome. Evidence does not support IVIG use. 138 A randomized, placebocontrolled 

trial did not find benefits in quality of life measures nor the Profile of Mood States 

(POMS) for IVIG. 138 Although scores were improved in IVIG and placebo treatment groups, no 

significant between group difference was demonstrated. 

13. Crohn’s disease. There is insufficient evidence to recommend IVIG. In a single center case 












collection report, 19 patients with acute Crohn’s disease (Crohn’s Disease Activity Index [CDAI] 

284.1 ± 149.8) who were resistant to steroids received IVIG daily for 7 to 10 days. 139 Four weeks 

after completing therapy, 14 patients were in clinical remission (CDAI < 150). Spontaneous 

remissions cannot be excluded. Prospective, randomized, placebo-controlled trials are needed to 

determine if IVIG has role in the treatment of Crohn’s disease. 

14. Cystic fibrosis. Evidence does not support IVIG use. 140 Some of these patients may be 

hypogammaglobulinemic and if so will be evaluated by a pharmacist and/or a physician on a case-bycase 

basis to determine a coverage recommendation for the client. 












15. CMV disease prophylaxis in bone marrow transplant or HSCT recipients. IVIG is not 

recommended. 38-39,58 IVIG has been used in the past for CMV prophylaxis, but CMV prophylaxis is 

currently based on using seronegative blood in seronegative recipients, screening for CMV 

antigenemia, and prophylaxis with ganciclovir in some patients. 31,39 However, IVIG is recommended 

for other indications in these patients. See Other Uses with Supportive Evidence. 

16. CMV infection, that is, preemptive therapy for CMV infection or treatment of CMV disease, in 

allogeneic bone marrow transplant or HSCT patients. IVIG is not recommended. Preemptive 

therapy is defined as receiving therapy when there is evidence of active, but asymptomatic, CMV 

infection and is based on tests that rapidly detect CMV viremia or antigenemia. 38,58 Preemptive 

therapy is used in most cases instead of prophylaxis for CMV management. First-line preemptive 

therapy for CMV infection is ganciclovir or foscarnet. 58 Although most studies using IVIG for 

preemptive therapy were randomized, the patient populations were heterogeneous, the IVIG dose 

varied, most but not all used ganciclovir, and they were not adequately controlled. 58 IVIG 

monotherapy does not appear to be effective for preemptive therapy. Current CDC, IDSA, and the 

American Society of Blood and Marrow Transplantation (ASBMT) guidelines do not include 

recommendations for use of IVIG in preemptive therapy of CMV infections. 31,39 

17. Diabetes mellitus. Evidence does not support IVIG use. 141-142 Antibodies against islet cell antigens 

are implicated in the autoimmune pathogenesis of type 1 diabetes mellitus. 22 In a 2-year randomized 

controlled trial, IVIG was given every 2 months to children and adults with type 1 diabetes. 141 No 

beneficial effect was shown with IVIG compared to control and the authors concluded that IVIG 

therapy is unlikely to be a viable option for immunotherapy. 

18. GVHD, acute (within first 100 days after transplantation). IVIG is not recommended unless the 

patient has severe hypogammaglobulinemia. 38-39 Current recommendations do not include using 

IVIG for this indication unless the patient has severe hypogammaglobulinemia defined as IgG < 500 

mg/dL. 38 IVIG is recommended in patients with severe hypogammaglobulinemia after 

transplantation to prevent bacterial infection and acute GVHD. (See Allogeneic bone marrow 

transplantation above under Other Uses with Supportive Evidence.) 

