Clinical UM Guideline


Subject:  Immune Globulin (Ig) Therapy
Guideline #:  CG-DRUG-09Current Effective Date:  07/15/2014
Status:RevisedLast Review Date:  05/15/2014

Description

Immune globulin or immunoglobulin (Ig) is a blood product that is given for the treatment of primary immunodeficiency diseases featuring low or dysfunctional antibody levels and for certain inflammatory, autoimmune and other diseases featuring low antibody levels.  Ig is also used for removal of harmful antibodies and for blocking damage from immune cells.  Ig may be administered intravenously (IVIg) or subcutaneously.

This document does not pertain to the use of the following:

Note: Please see the following related documents for additional information:

Clinical Indications

Medically Necessary: 

Immune globulin (Ig) therapy is considered medically necessary for treatment of individuals with any of the following indications:

  1. Antenatal alloimmune thrombocytopenia
  2. Autoimmune mucocutaneous blistering diseases that are refractory, which include: pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa aquisita
  3. Autoimmune neutropenia
  4. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
    1. As an initial trial (up to 12 weeks) of Ig, when the medical record indicates that the clinical presentation is not consistent with other polyneuropathies (for example, IgM neuropathy, hereditary neuropathy, diabetic neuropathy) and ONE of the following clinical and electrodiagnostic criteria are met:
      1. There is proximal muscle weakness or sensory dysfunction caused by neuropathy and nerve conduction studies (NCS) confirm there is electrodiagnostic evidence of a demyelinating neuropathy in at least two limbs; or
      2. There is distal muscle weakness and results of diagnostic testing meet a recognized set of diagnostic criteria as established by the American Academy of Neurology (AAN), or Inflammatory Neuropathy Cause and Treatment (INCAT)
    2. As continued use of Ig after initial trial for CIDP when the following criteria are met:
      1. Clinically significant improvement in neurological symptoms is documented on physical examination; and
      2. Continued need is demonstrated by documentation that attempts on an annual basis to titrate the dose or the interval of therapy result in worsening of symptoms
  5. Dermatomyositis, refractory; (IVIG is used as a second line treatment of dermatomyositis.  Corticosteroids are first-line treatments of dermatomyositis) 
  6. Eaton-Lambert myasthenic syndrome treatment
  7. Guillain-Barre Syndrome (acute demyelinating polyneuropathy) as an equivalent alternative to plasma exchange
  8. Human immunodeficiency virus (HIV)-infected children - prevention of opportunistic bacterial infection
  9. Hyperimmunoglobulinemia E syndrome (HIE) treatment
  10. Hypogammaglobulinemia and recurrent bacterial infection associated with B-cell chronic lymphocytic leukemia (CLL) that includes both:
    1. Documented history of recurrent bacterial infection or an active infection not responding to antimicrobial therapy; and
    2. Documentation that total IgG is less than 500 mg/dl
  11. IgG sub-class deficiency (IgG1, IgG2, IgG3, IgG4) when the following are met:
    1. One or more serum IgG subclasses are more than two standard deviations below the lower limits of the age adjusted mean; and
    2. History of recurrent sinopulmonary infections requiring antibiotic therapy; and
    3. Lack of, or inadequate response to immunization (for example, but not limited to pneumococcal antigen)
  12. Immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) in individuals with either of the following:
    1. Symptomatic thrombocytopenia (for example, but not limited to hematuria, petechiae, bruising, gastrointestinal bleeding, gingival bleeding); or
    2. Platelet count less than 20,000 per microliter (mcL) (adult) or 30,000  mcL (child)
  13. Kawasaki Syndrome:
    1. Within 10 days of onset; and
    2. Treatment for no more than 5 days
  14. Multifocal Motor Neuropathy (MMN) for either of the following:
    1. As an initial trial (up to 4 weeks) to treat MMN, when ONE of the following criteria are met:
      1. There is asymmetric weakness that predominantly affects distal muscles (without upper motor neuron signs) AND nerve conduction studies confirm a demyelinating neuropathy is present (conduction block, slowing, or abnormal temporal dispersion in at least one nerve); or
      2. Clinical history and exam do not suggest upper motor neuron disease (no bulbar weakness, no upper motor neuron signs) and labs show that GM-1 antibody titers are elevated; or
      3. After the initial exam and electrodiagnostic testing clinical presentation suggests MMN but the diagnosis remains uncertain
    2. Continued use of Ig after initial trial for MMN when the following criteria are met:
      1. Clinical results document an improvement in strength and function within three weeks of the start of the infusion period; and
      2. Continued need is demonstrated by documentation that attempts on an annual basis to titrate the dose or the interval of therapy result in worsening of symptoms
  15. Myasthenia Gravis, severe refractory
  16. Neonates - Prevention of infections in high-risk, preterm, low birth weight neonates
  17. Parvovirus B19 chronic infection and severe anemia associated with bone marrow suppression
  18. Polymyositis; routine use of Ig is not recommended. Ig may be considered in individuals with severe polymyositis for whom other treatments have been unsuccessful, have become intolerable, or are contraindicated
  19. Primary humoral immunodeficiency common variable immunodeficiency (CVID) when:
    1. There is a history of recurrent sinopulmonary infections requiring antibiotic therapy; and 
    2. There is a lack of, or inadequate response to immunization (for example, but not limited to pneumococcal antigen); and 
    3. There is no evidence of renal (nephrotic syndrome) and gastrointestinal (for example, protein losing enteropathy) as causes of hypogammaglobulinemia; and 
    4. The initial, pre-treatment total serum IgG is more than two standard deviations below the lower limits of the age adjusted mean
  20. Primary humoral immunodeficiency - Other (for example, congenital agammaglobulinemia, X-linked immunodeficiency, severe combined immunodeficiency [SCID], or Wiskott-Aldrich syndrome [WAS]) when:
    1. There is no evidence of renal (nephrotic syndrome) and gastrointestinal (for example, protein losing enteropathy) as causes of hypogammaglobulinemia; and 
    2. The initial, pre-treatment total serum IgG is more than two standard deviations below the lower limits of the age adjusted mean
  21. Stiff-person syndrome not controlled by other therapies
  22. Toxic shock syndrome caused by staphylococcal or streptococcal organisms refractory to several hours of aggressive therapy
  23. Transplantation when any of the following are met:
    1. Hematopoietic stem cell transplant for either of the following:
      1. Allogeneic bone marrow transplant (BMT) recipients, in the first 100 days after transplantation, to reduce the risk of graft-versus-host disease associated with interstitial pneumonia (infectious or idiopathic) and infections (cytomegalovirus infections, varicella-zoster virus infection, and recurrent bacterial infection); or
      2. Secondary hypoglobulinemia in individuals who are immunosuppressed (for example status post bone marrow transplant) and have a documented total IgG less than 500 mg/dl
    2. Solid organ transplantation for either of the following:
      1. Prior to a medically necessary solid organ transplantation for suppression of panel reactive anti-HLA antibodies in individuals with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA); or
      2. Transplant recipients at risk for CMV

