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 of 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.
This document does not pertain to the use of:
- Rho (D) Immune Globulin and WinRho SD injections for the prevention or treatment of Rh incompatibility; or
- Specific hyperimmune serum globulin after exposure to Botulinum, Cytomegalovirus, Diphtheria, Hepatitis B, Rabies, Tetanus, Vaccinia, or Varicella-Zoster; or
- Any Ig product for prophylaxis against disease (for example, GamaSTAN® SD [Grifols Therapeutics Inc., Research Triangle Park, NC] for hepatitis A prophylaxis).
Note: Please see the following related documents for additional information:
Immune globulin (Ig) therapy is considered medically necessary for the U.S. Food and Drug Administration (FDA) approved indications:
- Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) for an initial trial (up to 12 weeks), 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:
- 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
- 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), Saperstein, or Inflammatory Neuropathy Cause and Treatment (INTAC).
- Continued use of Ig after initial trial for CIDP is medically necessary when the following criteria are met:
- Clinically significant improvement in neurological symptoms is documented on physical examination; and
- 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.
The following FDA approved indications are also considered medically necessary for immune globulin (Ig) therapy:
- Treatment of primary humoral immunodeficiency (for example, congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked immunodeficiency, severe combined immunodeficiency (SCID), or Wiskott-Aldrich syndrome) when:
- There is no evidence of renal (nephrotic syndrome) and gastrointestinal (for example, protein losing enteropathy) as causes of hypogammaglobulinemia; and
- The initial, pre-treatment total IgG is less than 500 mg/dl.
- Treatment of IgG sub-class deficiency (IgG1, IgG2, IgG3, IgG4) when:
- One or more serum IgG subclasses are more than two standard deviations below the lower limits of the age adjusted norm; and
- History of recurrent sinopulmonary infections requiring antibiotic therapy; and
- Lack of, or inadequate response to immunization (for example, but not limited to pneumococcal antigen).
- Treatment of Kawasaki Syndrome:
- Within 10 days of onset; and
- Treatment for no more than 5 days.
- Treatment of immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) in individuals with either of the following;
- Symptomatic thrombocytopenia (for example, but not limited to hematuria, petechiae, bruising, gastrointestinal bleeding, gingival bleeding); or
- Platelet count less than 20,000 (adult) or 30,000 (child).
- Treatment of individuals with hypogammaglobulinemia and recurrent bacterial infection associated with B-cell chronic lymphocytic leukemia (CLL) that includes both:
- Documented history of recurrent bacterial infection or an active infection not responding to antimicrobial therapy; and
- Documentation that total IgG is less than 500 mg/dl.
Immune globulin (Ig) therapy is considered medically necessary for the following off-label indications:
- Multifocal Motor Neuropathy (MMN) initial trial (up to 4 weeks), when ONE of the following criteria are met:
- 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
- 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
- After the initial exam and electrodiagnostic testing clinical presentation suggests MMN but the diagnosis remains uncertain.
- Continued use of Ig after initial trial for MMN when the following criteria are met:
- Clinical results document an improvement in strength and function within three weeks of the start of the infusion period;
- 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.
Immune globulin (Ig) therapy is also considered medically necessary for the following off-label indications:
- Antenatal alloimmune thrombocytopenia;
- Autoimmune neutropenia;
- Dermatomyositis, refractory; (IVIG is used as a second line treatment of dermatomyositis. Corticosteroids are first-line treatments of dermatomyositis);
- Eaton-Lambert myasthenic syndrome treatment;
- Guillain-Barre Syndrome (acute demyelinating polyneuropathy) as an equivalent alternative to plasma exchange;
- Hyperimmunoglobulinemia E syndrome (HIE) treatment;
- Myasthenia Gravis, severe refractory;
- 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;
- 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;
- Prevention of infections in high-risk, preterm, low birth weight neonates;
- Stiff-person syndrome not controlled by other therapies;
- Toxic shock syndrome caused by staphylococcal or streptococcal organisms refractory to several hours of aggressive therapy;
- Solid organ transplant recipients at risk for CMV;
- Treatment of chronic parvovirus B19 infection and severe anemia associated with bone marrow suppression;
- 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) in allogeneic bone marrow transplant (BMT) recipients in the first 100 days after transplantation;
- Prevention of infection in HIV infected children;
- Refractory auto-immune mucocutaneous blistering diseases including: pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa aquisita;
- 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.