19. GVHD, chronic, prevention. IVIG is not recommended unless the patient has severe 

hypogammaglobulinemia. In the absence of severe hypogammaglobulinemia (i.e., IgG levels < 400 

mg/dL, which might be associated with bacteremia or recurrent sinopulmonary infections), routine 

monthly IVIG administration to HCST recipients > 100 days after allogeneic or autologous HCT is 

not recommended as a means of preventing bacterial infections. 38 In a randomized trial where IVIG 

or no IVIG prophylaxis were given from Day 90 to Day 360 post-transplantation, the incidence or 

mortality of chronic GVHD was not reduced with IVIG. 40 (See Allogeneic bone marrow 


20. Heart block, congenital. Evidence does not support IVIG use. 157-158 In a multicenter, prospective, 

open-label clinical trial IVIG did not prevent the recurrence of congenital heart block (CHB) or 

reduce maternal antibody titers in 20 mothers with a prior history of a child with CHB. A similarly 

designed European study found no benefit of IVIG as prophylactic therapy for CHB in high-risk 












mothers. 158 

21. Heart failure, chronic. There is insufficient evidence to recommend IVIG. In one randomized, 

placebo-controlled trial, IVIG given monthly for 26 weeks improved left ventricular ejection fraction 












(LVEF) in patients with chronic heart failure and LVEF < 40%. 159 In another controlled trial in 

patients with recent onset dilated cardiomyopathy LVEF < 40%, IVIG, given for 2 consecutive days 

with no maintenance IVIG, did not improve LVEF more than placebo. Larger trials are needed in 

well defined populations (cause and severity) to determine if IVIG has a role in the treatment of heart 

failure. 

22. HSCT in allogeneic recipients from HLA-identical sibling donors. IVIG is not recommended. In 

a placebo-controlled trial, prophylactic IVIG had no benefit over placebo for prophylaxis of infection, 

interstitial pneumonia, GVHD, transplantation-related mortality at 6 months, or survival at 24 

months. 160 IVIG is recommended in patients with severe hypogammaglobulinemia after 

transplantation to prevent bacterial infection and acute GVHD. 38 (See Allogeneic bone marrow 


23. Human immunodeficiency syndrome (HIV) infection, adults, for prophylaxis of infections. 

Evidence does not support IVIG use. 31,43 IVIG is not recommended, antiretroviral therapy (ART) 

should be used. 161-162 

24. In vitro fertilization (IVF). Evidence does not support IVIG use. Randomized placebo-controlled 

trials do not support the use of IVIG in women with repeated unexplained IVF failure. 31 

25. Multiple sclerosis, primary progressive. Evidence does not support IVIG use. 20 Clinical trials are 

needed. 20,163 Also see studies for multiple-sclerosis, secondary progressive below. 

26. Multiple sclerosis, secondary progressive. Evidence does not support IVIG use. 20 In a placebocontrolled 

trial in patients in an advanced stage of secondary progressive multiple sclerosis, IVIG 

therapy for 27 months had no beneficial effect on time to confirmed Expanded Disability Status Scale 

([EDSS], primary outcome) progression (HR: 1.11 [95% CI: 0.08, 1.53] for IVIG vs. placebo). 164 

The annual relapse rate was 0.46 for both groups. No significant differences between the treatment 

groups were found in any of the other clinical outcome measures or in the change of T2-lesion load 

over time. In another placebo-controlled trial, patients with primary progressive (n = 34) or 

secondary progressive (n = 197) multiple sclerosis were randomized to IVIG once monthly or placebo 

for 2 years. 165 Mean duration of multiple sclerosis was 14 to 15 years and mean EDSS scores were 

about 5.5 at baseline. In the intent-to-treat (ITT) population (both groups combined) IVIG delayed 

progression by 12 weeks compared to placebo and diminished the rate of patients with sustained 

progression by 15%; this effect was significant in those with primary progressive disease. In all, 51% 

of patients withdrew from the study. The study was not powered to show differences between the 

primary and secondary progressive groups and the number of patients with primary progressive 

disease was too small to draw valid conclusions. EDSS scores were similar with IVIG and placebo. 

Treatment with IVIG cannot be recommended for patients with secondary or primary progressive 

multiple sclerosis. 

