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Immune Globulin Therapy (IVIg and SCIg)*

» Summary» Procedure Codes
» Description» Selected References
» Prior Approval» Policy History
» Policy
 

Medical Policy: 05.01.17 
Original Effective Date: November 2007 
Reviewed: November 2014 
Revised: November 2014 


Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.


Description: 

The intent of the immune globulin drug policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines and clinical studies.  Human immune globulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens.  There are three formulations of human IgG available, intravenous (IVIg), subcutaneous (SCIg) and intramuscular (IMIg) depot injections. IMIg is not used often in the United States due to volume constraints, painful administration, difficulty in achieving therapeutic serum levels and potential infections. This policy addresses intravenous immune globulin (IVIg) and subcutaneous immune globulin (SCIg)
 
Commercial immune globulin products are made from plasma acquired from the fractionation of whole blood of healthy donors (approximately one-third) and the remainder of the plasma is acquired from plasmapheresis.  This pooled plasma, immune globulin is an antibody-containing solution that is comprised of antibodies to greater than 10 million antigens, allowing for a wide range of antibody diversity. IVIg has been used to correct immune deficiencies in patients with either inherited or acquired immunodeficiency disease and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis. A variety of off-label uses have been investigated; some of the most common are inflammatory myopathies, neuropathies, (e.g., Guillain-Barré syndrome), myasthenia gravis, multiple sclerosis and solid organ transplantation.
 
Several immune globulin products have been approved for subcutaneous infusion. Subcutaneous infusion immune globulin (SCIg) is used for treating patients with certain primary immunodeficiency diseases. As IVIg has been established as an efficacious, safe immune globulin replacement therapy or immunomodulatory therapy, Wellmark considers SCIg an alternative to IVIg for patients that meet the criteria for primary immune deficiency. Consideration will be given to those patients in whom IVIg has failed, is not tolerated, contraindicated or the patient is already stable on a SCIg product.


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Prior Approval: 

 

Prior approval is requiredSubmit a prior approval/treatment request now .


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Policy: 

There are several immune globulin products available. Each product varies with FDA-approved indications. SCIg products are currently only FDA approved for the treatment of primary immunodeficiency disease (PID) while other products are labeled for primary immunodeficiency diseases (PID), idiopathic thrombocytopenic purpura (ITP), B-cell chronic lymphocytic leukemia (CLL), chronic inflammatory demyelinating polyneuropathy (CIDP), Kawasaki disease and /or multifocal motor neuropath (MMN).

 

Below is a table of products and their FDA approved indications.

Brand name

route

PID

ITP

CLL

CIDP

KD

MMN

Bivigam

IV

X

 

 

 

 

 

Carimune NF

IV

X

X

 

 

 

 

Flebogamma DIF

IV

X

 

 

 

 

 

Gammagard Liquid

IV/SC*

X

 

 

 

 

X

Gammagard S/D

IV

X

X

X

 

X

 

Gammaked

IV/SC*

X

X

 

X

 

 

Gammaplex

IV

X

 

 

 

 

 

Gamunex-C

IV/SC*

X

X

 

X

 

 

Hizentra

SQ

X

 

 

 

 

 

HyQvia

SQ

X

 

 

 

 

 

Octagam

IV

X

 

 

 

 

 

Privigen

IV

X

X

 

 

 

 

  *Only PID is considered FDA approved for the subcutaneous route (SC), all conditions are FDA approved for the intravenous (IV) route.

 

 

I. Subcutaneous immune globulin (SCIg) therapy may be considered medically necessary for the treatment of primary immunodeficiencies (examples provided below) if IVIg therapy has failed, is not tolerated, and is contraindicated or the patient is currently stabilized on said therapy.

o Congenital agammaglobulinemia
o Hypogammaglobulinemia
o Common variable immunodeficiency (CVID)
o Severe combined immunodeficiency (SCID)
o Wiskott-Aldrich syndrome
o X-linked agammaglobulinemia (XLA)
 

 

Note: Patients with primary immunodeficiency syndromes need to meet all the following criteria for treatment with immune globulin:

  • Laboratory evidence of the following primary immunodeficiency such as:
    • X-linked or Congenital agammaglobulinemia (total IgG < 200mg/dL)
    • CVID or hypogammaglobulinemia (total IgG < 400mg/dL, or at least 2 standard 
      deviations below normal, on at least 2 occasions)
    • OR other laboratory evidence such as absence of B lymphocytes that supports evidence of immunoglobulin deficiency

AND

  • ONE of the following as a documented inability to mount an adequate immunologic response to inciting antigens, such as:

    • Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen such as pneumococcal vaccine (abnormal response is defined as less than a four-fold rise in antibody titer)

    • Lack of appropriate rise in antibody titer following provocation with a protein  antigen such as tetanus/diphtheria vaccine (an abnormal response is defined as less than a four-fold rise in antibody titer)

AND

  • Documentation of persistent and severe infections despite treatment with prophylactic antibiotics, such as:
    • Two or more bacterial infections due to decreased or reduced IgG
    • Unexplained recurrent or persistent bacterial infections despite antibiotic treatment
    • Infections failing to respond to conservative measures including prophylactic antibiotics

Approval will be for lifetime.