Not Medically Necessary: 

Immune globulin (Ig) therapy is considered not medically necessary for the indications listed above when criteria are not met.

Immune globulin (Ig) therapy is considered not medically necessary for all other indications not listed above as medically necessary, including but not limited to:

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

CPT 
90281Immune globulin (Ig), human, for intramuscular use [when specified for disease treatment as described in this document]
90283Immune globulin, (IgIV), human, for intravenous use
90284Immune globulin, (SCIg), human, for use in subcutaneous infusions, 100 mg each
  
HCPCS 
J1459Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1460Injection, gamma globulin, intramuscular, 1 cc [when specified for disease treatment as described in this document]
J1556Injection, immune globulin (Bivigam), 500 mg
J1557Injection, immune globulin, (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1559Injection, immune globulin (Hizentra), 100 mg
J1560Injection, gamma globulin, intramuscular, over 10 cc [when specified for disease treatment as described in this document]
J1561Injection, immune globulin, (Gamunex-C/Gammaked), non-lyophilized (e.g., liquid), 500 mg
J1566Injection, immune globulin, intravenous lyophilized (e.g., powder), not otherwise specified, 500 mg [Carimune]
J1568Injection, immune globulin, (Octagam), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1569Injection, immune globulin, (Gammagard Liquid), non-lyophilized (e.g., liquid), 500 mg
J1572Injection, immune globulin, (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (e.g., liquid); 500 mg
J1599Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg
S9338Home infusion therapy; immunotherapy, administrative services, professional pharmacy services, care coordination, all necessary supplies and equipment, per diem
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
 All diagnoses
  
Discussion/General Information

When exposed to infection, the human body produces antibodies to fight and create immunity against disease-causing agents, such as viruses and bacteria.  These antibodies can sometimes offer protection from illness if an individual is exposed to the same infectious agents in the future.  Under many circumstances, an individual's ability to produce immune globulin (Ig) is impaired and the use of other methods to boost the immune system becomes necessary.  Ig is a sterilized solution obtained from pooled human blood plasma, which contains the immunoglobulins (or antibodies) to prevent various infectious diseases.  Ig is sometimes used to aid in the prevention or progression of an illness by using a donor's antibodies to fight the illness.  This process is referred to as passive immunity, as opposed to active immunity, a circumstance in which the human body produces its own antibodies.  Passive immunity conveys only temporary protection and should not be confused with receiving an immunization, which provides longer-term protection.  The duration of Ig treatment is extremely variable depending upon the condition being treated and the individual receiving the therapy.  For some conditions, such as a primary immunodeficiency, treatment is continued indefinitely and diagnosis does not need to be reconfirmed.  For some conditions retreatment may not be needed; however, some individuals may require treatment every 3-4 weeks and others every 6-8 weeks.

Pooled Ig preparations contain many different types of immune globulins (differentiated on the basis of structure and biological activity) that target different specific immune functions of the body.  In this way, Ig imparts several types of immune fighting antibodies simultaneously.  The anti-inflammatory mechanisms of Ig action remain undetermined.  The therapeutic mechanism and the short-and long-term effects may not be the same for each condition.

Since preparations of Ig are derived from donor blood, there are concerns about the potential for contracting diseases, such as hepatitis and HIV.  The process used to prepare Ig for use in humans is monitored by the manufacturer and the U.S. Food and Drug Administration (FDA) for the presence of infectious agents.  First, the monitoring process begins with the screening of potential donors.  Second, all manufacturers use a multi-step process that extracts the desired immune globulins and attempts to remove all other substances.  Finally, samples of each batch of Ig are tested for the presence of infectious particles.  While all attempts are taken to reduce the risk of infection in the use of Ig, some small risk still exists.  Potential recipients of this treatment should take this risk into consideration when contemplating Ig therapy.  Different formulations of immune globulin are FDA-approved to be given subcutaneously (SC), intramuscular (IM) or intravenously (IV).   

