IVIG - BMC HealthNet Plan

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Pharmacy & Medical Clinical Guidelines – Immune Globulin Intravenous (IVIG) 

Document Number: 9.129 

Effective Date: 01/03/2012 

Product Applicability: MassHealth Commonwealth Care Commercial 

Summary: 

BMC HealthNet Plan will authorize coverage of IVIG products when appropriate criteria 

are met. This guideline has been adapted from the Express Scripts® Prior Authorization 

Policy for Immune Globulin Intravenous products 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 The donors in a typical pool of 

plasma have a wide range of antibodies against infectious agents. 2 These products have 

IgG subclasses similar to that found in normal humans. IVIG preparations vary slightly 

but are generally therapeutically equivalent. 1 There are minor IgA and IgG subclass 

differences and antibody titers also vary from lot-to-lot and among IVIG preparations. 

There are especially variations in IgG4 which is often reduced. 2 Some congenital 

hypogammaglobulinemias involve IgG subclass deficiencies (e.g., deficiencies of IgA or 

IgE in association with reduced IgG2 or IgG4). However, there is currently no clinical 

evidence that this is an important issue. In the U.S., 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 IgM. 

All of the U.S. licensed products are Food and Drug Administration (FDA)-approved for 

replacement therapy in patients with primary immunodeficiencies. Individual products 

are labeled for use in other conditions. IVIG is FDA-approved for the following five 

indications. 

This guideline provides information on BMC HealthNet Plan 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. 

BMC HealthNet Plan – IVIG 

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Primary (inherited) immunodeficiencies (e.g., common variable immunodeficiency, 3-11 

severe combined immunodeficiency, 3-11 congenital agammaglobulinemia [X-linked 

agammaglobulinemia], 3-10,165 Wiskott-Aldrich Syndrome 4-11 , congenital 

hypogammaglobulinemia 8 ). Gamunex-C may be administered via IV or subcutaneous 

(SC) infusion for primary immunodeficiency. 6 Immune globulin replacement therapy 

provides IgG antibodies to those who lack them. 12 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. 1,12 

Acute and chronic idiopathic [immune] thrombocytopenic purpura (ITP). 3,5-6,9 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. 1 

ITP is usually chronic in adults. 13 The clinical course of untreated disease is uncertain 

because patients with symptomatic thrombocytopenia are usually treated initially with 

glucocorticoids. Data suggest the course of ITP is more serious in adults than in children. 

At equivalent platelet counts, hemorrhagic complications may be more common in older 

adults than in younger adults. 

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

thrombocytopenia and symptomatic purpura. 13-15 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 guideline 

from the American Society of Hematology (ASH), glucocorticoids are appropriate initial 

therapy in patients with platelet count < 30,000/mm3 including asymptomatic patients, 

patients with minor purpura, and those with significant mucous membrane or vaginal 

bleeding. Glucocorticoids are also appropriate in patients with platelet count of 30,000 to 

50,000/mm3 if clinically important bleeding is present and for patients with severe lifethreatening 

bleeding regardless of the platelet count. 

Splenectomy is usually the next step after glucocorticoids for adults who have a relapse 

after initial therapy or who have not responded to corticosteroids, IVIG, or intravenous 

anti-D immune globulin (Rho [D] immune globulin, WinRho SDF®). 14-15 No treatment is 

required for asymptomatic adults when platelet counts of > 30,000/mm 3 are maintained 

unless there are coexisting conditions or preference (e.g., vocation necessitates exposure 

to trauma). Splenectomy is effective therapy for ITP in many patients. About two thirds 

of adults, who are either unresponsive to initial glucocorticoid therapy or who require 

continued use of glucocorticoids to maintain a safe platelet count, achieve and sustain a 

normal platelet count after splenectomy and require no further treatment. For elective 








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splenectomy, the ASH panel considered it appropriate to use prophylactic IVIG or oral 

glucocorticoid therapy in patients with platelet counts < 20,000/mm 3 to reduce the risk of 

intraoperative and postoperative bleeding. 13 Preoperative prophylaxis with IVIG is 

considered inappropriate for platelet counts > 50,000/mm 3 . There is no consensus on 

appropriate management of patients with persistent severe thrombocytopenia after 

splenectomy. 13-16 For adults who are refractory to primary treatment with glucocorticoids 

and splenectomy, the panel recommended against further treatment of patients with 

platelet counts > 30,000/ mm 3 who have no bleeding symptoms. Further treatment was 

recommended in patients with active bleeding with platelet counts < 30,000/mm 3 . 

IVIG has been studied more in children than in adults and has been used primarily in 

adults who are unresponsive to glucocorticoids and other therapies. 13-14 IVIG is used to 

treat internal bleeding when the platelet count remains < 5,000/mm 3 despite several days 

of corticosteroid therapy or when extensive or progressive purpura are present. Most data 

on IVIG in adults is from case series in patients with severe, chronic thrombocytopenia. 

Most of these patients (about 75%) had an increase in platelet count with IVIG. In 

patients who initially respond, the platelet count returns to pretreatment levels within 

about 3 to 4 weeks. There are no studies comparing IVIG to no therapy and no studies of 

the effect of IVIG on morbidity or mortality. For adults, the ASH guidelines concluded 

that evidence-based recommendations for appropriate indications for IVIG were not 

possible at that time. 13 Based on opinion, the ASH concluded that IVIG is appropriate 

initial therapy only in patients with platelet counts < 50,000/mm 3 who have severe, lifethreatening 

bleeding. IVIG is inappropriate initial treatment in patients with platelet 

counts of 30,000 to 100,000/mm 3 who are asymptomatic or who have only minor 

purpura. There was no agreement among the panel about the appropriateness of initial 

IVIG therapy in patients with platelet counts < 20,000/mm 3 who are asymptomatic or 

have only minor purpura, or for patients with risk factors for bleeding, such as 

hypertension, peptic ulcer disease, or a vigorous lifestyle. In adults who have responded 

incompletely to therapy with both prednisone and splenectomy, there was little ASH 

panel consensus on preferred regimens, but IVIG was considered one of the preferred 

options for patients with platelet counts < 10,000 or 15,000 to 20,000/mm 3 and bleeding 

symptoms and with platelets counts < 10,000/mm 3 without bleeding symptoms. 