27. Multiple sclerosis, relapsing remitting for the prevention of relapses. IVIG has been beneficial in 

controlled trials in preventing relapses in relapsing remitting multiple sclerosis, but additional studies 

are needed. 20,22,163 The studies of IVIG have usually involved small heterogeneous patient 

populations, have lacked complete data on clinical and MRI outcomes, or have used methods that 












have been questioned. It is possible that IVIG reduces the attack rate in relapsing remitting multiple 

sclerosis. 165 In a retrospective analysis of pregnant women with relapsing remitting multiple 

sclerosis, patients who received IVIG during pregnancy and postpartum or postpartum only had lower 

relapse rates than those who were untreated. 163 Randomized, double-blind trials are needed to 












confirm these findings, to determine the optimal dose, and to compare IVIG with beta interferon and 

glatiramer. Current evidence suggests IVIG is of little benefit in slowing disease progression. 163,165 

28. Neonates, for suspected or proven infection. Evidence does not support IVIG use. 166-167 In a large 

double-blind, randomized, controlled trial of adjunctive therapy with IVIG, newborn infants who had 

suspected or proven sepsis and who were receiving antibiotic therapy did not derive additional benefit 

over newborns not treated with IVIG. 167 There was no significant between-group difference in the 

rates of the primary outcome (major death or major disability by 2 years of age) which occurred in 

686/1,759 (39%) and 677/1,734 (39%) of IVIG and placebo-treated infants, respectively (relative risk 

1.00; 95% CI: 0.92, 1.08). No differences in secondary outcomes such as subsequent episodes of 

sepsis. 

29. Neonates, high-risk, preterm, low birth weight, infections in (prophylaxis and treatment 

adjunct). Evidence does not support IVIG use. 168 IVIG results in a 3% reduction in sepsis and a 4% 

reduction in any serious infection, but is not associated with reductions in other important outcomes; 

IVIG does not have any significant effect on mortality from any cause or from infections. 168 Early 

studies suggested prophylactic IVIG reduced nosocomial infections in low birth weight infants but 

these studies had many deficiencies. In a large prospective trial, prophylactic IVIG did not reduce the 

incidence of nosocomial infections in premature infants who weighed 501 to 1500 grams at birth. 164 

Morbidity, mortality, and duration of hospitalization were not different between IVIG and placebo. 

30. Nephropathy, membraneous. Evidence does not support IVIG use. 179 IVIG has been used in 

several types of glomerulnephritis in cases resistant to conventional therapy, but no controlled studies 

supporting their use exist. IVIG may increase the likelihood of remission when used at an early stage, 

but it does not appear to have an impact on the long-term prognosis of membranous nephropathy. 

The dose and length of treatment remain to be defined. 

31. Neuropathy, paraproteinemic. Evidence does not support IVIG use. Treatment of paraproteinemic 

neuropathies associated with multiple myeloma, amyloidosis, and Waldenstrom’s macroglobulinemia 

should be to treat the underlying disease. 31 IVIG is not indicated. Also see IgM Paraproteinemic 

demyelinating neuropathies above. 

32. Ophthalmopathy, euthyroid. Evidence does not support IVIG use. 23 

33. Otitis media, recurrent. Evidence does not support IVIG use. 23 

34. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection 

(PANDAS). Evidence does not support IVIG use. 31,170 Patients should be in a formal research 

protocol. In a randomized controlled trial, 29 children with new onset or severe exacerbations of 

obsessive compulsive disorder or tic disorder after streptococcal infections were randomized to IVIG, 

plasma exchange, or placebo. Patients who received either IVIG or plasma exchange improved 

compared to placebo. However, there are many limitations to this study. Additional studies are 

needed to determine the role of immunomodulatory therapies and antibiotic prophylaxis in 

PANDAS. 117 The Canadian expert panel of neurologists recommends IVIG as an option for 

treatment of PANDAS and states that diagnosis requires expert consultation. 20 












35. Plexopathy, progressive lumbrosacral. Evidence does not support IVIG use. 23 Only case reports 

are available. 