The development of this document is based on the FDA label, practice guidelines of medical specialty organizations, the published medical literature, and drug compendia off-label indications. 

Chronic inflammatory demyelinating polyneuropathy (CIDP)
CIDP is a neurological disorder characterized by progressive weakness and impaired sensory function in the legs and arms.  The disorder, which is sometimes called chronic relapsing polyneuropathy, is caused by damage to the myelin sheath (the fatty covering that wraps around and protects nerve fibers) of the peripheral nerves.  This myelin damage is often documented by nerve conduction study or nerve biopsy and there is often evidence of elevated cerebral spinal fluid (CSF) protein during the course of the disease.  CIDP is difficult to diagnose due to its heterogeneous presentation (both clinical and electrophysiological).  Sander and Latov (2003) acknowledged the diagnostic difficulty of CIDP.  They attributed this in part to the lack of clarity with the diagnostic criteria for CIDP.  Without proper diagnostic criteria, many individuals might remain untreated.  In their publication, Sander and Latov (2003) presented the American Academy of Neurology (AAN), Saperstein Diagnostic Criteria and the Inflammatory Neuropathy Cause and Treatment (INCAT) electrodiagnostic criteria.

Although CIDP can occur in both genders at any age, it is more common in young adults. In addition, the disorder occurs more frequently in men than women.  CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart of that acute disease.  The FDA approved Gamunex® (Talecris Biotherapeutics, Research Triangle Park, NC) for the treatment of CIDP in September 2008.  The FDA based its approval on clinical trials that showed Gamunex® was effective at improving certain motor functions for up to 48 weeks after the initial treatment.

Chronic Lymphocytic Leukemia (CLL)
The National Comprehensive Cancer Network® (NCCN®) clinical practice guidelines for Non-Hodgkin's Lymphoma (2013) recommends the use of IVIg for individuals with a "serum IVIG <500 mg/dL with recurrent sinopulmonary infections requiring IV antibiotics or hospitalization." 

(HIV)-infection
Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children were published by the Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children (2013) for the Department of Health and Human Services.  IVIg was the primary prophylaxis recommended to prevent serious bacterial infections (such as, Streptococcus pneumoniae and other invasive bacteria) in children with HIV-infection and hypogammaglobulinemia (IgG<400 mg/dL).

IgG Subclass Deficiency
There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD and IgE.  The most prevalent immunoglobulin present in the body is IgG. The IgG class of antibodies is itself composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3, and IgG4.  The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) jointly published the Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency where IgG subclass deficiency (IGGSD) diagnostic criteria were addressed (Bonilla, 2005):

IGGSD is defined as an abnormally low level of 1 or more IgG subclasses in patients with normal levels of total IgG and IgM; IgA level may also be low. IGGSD is defined as 1 or more IgG subclass levels are 2 standard deviations (SD) below the age-adjusted mean.

The Practice Parameter also notes the diagnosis of IGGSD is controversial, and the presence of 1 or more IgG subclasses alone is "Generally not considered sufficient for a diagnosis of immunodeficiency." In individuals with recurrent infections and 1 or more low levels of IgG subclasses, a demonstrable impairment in antibody response to vaccination or natural exposure is considered the most important determinant of disease (Bonilla, 2005).

Primary Immunodeficiency
The origin for CVID, a type of primary immunodeficiency, is uncertain. CVID is a heterogenous subset of hypogammaglobulinemia conditions. Frequent infectious complications include respiratory tract infections, otitis media, sinusitis, bronchitis and recurrent pneumonias. Lower respiratory tract infections include bronchiectasis, granulomatous lung disease and lymphocytic interstitial pneumonitis. The Practice Parameter (Bonilla, 2005) notes hallmarks of CVID include IgG levels that are reduced to greater than 2 SDs below the mean. Diagnosis of CVID should be considered in individuals "Older than 2 years with recurrent upper and/or lower respiratory tract infections with encapsulated (H. influenza, S penumoniae) or atypical (Mycoplasma species) bacteria." In updated reviews of CVID, it was noted when diagnosing CVID, IgG is typically below 5 g/L and this threshold was recommended (Ameratunga, 2013; Salzer, 2012).

Individuals with Wiskott-Aldrich syndrome (WAS) have humoral abnormalities which include dysgammaglobulinemia and impaired production of specific antibodies. Individuals with WAS have some degree of impaired vaccine antibody responses.

X-linked immunodeficiency and severe combined immunodeficiency (SCID) are primary immunodeficiencies. Individuals with SCID and X-linked immunodeficiency do not have the sufficient specific immunity and are prone to opportunistic infections.

The American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Foundation guideline, Clinical practice guideline: Adult sinusitis (2007) concluded that treatment with IVIg for chronic sinusitis or recurrent acute rhinosinusitis in those with humoral immune deficiency requires more research.