 

 

II. Intravenous immune globulin (IVIg) therapy may be considered medically necessary for the following conditions:

  • Primary immune deficiency syndromes, including combined immunodeficiencies
    • Common variable immunodeficiency (CVID)
    • Congenital agammaglobulinemia
    • X-linked agammaglobulinemia (XLA or Bruton’s)
    • X-linked hyper-IgM syndrome
    • Severe combined immunodeficiency (SCID)
    • Wiskott-Aldrich syndrome
    • Ataxia telangiectasia


Note: Patients with primary immunodeficiency syndromes need to meet the following criteria for treatment with immune globulin:

  • Laboratory evidence to provide evidence of immunoglobulin deficiency such as:

    • X-linked or Congenital agammaglobulinemia (total IgG < 200mg/dL)
    • CVID or hypogammaglobulinemia (total IgG < 400mg/dL, or at least 2 standard deviations below normal, on at least 2 occasions)
    • OR other laboratory evidence such as absence of B lymphocytes that supports evidence of immunoglobulin deficiency

AND

  • ONE of the following as a documented inability to mount an adequate immunologic response to inciting antigens, such as:
    •  Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen such as pneumococcal vaccine (abnormal response is defined as less than a four-fold rise in antibody titer)
    • Lack of appropriate rise in antibody titer following provocation with a protein antigen such as tetanus/diphtheria vaccine (an abnormal response is defined as
       less than a four-fold rise in antibody titer)

AND

  • Documentation of persistent and severe infections despite treatment with prophylactic antibiotics, such as:
    • Two or more bacterial infections due to decreased or reduced IgG
    • Unexplained recurrent or persistent bacterial infections despite antibiotic treatment
    • Infections failing to respond to conservative measures including prophylactic antibiotics

 

  • Acute humoral rejection

 

  • Autoimmune mucocutaneous blistering diseases, in patients with severe, progressive disease, for whom, conventional agents (e.g., corticosteroids, azathioprine, cyclophosphamide) have either been tried or are inappropriate for use
    • Pemphigus
    • Pemphigoid
    • Pemphigus vulgaris
    • Pemphigus foliaceus
    • Steven’s-Johnson syndrome
    • Toxic epidermal necrolysis (TEN)

 

  • Autoimmune and inflammatory disorders
    • Dermatomyositis refractory to treatment with steroids; in combination with other immunosuppressive agents such as azathioprine or methotrexate
    • Kawasaki syndrome

 

  • Neuroimmunological
    • Myasthenia gravis in patients with chronic debilitating disease in spite of treatment with cholinesterase inhibitors, or complications from or failure of steroids and/or azathioprine
    • Myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) in patients with contraindications to plasma exchange
    • Guillain-Barré syndrome
    • Chronic inflammatory demyelinating polyneuropathy; in patients with progressive symptoms for at least two months
    • Multifocal motor neuropathy
    • Eaton-Lambert myasthenic syndrome, in patients who have failed to respond to anticholinesterase medications and/or corticosteroids
    • Anti-NMDA (N-methyl D-aspartate) encephalitis
    • Stiff-person syndrome (SPS) or Moersch-Woltman syndrome, presence of anti-GAD antibodies and unresponsive to benzodiazepines and/or baclofen, valproate or gabapentin

 

  • Hematologic
    • Acute, severe immune thrombocytopenic purpura (ITP)
      1. Active bleeding with a platelet count < 30,000/m3; OR
      2. Preoperative treatment prior to a major surgical procedure 
    • Chronic idiopathic, immune thrombocytopenic purpura (ITP)
      1. Disease duration > 6 months
      2. Persistent thrombocytopenia despite treatment with corticosteroids and splenectomy 
    • Neonatal alloimmune thrombocytopenia
    •  Allogeneic post-bone marrow transplant setting
    • B-cell chronic lymphocytic leukemia (CLL); in patients with hypogammaglobulinemia and persistent bacterial infections
    • Warm autoantibody autoimmune hemolytic anemia; refractory to steroids and immunosuppressive agents
    • Anti-phospholipid syndrome
    • Severe anemia due to parvovirus B19

 

  • Infectious diseases
    • HIV-infected patients
    • Toxic shock syndrome
    • Kawasaki disease with aspirin
    • Patients with primary defective antibody synthesis

 

  • Transplantation

    • Prior to sold organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ

    • Following solid organ transplant, treatment of antibody-mediated rejection


Approval will be for lifetime.

 


IVIg is considered not medically necessary as a treatment of relapsing/remitting multiple sclerosis.
 
Other applications of IVIg therapy that are considered, not medically necessary including, but not limited to, the following conditions*

 

* If through clinical review of a member specific case, Catamaran identifies one of the following uses as supported by Wellmark recognized compendia, please notify Wellmark to make the appropriate update to this list.
 