36. Post-polio syndrome. There is insufficient evidence to recommend IVIG. In a double-blind, trial, 

135 patients (most were clinically unstable and had severely atrophic muscles in both legs) were 

randomized to either IVIG or placebo initially and then repeated 3 months later. 172 At 6 months, 

median muscle strength differed by 8.3% in favor of IVIG (P = 0.029) with 15% being considered 

clinically significant; quality of life measured by Short Form-36 questionnaire was not significantly 

different between therapies. This study was not large enough to identify patients who were most 

likely derive the greatest benefit. A 2011 Cochrane Review included the above study as well a 

randomized, double-blind, placebo controlled trial in 20 adults with post-polio syndrome. 173 

Treatment with IVIG had no beneficial effect on activity limitations and fatigue and inconsistent 

effects on muscle strength with one study finding an improvement in strength 172 and the other not. 

Additional studies are needed to clarify the role of IVIG in post-polio syndrome. 

37. Pure red cell aplasia due to myelodysplastic syndrome . Evidence does not support IVIG use. 31,28 

This condition does not usually respond to immunosuppressive therapy or IVIG. 28 

38. Recurrent spontaneous pregnancy loss (RSPL) [including antiphospholipid antibody-positive 

women]. Evidence does not support IVIG use. 22,175-177,145, According to guidelines from the American 

College of Obstetricians and Gynecologists (ACOG), IVIG is not effective for preventing recurrent 

early (< 15 weeks of gestation) pregnancy loss. 174 Patients with a positive test for lupus anticoagulant 

or anticardiolipin antibodies should be treated with heparin and low dose aspirin during the next 

pregnancy attempt. In a double-blind pilot study, IVIG did not improve obstetric or neonatal 

outcomes beyond those achieved with a heparin and low-dose aspirin regimen. 175 In another doubleblind 

trial (n = 82 of whom 47 had an index pregnancy) live birth rates did not differ significantly 

between IVIG-treated and placebo-treated women (70% vs. 63%; P = 0.76; OR 1.37 [ 95% CI: 0.41, 

4.61]). 176 The American Society for Reproductive Medicine (ASRM) also concluded after reviewing 

five randomized controlled trials which assessed IVIG treatment for RSPL, that IVIG is not effective 

for primary RSPL. 145 For secondary (indicates an antecedent pregnancy) RSPL, there was a higher 

percentage of successful pregnancies with IVIG, but the number of patients was not sufficient to rule 

out a chance finding. They concluded that IVIG as a treatment for RSPL is experimental and should 

only be used in a randomized clinical trial setting. 

39. Sickle cell disease. Evidence does not support IVIG use. 28,31 A Canadian expert panel of 

hematologists states that IVIG is not recommended for routine treatment of non-life-threatening 

delayed hemolytic transfusion reactions in patients with sickle cell disease but could be used for 

serious, life-threatening reactions. 28 

40. Systemic sclerosis (systemic scleroderma). Evidence does not support IVIG use. In a small open 

label trial, IVIG reduced skin fibrosis in patients with systemic sclerosis. 178 Placebo-controlled trials 

are needed. In the natural course of the disease, skin atrophy may develop which would affect the 

measurement of skin involvement, and it is not known how IVIG would affect the other 

manifestations of systemic sclerosis (blood vessels, visceral organs). According to American College 

of Rheumatology (ACR) guidelines for clinical trial design and outcomes in systemic sclerosis 179 

randomized, double-blind, placebo-controlled trials are preferred. The treatment and follow-up period 

must be long enough to permit observation of any disease modification, which is likely to require 18 

to 36 months, unless an extraordinarily effective therapy is identified. Responses selected should be 












quantitative, consistently and accurately reflect activity of systemic sclerosis in major target organs 

(not solely the skin), be sensitive to change, and be standardized, with limited variability.” 












41. Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). 