Transplantation
Jordan and colleagues (2004) reported outcomes of a randomized, double-blind, placebo-controlled clinical trial for the reduction of anti-HLA antibody levels and improvement of transplant rates with IVIg.  One hundred one participants with end stage renal disease (ESRD) and highly sensitized to HLA antigens (panel reactive antibody [PRA] greater than or equal to 50% monthly for 3 months) were enrolled in a National Institutes of Health (NIH) sponsored trial (IG02).  Participants received either IVIg 2 gm/kg monthly for 4 months or an equivalent volume of placebo with additional infusions at 12 and 24 months after entry, if not transplanted.  If transplanted, additional infusions were given monthly for four months.  Baseline PRA levels were similar in both groups.  However, IVIg significantly reduced PRA levels in the IVIg group compared with placebo.  Sixteen IVIg participants (35%) and eight placebo participants (17%) were transplanted.  Rejection episodes occurred in 9 of 17 IVIg and 1 of 10 placebo subjects.  Seven graft failures occurred (four IVIg; three placebo) among adherent participants with similar two-year graft survival rates (80% IVIg; 75% placebo).  With a median follow-up of two years after transplant, the viable transplants functioned normally.  The authors concluded that IVIg is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized individuals with ESRD.

In a review, Jordan and colleagues (2011) addressed clinical applications of Ig in solid organ transplantation, and suggested that IVIg has a much broader ability to regulate cellular immunity and is a modifier of complement activation and injury.  Published clinical data addresses the use of IVIg in desensitization and treatment of antibody-mediated rejection (AMR) and are supportive for use in kidney transplant recipients, but no clinical trials using IVIg in sensitized individuals have been performed.  Additionally, the available data regarding the use of IVIg for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive.  The authors pointed out that desensitization (immunomodulation) pre- and post-solid organ transplantation requires a coordinated approach so that AMR and infectious complications are minimized.  There are currently no FDA approved drugs/protocols for desensitization.

Kobashigawa and colleagues (2009) reported recommendations from an international consensus conference addressing those who are sensitized and awaiting heart transplant.  The 71-member panel examined diagnostic and treatment regimes from transplant centers and reached consensus for anti-HLA antibody screening and testing methodology.  The desensitization recommendations pre-transplant included IVIg, plasmapheresis, and possibly rituximab.

Kobashigawa and colleagues (2011) reported recommendations from an international consensus conference addressing antibody mediated rejection (AMR) in heart transplantation.  The conference participants noted that the problem of AMR is due to the many different features of AMR making the current methods for diagnosis and treatment difficult.  The panel examined diagnostic and treatment regimens from transplant centers and the published literature.  Regarding the use of IVIg, initial treatment for AMR may include high dose corticosteroids, plasmapheresis and IVIg.

A guideline addressing the use of Ig for sensitized individuals undergoing solid organ transplantation (SOT) was developed by the Canadian Blood Services and the National Advisory Committee of Blood and Blood Products of Canada and provides the following recommendations regarding non-kidney solid organ transplantation:

The committee further stated:

There is limited methodologically rigorous evidence for the use of IV Ig for solid organ transplantation.  Future studies are needed to delineate the effect of IV Ig on desensitization using standardized methods for desensitization; the effect of IV Ig on acute rejection rates, graft survival, and overall survival; the use of the combined modality IV Ig and PP compared either to PP or IV Ig alone; and the optimum dosage of IV Ig (Shehata, 2010).

Other Proposed Uses:

Alzheimer's Disease
Alzheimer's disease (AD) is an irreversible, neurodegenerative disease that primarily affects older adults and is the most common form of dementia.  AD is definitely diagnosed only after death, through autopsy of the brain tissue and corroborating with clinical measures.  However, prior to death, individuals with memory problems and other symptoms may lead to a diagnosis of "possible or probable Alzheimer's disease" (National Institute on Aging [NIA] and the National Institutes of Health [NIH], 2012).  Key features reported in the AD brain include atrophy, loss of neurons, deposition of amyloids in specific regions, neuritic plaques and neurofibrillary tangles (Dodel, 2010).  However, the specific cause and development of AD is unclear.  Amyloid-beta (Aβ) protein deposition in the CSF and CSF tau are two biomarkers being investigated in the pathophysiological process of AD, and these biomarkers are also being studied as potential targets to treat AD.  However, at this time, the NIA- Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease do not recommend the use of AD biomarkers tests for routine diagnostic purposes, but may be useful in "investigational studies, clinical trials, and as an optional clinical tool for use where available, and when deemed appropriate by the clinician."  There is a lack of biomarker standardization for AD and additional studies of biomarkers are recommended to "determine their value and validity in practice and research settings" (McKhann, 2011).

The use of IVIg as a treatment and prevention for AD has been investigated in phase I and II clinical trials in individuals with mild to moderate AD.  The results have been mixed and there is currently an ongoing phase III randomized trial in progress.  A review by Loeffler (2013) notes the results from an unpublished placebo-controlled, phase III trial reported no significant difference in the rate of cognitive decline between the IVIg treatment group and the placebo group. 

IVIg products consist of pooled plasma and contains different volumes of antibodies, including Aβ and tau antibodies, but the quantity and specific mechanism of action is still unclear.  There is a lack of published data from large trials demonstrating the long-term efficacy and safety of IVIg to treat or prevent AD.