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:
- Multiple sclerosis;
- Immune optic neuropathy.
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.
|90281||Immune globulin (Ig), human, for intramuscular use [when specified for disease treatment as described in this document]|
|90283||Immune globulin, (IgIV), human, for intravenous use|
|90284||Immune globulin, (SCIg), human, for use in subcutaneous infusions, 100 mg each|
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|J1459||Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g., liquid), 500 mg|
|J1460||Injection, gamma globulin, intramuscular, 1 cc [when specified for disease treatment as described in this document]|
|J1556||Injection, immune globulin (Bivigam), 500 mg|
|J1557||Injection, immune globulin, (Gammaplex), intravenous, non-lyophilized (e.g. liquid), 500 mg|
|J1559||Injection, immune globulin (Hizentra), 100 mg|
|J1560||Injection, gamma globulin, intramuscular, over 10 cc [when specified for disease treatment as described in this document]|
|J1561||Injection, immune globulin, (Gamunex-C/Gammaked), non-lyophilized (e.g. liquid), 500 mg|
|J1562||Injection, immune globulin (Vivaglobin), 100 mg|
|J1566||Injection, immune globulin, intravenous lyophilized (e.g. powder), not otherwise specified, 500 mg [Carimune]|
|J1568||Injection, immune globulin, (Octagam), intravenous, non-lyophilized (e.g. liquid), 500 mg|
|J1569||Injection, immune globulin, (Gammagard Liquid), non-lyophilized (e.g. liquid), 500 mg|
|J1572||Injection, immune globulin, (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (e.g. liquid); 500 mg|
|J1599||Injection, immune globulin, intravenous, nonlyophilized (e.g. liquid), not otherwise specified, 500 mg|
|S9338||Home 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 10/01/2014]|
| ||All diagnoses|
| || |
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
| ||All diagnoses|
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Our bodies naturally produce antibodies to fight and create immunity against disease-causing agents such as viruses and bacteria when infections occur. Once the body has been exposed to an infection, antibodies can sometimes protect us from becoming ill if we are exposed to the same infectious agents sometime in the future. Under many circumstances a person's ability to produce their own 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 in which the individuals's body is making its own antibodies. Passive immunity conveys only temporary protection and should not be confused with getting 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 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.
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. Individuals who suffer recurrent infections because they lack, or have very low levels of, one or two IgG subclasses, but whose other immunoglobulin levels, including total IgG, are normal, are said to have a selective IgG subclass deficiency.
Since preparations of Ig are derived from donor blood, concerns about the potential for contracting diseases, such as hepatitis and HIV exist. The process used to prepare Ig for use in humans is monitored by the manufacturer and the FDA for the presence of infectious agents. The monitoring process begins with the screening of potential donors. Next, 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 labeling, practice guidelines of medical specialty organizations, published literature and drug compendia off label indications.
The American Academy of Neurology (AAN) guideline (Goodin, 2008) Disease modifying therapies in multiple sclerosis, addresses intravenous immune globulin (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
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 diagnostic criteria were addressed:
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).
The American Academy of Otolaryngology–Head and Neck Surgery Foundation guideline, Clinical practice guideline: Adult sinusitis (2007) concluded that treatment with intravenous immune globulin (IVIg) for chronic sinusitis or recurrent acute rhinosinusitis in those with humoral immune deficiency requires more research.
Chronic inflammatory demyelinating polyneuropathy (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 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 and in men more so than women. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart of that acute disease. The Food and Drug Administration (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.
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 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.
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 broken-down 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).
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 by intravenous immunoglobulin (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 4 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 2 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 finding data suggesting that IVIg has a much broader ability to regulate cellular immunity and is a modifier of complement activation and injury. Published clinical data address 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 contentious. The panel examined diagnostic and treatment regimens from transplant centers and the published literature. In regards to the use of IVIg the conference recommendation was that the initial treatment for AMR may include high dose corticosteroids, plasmaperesis 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:
- There is insufficient evidence to recommend for or against the routine use of IV Ig for desensitization for patients undergoing heart transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making.