Evidence does not support IVIG use. 28,31 A Canadian expert panel of hematologists 

states that IVIG may be one option among adjunctive therapies when first-line therapy has 

failed. 28 

42. Thrombocytopenia, heparin-induced (HIT). IVIG is not recommended. HIT is a 

prothrombotic disorder, IVIG could potentially increase the risk of thrombosis and is not 

recommended. 28 

43. Thromobocytopenia, nonimmune. Evidence does not support IVIG use. 25 

44. Transplantation, solid organ (e.g., heart, kidney) for prophylaxis or 

treatment of cytomegalovirus (CMV) infections. Antiviral therapy is currently 

used. 44,152-153 Antiviral agents (ganciclovir, valganciclovir [Valcyte ]) and CMV 

immune globulin (Cytogam ® ) are effective in preventing and treating CMV in solid 

organ transplant recipients. 

45. West syndrome (infantile spasms). There is insufficient evidence to recommend IVIG. 151 

Clinical Background Information and References: 

1. Carimune NF [package insert]. Kankakee, IL: CSL Behring LLC (manufactured by CSL 

Behring AG, Bern, Switzerland); February 2009. 

2. Flebogamma 5% solution [package insert]. Los Angeles, CA: Grifols Biologicals, Inc 

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3. Gammagard S/D [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; 

December 2011. 

4. Gamunex – C 10% liquid. Research Triangle Park, NC: Talecris Biotherapeutics; October 

2010. 

5. Flebogamma 5% DIF solution [package insert]. Los Angeles, CA: Grifols Biologicals, 

Inc (manufactured by Instituto Grifols, SA, Barcelona, Spain); September 2009 

6. Octagam [package insert]. Centreville, VA: Octapharma USA, Inc (manufactured by 

Octapharma Pharmazeutika, Vienna, Austria and Octapharma, Sweden); February 2009. 

7. Privigen 10% liquid package insert]. Kankakee, IL: CSL Behring LLC (manufactured 

by CSL Behring AG, Berne, Switzerland); February 2011. 

8. Gammagard Liquid 10% [package insert]. Westlake Village, CA: Baxter; July 2011. 

9. Flebogamma 10% DIF solution [package insert]. Los Angeles, CA: Grifols Biologicals, 

Inc (manufactured by Instituto Grifols, SA, Barcelona, Spain); July 2010. 

10. Gammaked 10% injection [package insert]. Research Triangle Park, NC: Talecris 

Biotherapeutics; June 2011 

11. Gammagard S/D Ig A ≤ 1 mc g/ mL [package insert]. Westlake Village, CA: Baxter 

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clinicians. Transfusion. 2003;43:1460-1480. 

This guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. The 

use of this guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement is 

based on member benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Plan 

policies, clinical coding criteria, and the BMC HealthNet Plan agreement with the rendering or dispensing provider. 

Reimbursement policies may be amended at BMC HealthNet Plan’s discretion. BMC HealthNet Plan will always use the most 

recent CPT and HCPCS coding guidelines. All Plan policies are developed in accordance with state, federal and accrediting 

organization guidelines and requirements, including NCQA. 

This document is subject to further revision in response to additional terms and requirements imposed under the Integrated Care 

Program, including the ICP contract. 

BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire. 

Boston Medical Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan, 

Inc. 


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treatment of chronic heart failure. Int. J. Cardiol. 2006;112:40-45. 

160. Cordonnier C, Chevret S, Legrand M, et al; GREFIG Study Group. Should 

immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, 

double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med. 

2003;139:8-18. 

161. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use 

of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health 

and Human Services. October 14, 2011; 1-167. Available at 

http://www.aidsinfo.nih.gov/ContentFiles/Adultsand adolescentGL.pdf. Accessed January 

9. 2011. 

162. Centers for Disease Control and Prevention. Updated U.S. Public Health Service 

guidelines for the management of occupational exposures to HIV and recommendations 

for postexposure prophylaxis. MMWR 2005;54(no. RR-9):1-17. 

163. Gray O, McDonnell GV, Forbes RB. Intravenous immunoglobulins for multiple 

sclerosis. Cochrane Database Syst Rev. 2003;(4):CD002936. 

164. Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in 

secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet. 

2004;364:1149-1156. 

165. Goodin DS, Frohman EM, Garmany GP Jr, et al; Therapeutics and Technology 

Assessment Subcommittee of the American Academy of Neurology and the MS Council 

for Clinical Practice Guidelines. 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. 