Immune Optic Neuritis (ON)
Ig has been studied for treatment of autoimmune optic neuropathy, specifically, optic neuritis (ON).  Roed and colleagues (2005) conducted a randomized controlled trial of 68 participants receiving IVIg (n=34) and a control group (n=34) to investigate whether IVIg treatment in the acute phase of ON could improve visual outcome and reduce disease activity as measured by magnetic resonance imaging (MRI) 6 months after disease onset.  Infusions were given at days 0, 1, 2, 30, and 60.  Contrast sensitivity, visual acuity, and color vision were measured at baseline and after 1 week, 1 month, and 6 months.  Pattern reversal visual evoked potential studies and gadolinium-enhanced MRI were performed at baseline and after 1 and 6 months.  There was no difference in the primary outcome, contrast sensitivity after 6 months, between participants randomized to treatment with IVIg or placebo.  In addition, there was no significant difference in the secondary outcome measures, improvement in the visual function measures and MRI, at any time during follow-up.  Results showed no effect of IVIg on long-term visual function following acute optic neuritis, nor was there an effect of IVIg treatment in reducing latency on visual evoked potentials.

Multiple Sclerosis
The American Academy of Neurology (AAN) guideline (Goodin, 2008) Disease modifying therapies in multiple sclerosis, addresses IVIg for the treatment of multiple sclerosis and states:

The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation*). The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation*).
*Type C recommendation C—Possibly effective, ineffective or harmful for the given condition in the specified population.

The American Academy of Allergy Asthma and Immunology (AAAAI), in their Work Group Report on the appropriate use of intravenously administered immunoglobulin (2005) states:

IVIG may also be a potentially effective second line treatment in relapsing-remitting multiple sclerosis, although the optimal dosage remains to be established.*
*AAAAI Position Statements and Work Group Reports are not to be considered to reflect current AAAAI standards or policy after five years from the date of publication. For reference only. January 2005 

Neuromyelitis Optica (NMO)
Ig has been proposed for treatment of neuromyelitis optica (NMO), which is a rare disease syndrome of the central nervous system (CNS) that affects the optic nerves and spinal cord.  In the disease process of NMO, the immune system cells and antibodies attack and destroy myelin cells in the optic nerves and the spinal cord.  NMO leads to loss of myelin, which is a fatty substance that surrounds nerve fibers facilitating neural signals to move from cell to cell.  NMO can also damage nerve fibers and leave areas of degraded tissue.  The cause of NMO is not clear.  Individuals with NMO develop optic neuritis, which causes pain in the eye and vision loss.  Spinal cord complications include transverse myelitis, which causes weakness, numbness, and sometimes paralysis of the arms and legs, along with sensory disturbances and loss of bladder and bowel control.  There are no published clinical trials demonstrating efficacy of Ig treatment.  Published literature consists of case reports and case series (Bakker, 2004; Ii, 2008; Okada, 2007).

Black Box Warnings and Precautions

Black Box Warnings from the product information labels (2013) for the intravenous Ig formulations include the following:

Additional warnings and precautions from the production information labels (2013) include the following:

The subcutaneous Ig product information labels (2013) note reactions similar to other immune globulin products may occur.  The most common adverse reactions with subcutaneous injections include local reactions (i.e., swelling, redness, heat, pain and itching at the injection site).

Please see specific product information labels for additional warnings and precautions.

Definitions

Antibody: Specialized gamma globulin proteins found in the blood or lymph that act as an immune defense against foreign agents (antigens).

Antigen: A substance, that when introduced into the body stimulates the production of an antibody.  Antigens include toxins, bacteria, foreign blood cells, and the cells of transplanted organs.

Standard deviation: A measure of variability from the average or mean.  In laboratory testing results, the average may be expressed as one measurement or as a "reference range" for acceptable values between two measurements.  The upper and lower measurements reported are usually two standard deviations from the mean.

References

Peer Reviewed Publications:

  1. Abrahamian F, Agrawal S, Gupta S. Immunological and clinical profile of adult patients with selective immunoglobulin subclass deficiency: response to intravenous immunoglobulin therapy. Clin Exp Immunol. 2010; 159(3):344-350.
  2. Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory myasthenia gravis. Muscle Nerve. 2000; 23(4):551-555.
  3. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001; 45(6):825-835.
  4. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001; 45(5):679-690.
  5. Ahmed AR, Sami N. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002; 46(1):42-49.
  6. Ameratunga R, Woon S, Gillis D, et al. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol. 2013; 174(2):203-211.
  7. Ancona KG, Parker RI, Atlas MP, Prakash D. Randomized trial of methylprednisolone versus intravenous immunoglobulin for the treatment of acute idiopathic thrombocytopenic purpura in children. J Ped Hematol Oncol. 2002; 24(7):540-544.
  8. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003; 139(1):33-36.
  9. Bakker J, Metz L. Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004; 31(2):265-267.
  10. Cavaletti G. Current status and future prospective of immunointervention in multiple sclerosis. Curr Med Chem. 2006; 13(19):2329-2343.
  11. Cherin P, Pelletier S, Teixeira A, et al. Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002; 46(2):467-474.
  12. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001; 345(26):1870-1876.
  13. Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006; 46(5):741-753.
  14. Dodel R, Neff F, Noelker C, et al. Intravenous immunoglobulins as a treatment for Alzheimer's Disease: rationale and current evidence. Drugs. 2010; 70(5):513-528.
  15. Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013; 12(3):233-243.
  16. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001; 44(1):83-88.
  17. Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobulins in management of pemphigus vulgaris. J Am Acad Dermatol. 2000; 43(6):1049-1057.
  18. Frohman L, Dellatorre K, Turbin R, Bielory L. Clinical characteristics, diagnostic criteria and therapeutic outcomes in autoimmune optic neuropathy. Br J Ophthalmol. 2009; 93(12):1660-1666. 
  19. Genevay S, Saudan-Kister A, Guerne PA. Intravenous gammaglobulins in refractory polymyositis: lower dose for maintenance treatment is effective. Ann Rheum Dis. 2001; 60(6):635-636.
  20. Gerschlager W, Brown P. Effect of treatment with Intravenous immunoglobulin on quality of life in patients with stiff-person syndrome. Movement Disord. 2002; 17(3):590-593.
  21. Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology-therapeutic considerations and practical issues. Nat Clin Pract Neurol. 2007; 3(1):36-44.
  22. Hedlund-Treutiger I, Henter J, Elinder G. Randomized study of IVIG and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Ped Hematol Oncol. 2003; 25(2):139-144.
  23. Hughes R, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol. 2008; 7(2):136–144. 
  24. Ii Y, Shindo A, Sasaki R, et al. Reversible stenosis of large cerebral arteries in a patient with combined Sjögren's syndrome and neuromyelitis optica spectrum disorder. Rheumatol Int. 2008; 28(12):1277-1280.
  25. Jolles S. Sewell WA, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol. 2005; 142(1):1–11.
  26. 26.  Jordan S, Cunningham-Rundles C, McEwan R. Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant. 2003; 3(6):653-664.
  27. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004; 15(12):3256-3262.
  28. Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011; 11(2):196-202.
  29. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003; 76(4):631-636.
  30. Jordan SC, Vo A, Tyan D, Toyota M. Desensitization therapy with intravenous gammaglobulin (IVIG): applications in solid organ transplantation. Trans Am Clin Climatol Assoc. 2006; 117:199-211.
  31. Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011; 30(3):252-269.
  32. Kobashigawa J, Mehra M, West L, et al. Report from a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant. 2009; 28(3):213-225.
  33. Loeffler DA. Intravenous immunoglobulin and Alzheimer's disease: what now? J Neuroinflammation. 2013; 10(1):70.
  34. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7(3):263-269.
  35. Miyasaka N, Hara M, Koike T, et al.; GB-0998 Study Group. Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial. Mod Rheumatol. 2012; 22(3):382-393.
  36. Noseworthy JH, O'Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. 2001; 56(11):1514-1522.
  37. Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevent relapses of neuromyelitis optica. Intern Med. 2007; 46(19):1671-1672.
  38. Pescovitz M. Drugs for the hypersensitized patient. Curr Opin Organ Tran. 2005; 10(4):279-283.
  39. Petereit HF, Reske D, Pukrop R, et al. No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis. Mult Scler. 2006; 12(1):66-71. 
  40. Qureshi AI, Choudhry MA, Akbar MS, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology. 1999; 52(3):629-632.
  41. Relkin NR, Szabo P, Adamiak B, et al. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009; 30(11):1728-1736.
  42. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005; 64(5):804-810.
  43. Rose ME, Lang DM. Evaluating and managing hypogammaglobulinemia. Cleve Clin J Med. 2006; 73(2):133-144.
  44. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency- an update. Arthritis Res Ther. 2012; 14(5): 223.
  45. Sami N, Bhol KC, Ahmen AR. Treatment of oral pemphagoid with intravenous immunoglobulins as monotherapy. Long term follow-up: influence of treatment on antibody titers to human a6 integrin. Clin Exp Immunol. 2002; 129(3):533-540.
  46. Sander HW, Latov N. Research criteria for defining patients with CIDP. Neurology. 2003; 60(Suppl 3):S8–S15.
  47. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001; 24(3):311–324.
  48. Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol. 2000; 22(1):40-43.
  49. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev. 2010; 24 Suppl 1:S7-S27.
  50. Strasser-Fuchs S, Fazekas F, Deisenhammer F, et al. The Austrian Immunoglobulin in MS (AIMS) study: final analysis. Mult Scler. 2000; 6 Suppl 2:S9-S13.
  51. Teksam M, Tali T, Kocer B, Isik S. Qualitative and quantitative volumetric evaluation of the efficacy of intravenous immunoglobulin in multiple sclerosis: preliminary report. Neuroradiology. 2000; 42(12):885-889.
  52. Wolfe GI, Barohn RJ, Foster BM, et al. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve. 2002; 26(4):549-552.
  53. Yarmohammadi H, Estrella L, Doucette J, et al. Recognizing primary immune deficiency in clinical practice. Clin Vaccine Immunol. 2006; 13(3):329–332.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Allergy, Asthma and Immunology (AAAAI). Work Group Report on the appropriate use of intravenously administered immunoglobulin. 2005. Available at: http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/IGIV-2005.pdf. Accessed on March 31, 2014.