- There is insufficient evidence to make a recommendation for or against the routine use of IV Ig for desensitization for patients undergoing lung transplantation or for the treatment of rejection; however, other factors may influence decision-making.
- There is insufficient evidence to make a recommendation for or against the routine use of IV Ig for patients undergoing liver transplantation or for the treatment of rejection/ABO-incompatible liver transplantation.
The committee further stated that:
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 IVIG 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 IVIG (Shehata, 2010).
The National Comprehensive Cancer Network® (NCCN) clinical practice guidelines for Non-Hodgkin's Lymphoma (2012) addressed the use of Ig for recurrent sinopulmonary infections "requiring IV antibiotics or hospitalization" for those with CLL when the serum IgG levels are less than 500mg/dl.
Black Box Warnings and Precautions
Black Box Warnings from the product information labels (2005-2012) for the intravenous Ig formulations include the following:
- Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with the administration of human immune globulin intravenous (IVIG) products.
- Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products that contain sucrose.
- For individuals at risk of renal dysfunction or renal failure, administer IVIG at the minimum infusion rate practicable.
Warnings and precautions from the production information labels (2005-2012) include the following:
- IgA deficient individuals with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions.
- Monitor renal function, including blood urea nitrogen, serum creatinine and urine output in individuals at risk of developing acute renal failure.
- Hyperproteinemia, increased serum viscosity and hyponatremia may occur in individuals receiving IVIG therapy.
- Thromboembolic events may occur. Monitor individuals with known risk factors for thrombotic events and consider baseline assessment of blood viscosity for those at risk of hyperviscosity.
- Aseptic Meningitis Syndrome (AMS) may occur in individuals receiving IVIG therapy, especially with high doses or rapid infusion.
- Hemolytic anemia can develop subsequent to IVIG treatment. Monitor individuals for signs and symptoms of hemolysis and hemolytic anemia.
- Monitor individuals for pulmonary adverse reactions (transfusion-related acute lung injury, TRALI).
- Individuals receiving IVIG for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for development of fever, chills, nausea, and vomiting.
- IVIG is made from human plasma and may contain infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
- Passive transfer of antibodies may confound serologic testing.
The subcutaneous Ig product information labels (2006, 2011) 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.
Antibody: Specialized gamma globulin proteins found in the blood or lymph, and 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 2 measurements. The upper and lower measurements reported are usually 2 standard deviations from the mean.
Peer Reviewed Publications:
- 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.
- Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory myasthenia gravis. Muscle Nerve. 2000; 23(4):551-555.
- Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001; 45(6):825-835.
- Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001; 45:679-690.
- Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002; 46:42-49.
- 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.
- Bachot N, Revuz J, Roujeau J. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol. 2003; 139:33-36.
- Bakker J, Metz L. Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004; 31(2):265-267.
- Cavaletti G. Current status and future prospective of immunointervention in multiple sclerosis. Curr Med Chem. 2006; 13(19):2329-2343.
- 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.
- 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.
- 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):741-53.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Hughes R, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylatechromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neural. 2008; 7:136–144.
- Ii Y, Shindo A, Sasaki R, et al. Reversible stenosis of large cerebral arteries in a patient with combined Sjogren's syndrome and neuromyelitis optica spectrum disorder. Rheumatol Int. 2008; 28(12):1277-80.
- Jolles S. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. 2005; 142:1–11.
- Jordan S, Cunningham-Rundles C, McEwan R. Utility of intravenous immune globulin in kidney transplantation: Efficacy, safety, and cost implications. Am J of Transplantation. 2003; 3(6):653-664.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevent relapses of neuromyelitis optica. Intern Med 2007; 46:1671-1672.
- Pescovitz M. Drugs for the hypersensitized patient. Current Opinion in Organ Transplantation. 2005; 10(4):279-283.
- 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.
- Qureshi AI, Choudhry MA, Akbar M, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology. 1999; 52(3):629-632.
- 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.