The initial treatment of ITP in children is controversial, partly because most children 

recover completely within a few weeks without treatment and there is no proof that 

therapy prevents intracranial hemorrhage. 14-15,17 Serious bleeding is rare. 15 The relative 

efficacy of IVIG compared to corticosteroids in children is not clear. 14-15 The ASH 

guidelines consider IVIG inappropriate in children with platelet counts > 30,000/mm 3 

who are asymptomatic or have only minor purpura. 13 These guidelines recommend initial 

treatment with IVIG in severe, life-threatening bleeding regardless of the platelet count. 

The ASH guidelines also recommend IVIG as initial therapy with platelet counts < 

10,000/mm 3 if there is minor purpura and with platelet counts < 20,000/mm 3 if there is 

mucous membrane bleeding. However, most children with platelet counts ≤ 20,000/mm 3 








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do not require treatment with IVIG, high-dose corticosteroids or any other specific 

therapy. 17 Splenectomy should be considered in children with symptomatic, severe 

thrombocytopenia for at least one year. 13-14 In Rh-positive children who relapse after 

initial therapy, Rh0 [D] immune globulin is preferred, if it is effective, over IVIG. Longterm 

corticosteroids are usually unacceptable in children due to adverse effects and 

responses are not durable. Only 5% of children with ITP still have thrombocytopenia that 

requires therapy after one year. 

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

patients with hypogammaglobulinemia and/or recurrent bacterial infections. 5 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 vs. 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. 5 Efficacy of IVIG in 

conjunction with aspirin given in the acute phase of Kawasaki disease in reducing the 

prevalence of coronary artery abnormalities is well-established. 18 

Chronic inflammatory demyelinating polyneuropathy (CIDP) to improve 

neuromuscular disability and impairment and for maintenance therapy to prevent 

relapse. 6,19 Efficacy of IVIG was established in a multi-center, double-blind trial using 

immune globulin intravenous 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% confidence interval [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; 31 were randomly reassigned 

to continue with IVIG and 26 were reassigned to placebo (withdrawal period) for 24 

weeks. Subjects who continued on IVIG had a significantly longer time to relapse vs. 

patient on placebo (P = 0.011). The probability of relapse was 13% with IVIG vs. 45% 

with placebo (hazard ratio, 0.19 [95% CI, 0.05, 0.70]). 

Table 1. Outcomes in Intent-to-Treat Population Efficacy Period (24 weeks). 6 

IVIG 

Placebo 

Efficacy Period Responder* Non- Responder* Non- P- 

Responder 

Responder Value** 

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

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








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subjects 

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

subjects 

*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. 1,20-22 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. 21-23 Neurological disability score improved similarly with IVIG and plasma 

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

strength. About 2/3 of patients responded to IVIG and about 1/3 of these need no further 

treatment and 2/3 required repeated courses of IVIG. 22 Benefit from IVIG lasts for 2 to 

12 weeks, so treatment must be repeated. 

IVIG also is used for many off-label indications. 2 Most evidence for clinical effectiveness 

of IVIG is anecdotal (i.e., case reports, open series, or cohort studies). 24 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 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. These 

requests will be approved when indication-specific criteria below are met: 

FDA-Approved Indications 

1. Immunodeficiency, primary humoral (treatment) (e.g., X-linked 

agammaglobulinemia [Bruton’s agammaglobulinemia, congenital 

agammaglobulinemia), common variable immunodeficiency, severe combined 

immunodeficiency, Wiskott-Aldrich syndrome). 1,3-11,23,26,28,158 Approve for 12 months 

if IVIG is prescribed by an allergist/immunologist, immunologist, otolaryngologist 

(ear nose and throat [ENT] physician) or an infectious disease 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 








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and to prevent or control recurrent and chronic bacterial infections and to control 

symptoms. 26,158 

Also see Hyperimmunoglobulinemia E syndrome (Job’s syndrome). 

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

acute and chronic (treatment). 1,3,5-6,9 

A. Children (age ≤ 10 years) with ITP. Approve for one of the following (a, b, c, 

or d) when IVIG is prescribed by or in consultation with a hematologist. In 

children ≤ 10 years of age, use of IVIG is based on risk of bleeding and not on 

platelet counts. 

a. 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. 15 In clinical trials IVIG shortened the duration of 

severe thrombocytopenia. 

b. If IVIG is required to prevent bleeding in a child with persistent (3 to 

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

c. If inaccessibility or noncompliance is a concern and the child is at risk 

of bleeding, approve for 12 months. 13 

d. If splenectomy, other surgery, dental extractions, or other procedures 

likely to cause blood loss are needed, then approve for one month. 15 

Most children do not require therapy with IVIG. 29 In emergency situations, 

platelet transfusions given with IV corticosteroids and IVIG should be given for 

intracranial hemorrhaging or other life-threatening or serious bleeding. 29 

B. Adults and children (> 10 years) with ITP. Approve for one of the following 

(a, b or c) when IVIG is prescribed by or in consultation with a hematologist. 