2002;58:169-178. 

166. Ohlsson A, Lacy J. Intravenous immunoglobulin for suspected or subsequently 

proven infection in neonates. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD001239. 

Review. PubMed PMID: 20238315. 

167. The INIS Collaborative Group. Treatment of neonatal sepsis with intravenous 

immune globulin. N Engl J Med. 2011;365:1201-1211. Ohlsson A, Lacy JB. 

Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight 

infants. Cochrane Database Syst Rev. 2004;(1):CD000361. 

168. Fanaroff AA, Korones SB, Wright LL, et al. A controlled trial of intravenous 

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Policy History: 

Effective Date: 07/13/2006 

Approved by: Pharmacy and Therapeutics Committee, 7/13/2006 

Date of Review/Revision: 

03/13/2008 – P&T Annual Review, no significant changes 

03/12/2009 – P&T Annual Review, Chronic Inflammatory Demyelinating 

Polyneuropathy (CIDP) added to FDA indications, approval durations revised for select 

off-label indications 












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03/11/2010 – P&T Annual Review, no changes required 

03/10/2011 – P&T Annual Review, MS acute severe exacerbation, MS post-partum to 

prevent relapses added to indications; specialist requirement added to multiple 

indications; approval durations revised for select off-label indications; Miller Fisher 

Syndrome, Myasthenia gravis crisis, Autoimmune mediated diabetic proximal 

neuropathy (severe diabetic polyradiculopathy and/or plexopathy and many other terms), 

Graves ophthalmopathy (orbitopathy), Inclusion body myositis, after the first 

neurological event suggestive of demyelinative disease (multiple sclerosis), multiple 

sclerosis with refractory optic neuritis, and selective IgG subclass deficiency removed 

from indications; additional drug requirements added to select indications 

07/14/2011 – policy applied to Commercial. 

03/08/2012 – P&T Annual Review, Primary immune deficiency – requirement for predose 

IgG was removed; Idiopathic thrombocytopenia (ITP) – changes made to reflect 

American Society of Hematology guidelines regarding platelet count requirements for 

adults and children, for pregnant women, requirement for platelet count and trial of 

steroid was removed; Multiple sclerosis – added coverage for children and adolescents, 

several neurologic diseases were added to exclusions; added criteria for Hizentra. 

Last Review Date: 03/14/2013 – P&T Annual Review, added Bivigam (IVIG) to policy. 

Approval Dates 

Regulatory Approval: N/A 

Internal Approval: 

Initial approval by Pharmacy & Therapeutics Committee – 07/13/2006; QIC 

Authorizing entity 

QIC 

IMPORTANT NOTES: 

‣ Not all services are covered for all products or employer groups. This medical policy 

expresses the Plan's determination of whether certain services or supplies are medically 

necessary, experimental or investigational or cosmetic. The Plan has reached these 

conclusions based upon the regulatory status of the technology and a review of clinical 

studies published in peer-reviewed medical literature. Even though this policy may 

indicate that a particular service or supply is considered covered or not covered, this 

conclusion is not based upon the terms of a member’s particular benefit plan. Each 

benefit plan contains its own specific provisions for coverage and exclusions. Not all 

services that are determined to be medically necessary will necessarily be covered 












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services under the terms of a member’s benefit plan. Members and their providers need 

to consult the applicable benefit plan document (e.g., Evidence of Coverage) to 

determine if there are any exclusions or other benefit limitations applicable to this service 

or supply. If there is a discrepancy between this medical policy and the benefit plan 

document, the provisions of the benefit plan document will govern. In addition, this policy 

and the benefit plan document are subject to applicable state and federal laws that may 

mandate coverage for certain services and supplies. 

‣ To the extent applicable, this Policy and/or Procedure applies to BMCHP subcontractors 

and downstream entities, if any, providing services with respect to BMCHP’s Integrated 

Care Program. 












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IVIG, SCIG - BMC HealthNet Plan

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