- Rose ME, Lang DM. Evaluating and managing hypogammaglobulinemia. Cleve Clin J Med. 2006;73(2):133-144.
- 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.
- Sander H, Latov N. Research criteria for defining patients with CIDP. Neurology 2003; 60(Suppl 3):S8–S15.
- Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001; 24:311–324.
- Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol. 2000; 22(1):40-43.
- 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.
- Strasser-Fuchs S, Fazekas F, et al. The Austrian Immunoglobulin in MS (AIMS) study: final analysis. Mult Scler. 2000; 6 Suppl 2:S9-S13.
- 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.
- Wolfe GI, Barohn RJ, Foster BM et al. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve. 2002; 26(4):549-552.
- Yarmohammadi H, Estrella L, Doucette J, et al. Recognizing primary immune deficiency in clinical practice. Clinical and Vaccine Immunology. 2006; 13(3):329–332.
Government Agency, Medical Society, and Other Authoritative Publications:
- 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 January 13, 2013.
- American Academy of Otolaryngology–Head and Neck Surgery Foundation. Clinical practice guideline: Adult sinusitis. Otolaryngology–Head and Neck Surgery. 2007; 137:S1-S31.
- Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003313. DOI: 10.1002/14651858.CD003313.
- American College of Obstetricians and Gynecologists (ACOG).Practice Bulletin No. 6, Sept 1999.
- American Society of Health-System Pharmacists® (AHFS) Hospital Formulary Service® (AHFS). Immune Globulin. AHFS Drug Information 2012®. Bethesda, MD.
- Bivigam™ [Product Information]. Boca Raton, FL. Biotest Pharmaceuticals Corporation. December 19, 2012. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/
LicensedProductsBLAs/FractionatedPlasmaProducts/UCM334609.pdf. Accessed on January 30, 2013.
- 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
- Carimune® NF, Nanofiltered [Product Information]. Kankakee, IL. CSL Behring LLC. October 2008. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/UCM152763.pdf. Accessed on October 29, 2012.
- Centers for Medicare and Medicaid Services. National Coverage Determinations:
- 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: 890–900.
- Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2009; Issue 1. Art No.:CD001797.
- Flebogamma 5% DIF® [Product Information]. Los Angeles, CA. Frigols Biologicals, Inc. December 2011. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM172599.pdf. Accessed on October 29, 2012.
- Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012, Issue 12. Art. No.: CD002277.
- Gammagard Liquid® [Product Information]. Westlake Village, CA. Baxter Healthcare Corporation. June 2012. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM070010.pdf. Accessed on October 29, 2012.
- Gammagard S/D® [Product Information]. Westlake Village, CA. Baxter Healthcare Corporation. October 2008. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM197905.pdf. Accessed on October 30, 2012.
- Gammaplex® [Product Information]. Temecula, CA. FFF Enterprises, Inc. October 7, 2009. Available at: http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/ucm182874.htm. Accessed on October 29, 2012.
- Gamunex-C® [Product Information]. Research Triangle Park, NC. Talecris Biotherapeutics, Inc. October 13, 2010. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM069968.pdf. Accessed on October 30, 2012.
- Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58:169-178. Reaffirmed July 19, 2008.
- Hizentra® [Product Information]. Kankakee, IL. CSL Behring LLC. October 3, 2011. Available at: http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/ucm202630.htm. Accessed on October 29, 2012.
- 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; 3(4):326-332.
- Hughes RAC, Raphaël J-C, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD002063. DOI: 10.1002/14651858.CD002063.pub3.
- Immune Serum Globulin. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated January 4, 2013. Available at: http://www.micromedexsolutions.com. Accessed on January 11, 2013.
- 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.
- Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guidelines for management of neuropathy. Available at: http://pnsociety.com/index.php?option=com_content&view=article&id=87&Itemid=105. Accessed on: October 29, 2012
- Guideline for management of chronic inflammatory demyelinating polyradiculoneuropathy. (2005)
- Guideline for management of paraprotein-associated demyelinating neuropathy. (2006).
- Lunn MPT, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD002827. DOI: 10.1002/14651858.CD002827.pub2.