a. 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). IVIG may be added to corticosteroid therapy if 

thrombocytopenia persists or worsens after about 3 days of 

corticosteroid therapy. 30 

According to ASH guidelines if platelet count is < 20,000 to 30,000 

mm 3 initial therapy is corticosteroids. 13,29 ASH guidelines state that 

splenectomy is effective in normalizing platelet counts in patients who 

have been refractory to glucocorticoids for several weeks or years, but 








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there are inadequate data to make evidence-based recommendations on 

the appropriate indications and timing for splenectomy and on when 

the benefits of splenectomy outweigh the potential risks. 

b. To increase platelet counts before surgical procedures (e.g., 

splenectomy) or dental procedures. Approve for one 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 . 

c. 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). IVIG may be added to corticosteroid therapy if 



Patients with platelet count < 20,000 mm 3 at risk for intracerebral 

bleeding, will be hospitalized and treated with high-dose corticosteroid, 

IVIG and platelet transfusions. 13 

C. Pregnant women with ITP. Approve for one of the following (a, b, or c) when 

IVIG is prescribed by or in consultation with a hematologist. 

a. Platelet count is < 30,000 mm 3 in second or third trimester. Approve 

IVIG for three months. 13 

b. Platelet count is < 10,000 mm 3 in first trimester AND a corticosteroid 

has been tried. 13 Approve IVIG for three 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). IVIG may be added to corticosteroid therapy if 



c. Before normal vaginal delivery, cesarean section or spinal or epidural 

anesthesia. Approve IVIG for 2 weeks. 15,29 

Newborns of mothers with ITP. Infants are hospitalized. 

3. Kawasaki disease (treatment adjunct).1,5,31 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]. May approve a second dose of IVIG in patients who fail to respond to 








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

inflammation 24 to 48 hours after completing the initial IVIG infusion 32 ). 

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. 18,32 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 risk of 

coronary artery aneurysms from 17% to 4%. 32 

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

hypogammaglobulinemia and with a previous history of a serious bacterial 

infection. 5,27,33-36 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 disease 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. 32,35 

In placebo-controlled trials, IVIG significantly reduced bacterial infections. 27,38 

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 lifethreatening 

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. 30 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. IVIG is FDA-approved to improve neuromuscular disability and 

impairment and for maintenance therapy to prevent relapse. 6 IVIG is recommended as 

an equivalent alternative to plasma exchange in children and adults. 1,20-22,37 In the 

pivotal trial for CIDP, IVIG was effective at improving certain motor functions for up 

to 48 weeks after initial therapy. 38 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. 21,23 Neurological disability score improved 

similarly with IVIG and plasma exchange. 24 IVIG was also significantly more 

effective than placebo in improving muscle strength. 








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About 2/3 of patients responded to IVIG and about 1/3 of these need no further 

treatment and 2/3 required repeated courses of IVIG. 22 Benefit from IVIG lasts for 2 

to 12 weeks, so treatment must be repeated. 

Other Uses with Supportive Evidence 

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

transplantation (HSCT) 23,39-40 (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 first 100 days after transplantation, IVIG should not be routinely given to 

HSCT recipients to prevent bacterial infection. 39 However, IVIG is recommended 

for routine use in HSCT recipients (adults, adolescents, pediatric) with unrelated 

marrow grafts (allogeneic) who experience severe hypogammaglobulinemia (IgG 

< 400 mg/dl) within the first 100 days after transplant. To prevent late disease (> 

100 days after HSCT), routine monthly IVIG administration to HSCT recipients is 

not recommended as a means of preventing bacterial infections. 39,41 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. 41 Patients 

with severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 

mg/dL) can continue receiving IVIG. 39,41-42 IVIG supplementation is often used in 

patients with severe infections and IgG levels < 400 mg/dL to maintain levels 

until infections resolve. 42 

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. 43 

Currently marketed IVIG products do not have this indication. 








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

(See Exclusions.) 

GVHD, chronic, prevention. Not recommended. (See Exclusions.) 

HSCT in allogeneic recipients from HLA-identical sibling donors. Not 

recommended. (See Exclusions.) 

Autologous bone marrow transplantation or HSCT. Not recommended in 

autologous transplants. 1 (See Exclusions.) 

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

for cytomegalovirus (CMV) disease prophylaxis in HSCT recipients. 39 (See 

Exclusions.) 

7. Human immunodeficiency virus (HIV) infected infants and children younger 

than 13 years of age. HIV infected infants and children is divided into A. Prevention 

of recurrent bacterial infections and B. Passive immunization for Varicella. 

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 (a, b, and c). 

a. IVIG is prescribed by an infectious disease specialist or an 

immunologist, and 

b. The patient is receiving highly active antiretroviral therapy (HAART) 

(Note: HAART is a combination of three or more anti-HIV drugs 

taken at the same time), and 

c. The patient has one of the following (i, ii, or iii) 

i. functional antibody deficiency as demonstrated by recurrent, 

serious bacterial infections, defined as 2 or more serious bacterial 

infections, such as bacteremia, meningitis, or pneumonia during a 

1-year period despite administration of highly active antiretroviral 

therapy (HAART) and prophylactic cotrimoxazole (TMP-SMZ) or 

other antimicrobials 44-48 or 

ii. functional antibody deficiency as demonstrated by the absence of 

detectable antibody response against protein and polysaccharide 

antigens, 47 or 

iii. hypogammaglobulinemia (IgG < 400 mg/dL [4.0 g/L]). 47 

IVIG is no longer recommended for primary prevention of serious bacterial 

infections in HIV-infected children unless hypogammaglobulinemia is present or 

functional antibody deficiency is demonstrated by either poor specific antibody 

titers or recurrent bacterial infections. 47 








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B. Passive immunization for Varicella (chickenpox) in HIV-infected infants 

and children younger than 13 years of age. Approve a single dose of IVIG 

if varicella zoster immune globulin (VariZIG ® ) is not available (or cannot be 

obtained) 48 for patients who meet the following criteria (a, b, and c). 