  2. American Academy of Otolaryngology–Head and Neck Surgery Foundation. Clinical practice guideline: Adult sinusitis. Otolaryngol Head Neck Surgery. 2007; 137(3 Suppl):S1-S31.
  3. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev. 2002;(3):CD003313.
  4. American College of Obstetricians and Gynecologists (ACOG).Practice Bulletin No. 6, Sept 1999.
  5. Bivigam™ [Product Information]. Boca Raton, FL. Biotest Pharmaceuticals Corporation. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM334609.pdf. Accessed on March 31, 2014.
  6. Bonilla FA, Bernstein IL, Khan DA, et al.; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(5 Suppl 1):S1-63.
  7. Carimune® NF, Nanofiltered [Product Information]. Kankakee, IL. CSL Behring LLC. September 23, 2013. Available at:  http://www.fda.gov/downloads/BiologicsBloodVaccines/UCM152763.pdf. Accessed on March 31, 2014.
  8. Centers for Medicare and Medicaid Services. National Coverage Determinations. Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases. NCD #250.3. Effective October 1, 2002. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=158&ncdver=1&bc=AgAAQAAAAAAA&. Accessed on March 31, 2014.
  9. Donofrio PD, Berger A, Brannagan TH, et al. Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM AD HOC committee. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Muscle Nerve. 2009; 40(5):890–900.
  10. Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2009;(1):CD001797.
  11. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve society – first revision. Eur J Neurol. 2010; 17(3):356-363.
  12. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision. J Peripher Nerv Syst. 2010; 15(3):185-195.
  13. 13.  Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision. J Peripher Nerv Syst. 2010; 15(3):185-195.
  14. Flebogamma 5% DIF® [Product Information]. Los Angeles, CA. Frigols Biologicals, Inc. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM172599.pdf. Accessed on March 31, 2014.
  15. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012;(12):CD002277.
  16. Gammagard Liquid® [Product Information]. Westlake Village, CA. Baxter Healthcare Corporation. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM070010.pdf. Accessed on March 31, 2014.
  17. Gammagard S/D® [Product Information]. Westlake Village, CA. Baxter Healthcare Corporation. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM197905.pdf. Accessed on March 31, 2014.
  18. Gammaked [Product Information].  Research Triangle Park, NC. Talecris Biotherapeutics, Inc. September 2013. Available at: http://www.gammaked.com/filebin/pdf/2013-09-gammaked.pdf. Accessed on March 31, 2014.
  19. Gammaplex® [Product Information]. Temecula, CA. FFF Enterprises, Inc. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM182963.pdf. Accessed on January 13, 2014.
  20. Gamunex-C® [Product Information]. Research Triangle Park, NC. Talecris Biotherapeutics, Inc. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM069968.pdf. Accessed on March 31, 2014.
  21. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58(2):169-178. Reaffirmed July 19, 2008.
  22. Hizentra® [Product Information]. Kankakee, IL. CSL Behring LLC. September 12, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM203150.pdf. Accessed on March 31, 2014.
  23. Hughes RA, Bouche P, Cornblath DR, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006; 13(4):326-332.
  24. Hughes RAC, Raphaël JC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2006;(1):CD002063.
  25. Immune globulin Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 9, 2011. Accessed on January 13, 2014.
  26. Immune Globulin. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 13, 2013. Available at: http://www.micromedexsolutions.com. Accessed on March 31, 2014.
  27. International Neonatal Immunotherapy Study (INIS) Collaborative Group; Brocklehurst P, Farrell B, King A, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. 2011; 365(13):1201-1211.
  28. Lunn MPT, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev. 2006;(2):CD002827.
  29. Majhail NS, Rizzo JD, Lee, SJ, et al.; Center for International Blood and Marrow Transplant Research (CIBMTR), American Society for Blood and Marrow Transplantation (ASBMT), European Group for Blood and Marrow Transplantation (EBMT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT), Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ), East Mediterranean Blood and Marrow Transplantation Group (EMBMT), and Sociedade Brasileira de Transplante de Medula Ossea (SBTMO). Biol Blood Marrow Transplant. 2012; 18(3):348-371.
  30. National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology™. © 2014 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on March 31, 2014.
    • Non-Hodgkin's Lymphomas. (V.2.2014). Revised March 27, 2014.
    • Multiple Myeloma (V.2.2014). Revised November 8, 2013.
    • Prevention and Treatment of Cancer Related Infections (V.1.2013). Revised May 2, 2013.
  31. National Institute on Aging [NIA] and the National Institutes of Health [NIH]. Alzheimer's Fact Sheet. Published 2012. Available at: http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet. Accessed on March 31, 2014.
  32. National Institutes of Health (NIH). National Institute of Neurological Disorders and Stroke (NINDS).
  33. Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003;(4):CD004000.
  34. Octagam® [Product Information]. Centreville, VA. Octapharma USA, Inc. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM064946.pdf. Accessed on March 31, 2014.
  35. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev. 2004;(1):CD000361.
  36. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012; 130(3 Suppl):S1-S24.
  37. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006; 117(4 Suppl):S525-S553.
  38. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children. Department of Health and Human Services. Updated November 2013. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf.  Accessed on March 31, 2014.  
  39. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012; 78(13):1009-1015.
  40. Privigen® [Product Information]. Kankakee, IL. CSL Behring, LLC. September 23, 2013. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM303092.pdf. Accessed on March 31, 2014.
  41. Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2008;(4):CD006501. 
  42. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: Adult sinusitis. Otolaryngology Head and Neck Surgery. 2007; 137(3 Suppl):S1-S31.
  43. Sullivan KM, Dykewicz CA, Longworth DL, et al. Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program. 2001; 2001(1):392-421.
  44. Van den Bergh PY, Hadden RD, Bouche P, et al.; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur J Neurol. 2010; 17(3):356-363.
  45. van Schaik IN, Winer JB, de Haan R, Vermeulen M. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2002;(2):CD001797.
  46. van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev. 2005;(2):CD004429.
  47. Walker L, Pirmohamed M, Marson AG. Immunomodulatory interventions for focal epilepsy syndromes. Cochrane Database Syst Rev. 2013;(6):CD009945.
Index