- NCCN Clinical Practice Guidelines in Oncology™. © 2012 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on October 29, 2012.
- Non-Hodgkin's Lymphomas. (V.3.2012). Revised July 9, 2012.
- National Institutes of Health (NIH). National Institute of Neurological Disorders and Stroke (NINDS).
- Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004000. DOI: 10.1002/14651858.CD004000.
- Octagam® [Product Information]. Centreville, VA. Octapharma USA, Inc. December 2005. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/
FractionatedPlasmaProducts/ucm064946.pdf. Accessed on October 30, 2012.
- Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI: 10.1 002/ 14651858.CD000361.pub2.
- 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.
- Privigen® [Product Information]. Kankakee, IL. CSL Behring, LLC. July 26, 2007. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/Licensed
FractionatedPlasmaProducts/UCM303092.pdf. Accessed on October 30, 2012.
- Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database of Syst Rev. 2008; Issue 4. Art.No.:CD006501.
- Rosenfeld R, Andes D, Bhattacharyya N, et al. Clinical practice guideline: Adult sinusitis. Otolaryngology–Head and Neck Surgery. 2007; 137:S1-S31.
- 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.
- van Schaik IN, Winer JB, de Haan R, Vermeulen M. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database of Systematic Reviews. 2002; Issue 2. Art. No.: CD001797.
- van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD004429.
- Vivaglobin® [Product Information]. Kankakee, IL. ZLB Behring, LLC. January 9, 2006. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/Licensed
FractionatedPlasmaProducts/ucm070360.pdf. Accessed on October 30, 2012.
Intravenous Immune Globulin, Human (IVIg)
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.
| ||01/01/2014||Updated Coding section with 01/01/2014 HCPCS changes; removed C9130 deleted 12/31/2013.|
|Revised||02/14/2013||Medical Policy & Technology Assessment Committee (MPTAC) 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.|
|Revised||02/16/2012||MPTAC review. Medically necessary clinical indications for primary humoral immunodeficiency clarified to address initial, pretreatment, total IgG. |
|Revised||11/17/2011||Medical Policy & Technology Assessment Committee (MPTAC) review. Definitions section added. Discussion/General Information section updated.|
|Revised||11/16/2011||Hematology/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.|
|Revised||08/18/2011||MPTAC 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.|
|Revised||11/18/2010||MPTAC 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.|
|Revised||11/19/2009||MPTAC review. Diagnostic criteria added for CIDP and MMN. Place of service removed. Discussion and references updated.|
|Revised||11/20/2008||MPTAC review. CIDP moved from off label indications to medically necessary criteria. Discussion and references updated. Updated Coding section with 01/01/2009 HCPCS changes.|
| ||10/01/2008||Updated Coding section with 10/01/2008 ICD-9 changes.|
|Reviewed||02/21/2008||MPTAC 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.|
| ||01/01/2008||Updated Coding section with 01/01/2008 HCPCS changes; removed HCPCS J1567, Q4087. Q4088, Q4091, Q4092 deleted 12/31/2007.|
| ||10/01/2007||Updated Coding section with 10/01/2007 ICD-9 changes.|
| ||07/01/2007||Updated Coding section with 07/01/2007 HCPCS changes.|
|Reviewed||03/08/2007||MPTAC review. References updated. Coding updated; removed HCPCS J1563, J1564, Q9941, Q9942, Q9943, and Q9944, deleted 12/31/2005.|
|Revised||03/23/2006||MPTAC review. |
| ||01/01/2006||Updated Coding section with 01/01/2006 CPT/HCPCS changes|
| ||11/18/2005||Added reference for Centers for Medicare & Medicaid Services (CMS) -National Coverage Determination (NCD).|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
|Pre-Merger Organizations ||Last Review Date||Document Number||Title|
|Anthem, Inc.||09/18/2003||DRUG.00013||Intravenous Immune Globulin Therapy|
|WellPoint Health Networks, Inc.||04/28/2005||2.09.17||Intravenous Immunoglobulin as a Treatment of Recurrent Spontaneous Abortion and Associated Laboratory Tests|
| ||12/02/2004||Pharmacology Toolkit||Intravenous Immune Globulin|