a. IVIG is prescribed by an infectious disease specialist or an 

immunologist, and 

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

i. has no history of varicella infection, or 

ii. has seronegative status for varicella-zoster virus (VZV), or 

iii. has lack of evidence of age appropriate vaccination (child has not 

received 2 doses of varicella vaccine) 

iv. the child has been immunized but is moderately to severely 

immune compromised. 46 

c. The patient has not received a dose of IVIG within 2 to 3 weeks of 

exposure to varicella. 46-47 

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. 46 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. 47 Studies that showed IVIG was beneficial for prevention of 

bacterial infections in HIV-infected children were done before HAART was 

available. 42 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. 45 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. 45-46,50 Also see 

HIV-associated thrombocytopenia, children. 








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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. 43 Currently marketed IVIG products do not have this 

indication. There is no evidence that IVIG confers incremental benefit to 

antiretroviral therapy and prophylactic antibiotics given according to current 

standards of practice. 1 In children with advanced HIV disease who are receiving 

zidovudine, IVIG decreases the risk of serious bacterial infections, but this benefit 

is apparent only in children who are not receiving TMP-SMZ as prophylaxis and 

for children with CD4 T lymphocyte counts > 200 to 400 cells/mm 3 . 

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, or anakinra) or if 

these therapies are contraindicated. No controlled trials are available using IVIG. 27,51 

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

nonsteroidal anti-inflammatory 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. 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. 24,30 

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, c, or d): 

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 ® ), etanercept (Enbrel ® )], tacrolimus), or 

B. Patient has contraindications to or has had significant adverse effects from 

conventional therapy [for corticosteroids e.g., poorly controlled diabetes, 

advanced osteoporosis, severe infections, prior GI bleeding; for 

immunosuppressives e.g., infections, bone marrow suppression) 52 , or 

C. The disease is rapidly progressive, extensive, or debilitating (cannot be 

controlled with conventional therapy), 52-55 or 

D. The disease is so serious 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 








12 of 45

ecalcitrant disease or in those with contraindications to conventional therapy. 27,53- 

55 The total duration of treatment with IVIG can be at least 2 years or longer. 55 

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, placebo-controlled 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. 56 

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. 31,57-58 

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 intravenous ganciclovir and IVIG in combination. 39,60 Whether 

adding IVIG adds efficacy is controversial, 59,61 and there is no data to support adding 

IVIG for the treatment of any manifestation of CMV disease other than pneumonia. 59 

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. 59 For other types of CMV disease, the 

EBMT recommends ganciclovir or foscarnet without IVIG. 59 These recommendations 

are consistent with those from the National Comprehensive Cancer Network 

(NCCN). 60 

For 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 meets one of the following criteria (a, b, or c). 

a. The patient has not responded to conventional therapy with BOTH a 

systemic corticosteroid AND an immunosuppressant agent (e.g., 








13 of 45

azathioprine, methotrexate, cyclosporine, cyclophosphamide, 

mycophenolate mofetil), 1,20-21,27,62 or 

b. Conventional therapies (systemic corticosteroids and 

immunosuppressants) are contraindicated, or 

c. Conventional therapies (systemic corticosteroids and 

immunosuppressants) are not tolerated due to adverse effects, or 

d. The dose of corticosteroids cannot be decreased because the disease is 

only adequately controlled with higher doses of steroids. 1,20-21,27,62 

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 and neuromuscular symptoms and in rash. IVIG 

may be used in dermatomyositis patients with severe active illness for whom 

other interventions have been unsuccessful or intolerable. 24 IVIG has been used to 

maintain response in dermatomyositis. 62 

IVIG may be considered amongst the treatment options for patients with 

polymyositis not responding to first line immunosuppressive treatment. 63 In 

uncontrolled series, IVIG has been effective in polymyositis. 63 

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-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. 64 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. 65 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, ischemiareperfusion 

injuries, and acute rejections episodes in renal and cardiac allograft 

recipients. 66-67 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. 66 








14 of 45

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. 66 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 2 drugs for seizures and a corticosteroid. 

Exceptions are not recommended for West syndrome (infantile spasms). 68 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, 

Rasmussen syndrome, Landau-Kleffner syndrome, mixed seizures of early onset with 

immune deficiency [IgA or IgG subclass deficiency]) 21,23,27 , as a last resort, especially 

in patients who may be candidates for surgical resection. 23,63,69 Controlled trials are 

needed on well-defined populations. The Canadian expert panel of neurologists does 

not recommend IVIG for pediatric intractable epilepsy. 20 The EFNS recognizes IVIG 

may have a favorable effect in childhood refractory epilepsy (good practice point). 63 

18. Evans syndrome. Refer to ITP or to warm autoimmune hemolytic anemia (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. 30 

19. Guillain-Barré syndrome (GBS). Approve for 12 months in the following situations 

(A or B). 