Bivigam
Carimune NF
Flebogamma DIF
Gammagard
Gammaplex
Gamunex-C
Hizentra
Immune Globulin
Intravenous Immune Globulin, Human (IVIg)
IVIg
Octagam
Privigen

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
StatusDateAction
Revised05/15/2014Medical Policy & Technology Assessment Committee (MPTAC) review. 
Revised05/14/2014Hematology/Oncology Subcommittee review. Clarified medically necessary language for IgG sub-class deficiency (IgG1, IgG2, IgG3, IgG4). Revised medically necessary indications by addressing common variable immunodeficiency (CVID) separately from other primary humoral immunodeficiencies. Updated criteria for common variable immunodeficiency (CVID). Updated criteria for primary humoral immunodeficiency - other (e.g., congenital agammaglobulinemia, X-linked immunodeficiency, severe combined immunodeficiency [SCID] or Wiskott-Aldrich syndrome [WAS]). Updated Discussion and Reference sections.
Revised02/13/2014MPTAC review. Revised formatting for medically necessary indications. Updated Discussion/General Information, Coding, and Reference Sections. Black Box warnings updated. Updated trade names in Index section: removed Vivaglobin, Gamunex, and updated Flebogamma DIF.
 01/01/2014Updated Coding section with 01/01/2014 HCPCS changes; removed C9130 deleted 12/31/2013.
Revised02/14/2013MPTAC review. Clarified acronyms in Clinical Indication section. Discussion/General Information and Reference sections updated. Added Bivigam, black box warnings and precautions. Updated Coding section with 04/01/2013 HCPCS changes.
Revised02/16/2012MPTAC review. Medically necessary clinical indications for primary humoral immunodeficiency clarified to address initial, pretreatment, total IgG.  
Revised11/17/2011MPTAC review. Definitions section added. Discussion/General Information section updated.
Revised11/16/2011Hematology/Oncology Subcommittee review. Medically necessary criteria revised for CLL bacterial infection and Ig levels and secondary hypoglobulinemia Ig levels, as well as medically necessary criteria for IVIg treatment prior to solid organ transplant. Discussion/General Information and References updated. Updated Coding section with 01/01/2012 HCPCS changes; removed C9270 deleted 12/31/2011.
Revised08/18/2011MPTAC review. Added additional information to the FDA labeled medically necessary criteria. Multiple sclerosis, immune optic neuropathy, chronic lymphocytic leukemia when Ig levels are normal, non kidney solid organ transplant for desensitization or rejection added as not medically necessary. Discussion/General Information and References updated.
Revised11/18/2010MPTAC review. Title and medically necessary criteria changed to address Immune Globulin (Ig) Therapy. Medically necessary criteria also clarified for Ig use in hypogammaglobulinemia /recurrent bacterial infection associated with B-cell chronic lymphocytic leukemia. Additional information about Ig product examples and routes of administration added to Discussion/General Information. References updated. Updated Coding section to include 01/01/2011 HCPCS changes.
Revised11/19/2009MPTAC review. Diagnostic criteria added for CIDP and MMN. Place of service removed. Discussion and references updated.
Revised11/20/2008MPTAC review. CIDP moved from off label indications to medically necessary criteria. Discussion and references updated.  Updated Coding section with 01/01/2009 HCPCS changes.
 10/01/2008Updated Coding section with 10/01/2008 ICD-9 changes.
Reviewed02/21/2008MPTAC review. Discussion/General Information updated with AAN and AAAAI IVIg for MS position; AAO Head and Neck Surgery IVIg for PID position. References updated. Updated Coding section with 04/01/2008 HCPCS changes.
 01/01/2008Updated Coding section with 01/01/2008 HCPCS changes; removed HCPCS J1567, Q4087. Q4088, Q4091, Q4092 deleted 12/31/2007.
 10/01/2007Updated Coding section with 10/01/2007 ICD-9 changes.
 07/01/2007Updated Coding section with 07/01/2007 HCPCS changes.
Reviewed03/08/2007MPTAC review. References updated. Coding updated; removed HCPCS J1563, J1564, Q9941, Q9942, Q9943, and Q9944, deleted 12/31/2005.
Revised03/23/2006MPTAC review. 
 01/01/2006Updated Coding section with 01/01/2006 CPT/HCPCS changes
 11/18/2005Added reference for Centers for Medicare & Medicaid Services (CMS) -National Coverage Determination (NCD).
Revised07/14/2005MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger OrganizationsLast Review DateDocument NumberTitle
Anthem, Inc.09/18/2003DRUG.00013Intravenous Immune Globulin Therapy
WellPoint Health Networks, Inc.04/28/20052.09.17Intravenous Immunoglobulin as a Treatment of Recurrent Spontaneous Abortion and Associated Laboratory Tests
 12/02/2004Pharmacology ToolkitIntravenous Immune Globulin