A. IVIG is prescribed by a neurologist or specialist with experience in diagnosing 

and treating patients with GBS AND 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. IVIG is prescribed by a neurologist or specialist with experience in diagnosing 

and treating patients with GBS AND 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. 20,22 IVIG is recommended as an equivalent alternative to plasma exchange 

in children and adults. 20,23 IVIG is the treatment of choice, since plasma exchange 

(which is equivalent to treatment with IVIG) is not always readily available. 21,23,70 

In controlled trials, IVIG was as effective or more effective than plasma exchange 








15 of 45

in improving strength, time to unaided walking, or discontinuation of 

ventilation. 20-21 The American Academy of Neurology recommends IVIG in 

patients who require aid to walk within 2 or 4 weeks from the onset of 

neuropathic symptoms. 70 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, the authors concluded that IVIG and plasmapheresis seem not to 

have influenced patients’ outcomes. 63 

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. 71 IVIG is not 

indicated or proven to be effective in mildly affected GBS patients. European 

Federation of Neurological Societies (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. 63 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. 72 Further, the literature suggests that best medical management 

may suffice for many patients. 

20. HIV-associated thrombocytopenia, adults. 

Approve for one month in nonsplenectomized patients who are Rh0 [D] antigenpositive 

who have tried Rh0 [D] immune globulin AND patient has significant 

bleeding OR platelet count less than 20,000/mm 3 . Patients with a contraindication 

to Rh0 [D] immune globulin are not required to have tried it. 

Approve for one month in splenectomized patients or in patients who are Rh0 [D] 

antigen-negative AND patient has significant bleeding OR platelet count < 

20,000/mm 3 . 

Treatment choices are similar to those for ITP, and IVIG is only indicated with 

significant bleeding. 27 Corticosteroids are usually effective but cause many adverse 

effects in these immunocompromised patients. Splenectomy and Rh0 [D] immune 

globulin may be effective. Platelet counts may increase with HAART. Evidence for 

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

current standard practices for treatment of HIV. 27,73-74 In one small study, 9 Rh0 [D] 

positive nonsplenectomized adults and children with HIV infection with platelet 

counts

0.07); mean duration of effect was 41 days with Rh0 [D] immune globulin vs. 19 

days with IVIG (P = 0.01). Rh0 [D] immune globulin is FDA approved in nonsplenectomized, 

Rh0 [D] positive patients for the treatment of childhood acute or 

chronic ITP, chronic ITP in adults, and ITP secondary to HIV infection (adults and 

children). 75 The safety and efficacy of Rh0 [D] immune globulin has not been 

evaluated in patients who are splenectomized or in patients who are Rh0 [D] negative. 

A Canadian expert panel of hematologists recommends IVIG as a treatment option 

for this condition when there is active bleeding or when platelet counts are < 10,000/ 

mm 3 . 30 Their recommendations do not discuss use of Rh0 [D] immune globulin. 

21. HIV-associated thrombocytopenia, infants and children. Approve for 5 days of 

therapy if platelet count is < 20,000 IVIG 43 and is being used in children who are on 

antiretroviral therapy. A Canadian expert panel of hematologists recommends IVIG 

as a treatment option for this condition when there is active bleeding or when platelet 

counts are < 10,000/mm 3 . 30 They do not discuss using Rh0 [D] immune globulin for 

this indication. 

22. Hyperimmunoglobulinemia E (hyper-IgE) syndrome (Job’s syndrome) 

(treatment). Approve for 12 months. IVIG is effective in the treatment of severe 

eczema, 1 atopic dermatitis, 1 and recurrent respiratory infections 23 in these patients. 

IVIG also decreases enhanced IgE production. This is a rare syndrome and IVIG use 

is based on case reports. This is a primary immunodeficiency. 

23. IgM paraproteinemic demyelinating neuropathy (or other paraproteinemic 

demyelinating neuropathies). Approve for 12 months. When compared to placebo 

in a small, short-term (4 weeks), double-blind, crossover trial, IVIG produced a 

modest but statistically significant decrease in overall disability and a significant 

improvement in many secondary outcome measures (e.g., time to walk 10 meters, 

grip strength, and sensory symptom scores). 21,76 However, the short duration of 

follow-up makes it unclear whether this is clinically significant. 77 Long term studies 

are needed. IVIG is used in severe cases. 21 IVIG or plasma exchange are 

recommended for initial therapy in patients with significant disability or rapid 

worsening, although efficacy is unproven. 77 In patients with moderate or severe 

disability, immunosuppressive therapy (e.g., chlorambucil, cyclophosphamide) 

should be considered; long-term efficacy remains unproven. 63,77 The Canadian expert 

panel of neurologists does not recommend IVIG for IgM paraproteinemic 

neuropathy. 20 Less common paraproteinemic demyelinating neuropathies (i.e., 

Chronic Ataxic Neuropathy with Ophthalmoplegia, IgM Monoclonal gammopathy 

cold Agglutinins and Disialoganglioside antibodies [CANOMAD] or neuropathy with 

an IgA or IgG paraprotein) may respond to IVIG. 22 

24. Juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis. Approve for 12 

months in patients who have tried at least 2 other drug therapies and are being treated 








17 of 45

y a rheumatologist or in consultation with a rheumatologist. IVIG has been used in 

children with polyarticular or systemic JRA that was unresponsive to standard 

therapy (corticosteroids, methotrexate, abatacept [Orencia ® ], adalimumab [Humira ® ], 

etanercept [Enbrel ® ]). 27 

25. Lambert-Eaton myasthenic syndrome (treatment). Approve for 12 months in 

patients who meet all of the following criteria (A, B, and C). 


or experienced in the treatment of neuromuscular diseases, and 

B. The patient (non-paraneoplastic diagnosis) has tried at least one of the 

following therapies (a, b, or c), and 

a. corticosteroid, or 

b. azathioprine, or 

c. another immunosuppressive agent (e.g., cyclosporine, myophenolate 

mofetil) 

C. The patient meets one of the following criteria (a b, c, or d). 

a. The patient has had an inadequate response to one of these therapies 

(corticosteroid, azathioprine, or another immunosuppressive agent), or 

b. The patient could not tolerate one of these therapies (corticosteroid, 

azathioprine or another immunosuppressive agent) 20 , or 

c. The patient has contraindications to BOTH a corticosteroid and 

azathioprine, or 

d. The patient has paraneoplastic Lambert-Eaton myasthenic syndrome 

(these patients 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. Plasma exchange, steroids, and immunosuppressive agents have not been 

studied in randomized controlled trials. 78 IVIG may be useful as adjunctive 

therapy in difficult to treat patients. 20-21,27 

26. 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. 30 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. 








18 of 45

27. 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 life-threatening nature of this condition. 20 

28. Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) 

or Lewis- Sumner Syndrome. Approve for 12 months. MADSAM/Lewis Sumner 

Syndrome is a rare variant of CIDP that responds to IVIG, plasma exchange, and 

prednisone. 79 Therapy is the same as for CIDP. 27 

29. Multifocal motor neuropathy (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. 20-23,27,80 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 multifocal 

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

30. 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.27,60 In a randomized placebo-controlled trial, prophylactic use of IVIG 

reduced serious and life-threatening infections in immunosuppressed patients with 

multiple myeloma. 30 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. 30 

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 IVIG should be considered in the setting 

of recurrent, life-threatening infections in patients with multiple myeloma. 81 

31. Multiple sclerosis, acute severe exacerbation. Approve one 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). 








19 of 45

32. Multiple Sclerosis, post-partum to prevent relapses. Approve IVIG for 6 months 

for women in the post partum period who are 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. 82 

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). 83-85 In a randomized, confirmatory, multicenter, double-blinded-placeboperiod 

(days 1-3 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]). 182 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 three 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). 

33. 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. 


or experienced in the treatment of neuromuscular diseases, 86 and 

B. The patient meets one of the following criteria (a, b, c, or d). 








20 of 45

a. The patient has an exacerbation of myasthenia gravis 20 , or 

b. The patient requires stabilization of myasthenia gravis before 

surgery 19 , or 

c. The patient has been started on an immunosuppressive drug (e.g., 

azathioprine, cyclosporine, cyclophosphamide, mycophenolate 

mofetil) 27 , or 

d. 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. 71 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 longterm 

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. 21 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. 20-23 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 28.86 The greatest 

improvement occurred in patients with more severe disease (QMG Score for 

Disease Severity > 10.5). 

34. 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. 23,27,30,87 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. 87 

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

autoimmune neutropenia is often due to an underlying malignancy. 30 Limited 

information is available on the use of IVIG. 








21 of 45

35. Opsoclonus myoclonus (infantile polymyoclonia, acute cerebellar 

encephalopathy, oculocerebellomyoclonic syndrome, dancing eyes-dancing feet 

syndrome). Approve for 12 months. Symptoms have improved with ACTH or IVIG 

or plasma exchange. 27 There are no controlled trials (rare condition). ACTH is usually 

the initial therapy but is not used long-term due to adverse effects. 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 one year. Objective evidence of clinical 

improvement should be required for sustained use of IVIG. 20 

Pemphigus. See autoimmune mucocutaneous blistering diseases. 

36. Post transfusion purpura. Approve IVIG for one (five-day) course of therapy. IVIG 

may be considered as first-line therapy in severely affected patients 30 (i.e., platelet 

count usually < 10,000 2 to 14 days after transfusion and bleeding). 27 There are 

multiple case reports indicating IVIG is effective in some patients. 23,27,30 This 

syndrome is so rare that case series reports are all that is available for evidence. 

37. 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 disease specialist, 

immunologist, hematologist, or transplant specialist, and 

B. The patient has a chronic immunodeficient condition (e.g., patients with 

human immune deficiency virus [HIV] infection, solid organ transplants [e.g., 

renal, liver], chemotherapy for hematologic malignancy), 27,88 and 

C. The patient has clinically significant anemia as determined by the prescribing 

physician OR the patient is transfusion dependent. 27 

In immunosuppressed patients lacking neutralizing antibodies, IVIG has been 

useful for the treatment of persistent B19 infection. 89 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. 89 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. 27,89 Persistent B19 infection in apparently immunocompetent individuals 

who possess neutralizing antibodies does not respond well to IVIG. 89 In 

immunocompetent children, adolescents and adults, parvovirus B19 is self 

limiting and does not require treatment with IVIG. 88 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 








22 of 45

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. 27 

38. Pure red cell aplasia, immunologic subtype. Approve for 12 months if patient has 

tried prednisone and either cyclophosphamide or cyclosporine. 30 Based on case 

reports about 50% of patients benefit with IVIG therapy. 

39. 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. 90-92 

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

corticosteroid, 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. 90,94,98 , IVIG 

was continued to maintain remission. This is a rare disorder and no randomized 

controlled studies are available for any treatment. 

41. 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 received IVIG and immunosuppressive therapy pre-transplant. 95 Four of 

the 6 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. 

42. 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, or gabapentin. 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. 20,21,63,96 

43. Systemic lupus erythematosus (SLE). Approve for 12 months if patient has tried 

azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, rituximab or 

a corticosteroid. Evidence does not support routine use of IVIG but IVIG may be 








23 of 45

used in patients with severe active SLE for whom other interventions have been 

unsuccessful or intolerable. 24 Well-controlled trials are needed to determine which 

subsets of patients will benefit the most from IVIG. IVIG is used to treat severe 

thrombocytopenia or immune neutropenia. 97 Its role in non-hematologic 

manifestations of lupus is less clear. It has been used effectively to treat lupus 

nephritis. 97-98 First line therapy for active SLE is corticosteroids and antimalarial 

drugs (hydroxychloroquine). Second-line drugs are azathioprine, methotrexate, 

cyclophosphamide, or rituximab. 

44. 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. 23 

45. Thrombocytopenia, fetal alloimmune. Approve maternal antenatal infusion of IVIG 

for 6 months. 23,30,99 Antenatal therapy with IVIG is effective in increasing fetal 

platelet counts in neonatal alloimmune thrombocytopenia. 99-100 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. 30 

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

Small bowel transplant. 

46. 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 (Zyrtec ® ), 

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 9 of 10 patients with chronic 

autoimmune urticaria who had poor responses to antihistamines with 3 of the 

patients having prolonged remission. 101 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. 102 There was clinical 

improvement in 26 patients with reduced urticaria or angioedema and decreased 








24 of 45

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. 103 IVIG also induced remission 

or improved symptoms in 5 of 8 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. 104 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. 105-106 

47. 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. 107 

For chronic uveitis, long term immunosuppressive therapy, often with 2 or 3 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. 107-108 In one report IVIG for 

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

retinochoroidopathy (an autoimmune posterior uveitis). 109 

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. 

48. 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 ageappropriate 

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. 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. 110 The 

patient groups listed are recommended by the Advisory Committee on 

Immunization Practices (ACIP). In situations where administration of VariZIG ® 








25 of 45

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. 

49. 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. 31 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. 31,111 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.112 IVIG was effective in inducing 

complete remission 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. 27 Minimal 

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

ANCA-associated systemic vasculitis. 31 

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

See other criteria for these diseases. 

EXCLUSIONS 

Coverage of IVIG is not recommended in the following circumstances: 

1. Adrenoleukodystrophy. Evidence does not support IVIG use. 20,27 

2. Alzheimer’s disease. Further studies are needed. 113-115 A small (n = 8) study 

originally designed as an open label, dose finding, Phase I trial of IVIG in patients 

with mild Alzheimer’s disease (AD) was extended due to unexpectedly positive 

therapeutic response at 6 months. 113,116 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 








26 of 45

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 re-administered for 9 months. MMSE increased on 

average 2.5 point 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. 117,118 A large retrospective 

case-control analysis found a significant association between IVIG use and 

Alzheimer’s disease diagnosis. 119 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 

4. Anemia, aplastic. Evidence does not support IVIG use. 27,30 

5. Anemia, Diamond-Blackfan. Evidence does not support IVIG use. 27 

6. Asthma. Evidence does not support IVIG use. 24 Data showing the beneficial effects 

of IVIG are limited. 23,120-121 Further randomized controlled trials are needed in 

carefully defined groups with persistent requirements for high doses of systemic 

corticosteroids. Uncontrolled studies suggest efficacy, but 2 of 3 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. 122-127 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. 128 Double-blind, placebo-controlled 

trials that are at least 4 months long are needed. 

8. Autism. Evidence does not support IVIG use. 20,27 

9. Autologous bone marrow transplantation or HSCT. Not recommended in 

autologous transplants because the benefit is slight.1 Routine use of IVIG among 

autologous recipients is not recommended. 39,129 

10. Behcet’s syndrome, ocular manifestations. Evidence does not support IVIG use. 24 

In an uncontrolled case series IVIG was effective in controlling the acute ocular 








27 of 45

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

corticosteroids and cyclosporine. 130 A controlled trial is needed. 

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

Limited information is available. Standard treatment is to reduce the dose of 

immunosuppressive therapy and therapy with cidofovir (Vistide®) or leflunomide. 131 

In a report from one center, 8 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. 132 Prospective randomized, multi-center trials 

are needed to validate these results. 

12. Chronic fatigue syndrome. Evidence does not support IVIG use. 24 

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 284.1 ± 149.8) who were resistant to steroids received IVIG daily for 7 

to 10 days. 133 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. 24 Some of these patients may be 

hypogammaglobulinemic and if so will be evaluated by a pharmacist and/or a 

physician on a case-by-case basis to determine a coverage recommendation for the 

client. 

15. CMV disease prophylaxis in bone marrow transplant or HSCT recipients. IVIG 

is not recommended. 39,59 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. 27 However, it 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. 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. 39,59 Preemptive therapy is used in most 

cases instead of prophylaxis for CMV management. First-line preemptive therapy for 

CMV infection is ganciclovir or foscarnet. 59 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 guidelines do not include recommendations for use of IVIG in 

preemptive therapy of CMV infections. 39 

17. Diabetes mellitus. Evidence does not support IVIG use. 134-135 Antibodies against islet 

cell antigens are implicated in the autoimmune pathogenesis of type 1 diabetes 

mellitus. 23 In a 2-year randomized controlled trial, IVIG was given every 2 months to 








28 of 45

children and adults with type 1 diabetes. 134 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). Not recommended. 

Current recommendations do not include using IVIG for this indication. 39 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. Not recommended. Chronic defined as persisting or 

developing after 100 days. IVIG has been recommended for use in producing immune 

system modulation for preventing GVHD, 39 but 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. 41 (See 

Allogeneic bone marrow transplantation above under Other Uses with Supportive 

Evidence.) 

20. Heart block, congenital. Evidence does not support IVIG use. 24 

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%. 136 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. Not 

recommended. In a placebo-controlled trial, prophylactic IVIG had no benefit over 

placebo for prophylaxis of infection, interstitial pneumonia, GVHD, transplantationrelated 

mortality at 6 months, or survival at 24 months. 137 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.) 

23. Human immunodeficiency syndrome (HIV) infection, adults, for prophylaxis of 

infections. Evidence does not support IVIG use. 27,44 HAART should be used. 

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. 27 

25. Multiple sclerosis, primary progressive. Evidence does not support IVIG use. 20 

Clinical trials are needed. 20,139 Also see studies for secondary progressive below. 

26. Multiple sclerosis, secondary progressive. Evidence does not support IVIG use. 20 In 

a placebo-controlled 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). 140 The annual relapse rate was 








29 of 45

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. 141 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 

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. 20,21,23,139 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. 141 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. 139 

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. 139,141 

28. Neonates, for suspected or proven infection. Evidence does not support IVIG 

use. 156 There is not sufficient evidence to support routine administration of IVIG to 

prevent mortality from suspected or subsequently proven infections in neonates. A 

large study of the effectiveness of IVIG in neonates with suspected infection has been 

completed, results are not yet available. 156-157 Further research is needed. 

29. Neonates, high-risk hypogammaglobulinemic. Evidence does not support IVIG 

use. 24 

30. Neonates, high-risk, preterm, low birth weight, infections in (prophylaxis and 

treatment adjunct). Evidence does not support IVIG use. 1,142 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. 142 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. 143 Morbidity, mortality, and duration of 

hospitalization were not different between IVIG and placebo. 








30 of 45

31. Nephropathy, membraneous. Evidence does not support IVIG use. 24 

32. Nephrotic syndrome. Evidence does not support IVIG use. 24 

33. Neuropathy, paraproteinemic. Evidence does not support IVIG use. 24 Treatment of 

paraproteinemic neuropathies associated with multiple myeloma, amyloidosis, and 

Waldenstrom’s macroglobulinemia should be to treat the underlying disease. 27 IVIG 

is not indicated. Also see IgM Paraproteinemic demyelinating neuropathies above. 

34. Ophthalmopathy, euthyroid. Evidence does not support IVIG use. 24 

35. Otitis media, recurrent. Evidence does not support IVIG use. 24 

36. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal 

infection (PANDAS). Evidence does not support IVIG use. 27,144 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. 145 The Canadian expert panel of neurologists recommends 

IVIG as an option for treatment of PANDAS and states that diagnosis requires expert 

consultation. 20 

37. Plexopathy, progressive lumbrosacral. Evidence does not support IVIG use. 24 

38. 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. 146 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 to improve the most. 

39. Pure red cell aplasia due to myelodysplastic syndrome . Evidence does not support 

IVIG use. 27,30 This condition does not usually respond to immunosuppressive therapy 

or IVIG. 30 

40. Recurrent spontaneous pregnancy loss (RSPL) [including antiphospholipid 

antibody-positive women]. Evidence does not support IVIG use. 23 , According to 

guidelines from the American College of Obstetricians and Gynecologists, IVIG is 

not effective for preventing recurrent early (< 15 weeks of gestation) pregnancy 

loss. 147 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. 148 The American Society for Reproductive Medicine also concluded after 

reviewing 5 randomized controlled trials which assessed IVIG treatment for RSPL, 

that IVIG is not effective for primary RSPL. 149 For secondary (indicates an 

antecedent pregnancy) RSPL, there was a higher percentage of successful 








31 of 45

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. 

41. Sickle cell disease. Evidence does not support IVIG use. 27,30 A Canadian expert panel 

of hematologists states that IVIG is not recommended for routine treatment of nonlife-threatening 

delayed hemolytic transfusion reactions in patients with sickle cell 

disease but could be used for serious, life-threatening reactions. 30 

42. Surgery or trauma, for prophylaxis of infections. Evidence does not support IVIG 

use. 24 

43. 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. 150 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 guidelines for clinical trial design and outcomes in systemic 

sclerosis 151 ―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 18-36 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.” 

44. Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome 

(HUS). Evidence does not support IVIG use. 27,30 A Canadian expert panel of 

hematologists states that IVIG may be one option among adjunctive therapies when 

first-line therapy has failed. 30 

45. Thrombocytopenia, heparin-induced. IVIG is contraindicated. IVIG could 

potentially increase the risk of thrombosis. 

46. Thromobocytopenia, nonimmune. Evidence does not support IVIG use. 24 

47. Transfusion reaction. Evidence does not support IVIG use. 30 According to the 

Canadian expert panel of hematologists there is no role for IVIG in routine 

management of hemolytic transfusion reaction but is an option in urgent situations. 30 

Patients are hospitalized. 

48. Transplantation, solid organ (e.g., heart, kidney) for prophylaxis or treatment of 

cytomegalovirus (CMV) infections. Antiviral therapy is currently used. 45,152-153 

Antiviral agents (ganciclovir, valganciclovir (Valcyte)) and CMV immune globulin 

(Cytogam ® ) are effective in preventing and treating CMV in solid organ transplant 

recipients. 

49. West syndrome (infantile spasms). There is insufficient evidence to recommend 

IVIG. 68 








32 of 45

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162. Santoro RC and Prejano S. Postpartum-aquired haemophilia A; a description of 

three cases and literature review. Blood Coag Frbrinolysis. 2009;20:461-465. 

163. Argyriou AA and Makris N. Review Article: Multiple sclerosis and reproductive 

risks in women. Reprod Sci. 2008;15:755-764 

Document History: 

Approved by: Pharmacy and Therapeutics Committee, 7/13/2006 

Change Date (03/13/2008) – P&T Annual Review, no significant changes 

Change Date (03/12/2009) – P&T Annual Review, Chronic Inflammatory 

Demyelinating Polyneuropathy (CIDP) added to FDA indications, approval durations 

revised for select off-label indications 

Change Date (03/11/2010) – P&T annual review, no changes required 

Change Date (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 

Change Date (07/14/2011) – policy applied to Commercial 








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IMPORTANT NOTE: 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 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. 








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IVIG - BMC HealthNet Plan

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