  • Chronic progressive multiple sclerosis
  • Refractory rheumatoid arthritis and other connective tissue diseases including systemic lupus erythematosus
  • Recurrent spontaneous abortion
  • Inclusion-body myositis
  • Polymyositis, including refractory polymyositis
  • Other vasculitides besides Kawasaki disease, including vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA; e.g., Wegener’s granulomatosis, polyarteritis nodosa), Goodpasture’s syndrome, and vasculitis associated with other connective tissue diseases
  • Thrombotic thrombocytopenic purpura
  • Hemolytic uremic syndrome
  • Paraneoplastic syndromes, other than Eaton-Lambert myasthenic syndrome
  • Demyelinating polyneuropathy associated with IgM paraproteinemia
  • Epilepsy
  • Chronic sinusitis
  • Asthma
  • Chronic fatigue syndrome
  • Aplastic anemia
  • Diamond-Blackfan anemia
  • Red cell aplasia
  • Acquired factor VIII inhibitors
  • Hemophagocytic syndrome
  • Acute lymphoblastic leukemia
  • Multiple myeloma
  • Immune-mediated neutropenia
  • Nonimmune thrombocytopenia
  • Cystic fibrosis
  • Recurrent otitis media
  • Diabetes mellitus
  • Behçet’s syndrome
  • Adrenoleukodystrophy
  • Organ transplant rejection other than as described above
  • Uveitis
  • Demyelinating optic neuritis
  • Recent-onset dilated cardiomyopathy
  • Fisher syndrome
  • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
  • Autism
  • Complex regional pain syndrome
  • Alzheimer disease
  • IGG sub-class deficiency
  • Sepsis including neonatal sepsis
  • Crohn’s disease
  • Opsoclonus-myoclonus
  • Birdshot retinopathy
  • Epidermolysis bullosa acquisita
  • Necrotizing fasciitis
  • Polyradiculoneuropathy (other than CIDP)

_____________________________________________________________________________________________________________________________________________________________________________________________

 

CLINICAL RATIONALE

 

Immune globulin therapies have been around for more than 50 years and have been providing lifesaving treatment for patients with antibody deficiencies. Prior to the 1970’s, immune globulin therapies were administered subcutaneously or intramuscularly. IVIg was then developed and has continued to evolve. The products today are considered third and fourth generation.

 

Immune globulin (Ig) is a blood product that is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens.  These purified antibodies (B cells) have a wide variety of indications. Although Ig products are often used interchangeably, no two products are identical. There are manufacturing and content differences among products (e.g.; sugar content, IgA content and osmolality/osmolarity).


Ig provides passive immunity. Ig has been used to correct immune deficiencies in patients with either inherited or acquired immunodeficiencies and have also been investigated as an immunomodulator in diseases thought to have an autoimmune basis.  Currently there are six indications that are FDA approved for specific Ig products: 1) treatment of primary immune deficiencies (PID) 2) increase the platelet count of idiopathic thrombocytopenic purpura to prevent or control bleeding 3) chronic inflammatory demyelinating polyneuropathy (CIDP) 4) multifocal motor neuropathy (MMN) 5) prevention of bacterial infections in patients with chronic lymphocytic leukemia (CLL) 6) prevention of coronary artery aneurysms in Kawasaki disease. Not all the currently available products are approved for every indication.   A variety of off-label uses have been investigated, such as inflammatory myopathies, neuropathies (e.g., Guillain-Barré syndrome), myasthenia gravis, multiple sclerosis and solid organ transplantation. The off-label use of Ig has been reported to compromise from 50-80% of its actual use.

 
It is important to note that an FDA off-label designation does not suggest that the indication is inappropriate. Since a majority of requests for Ig therapy may be for off-label uses, versus FDA approved uses, a prior authorization policy exists to ensure that Ig therapy is being used for indications that are evidence-based. This policy is reviewed annually and updated regularly in order to review potential new approvable indications.


PRIMARY AND SECONDARY IMMUNODEFICIENCIES
All Ig products (IVIg and SCIg) are FDA approved for the indication of PID. There are over 130 primary immunodeficiency diseases according to the World Health Organization. They may be inherited or a genetic defect and can affect anyone regardless of age or gender. Although the diseases differ, they share one common feature: each results in a defect in one of the functions of the body’s normal immune system. Patients with significantly decreased humoral immunity are dependent upon Ig therapy for survival. Patients with PID have an increased risk of infection as a result of this disruption to the immune system. This increased susceptibility to infections may manifest itself as repeated or persistent infections. Appropriate treatment preserves organ function, improves quality of life, prevents infection-related death and increases lifespan.


Per the American Academy of Allergy, Asthma and Immunology (AAAAI) Position Paper: Use of IVIG January 2005, the decision to treat with Ig should be based on 1) abnormalities of serum immune globulin concentration, 2) clinical history of infections, and when appropriate 3) the demonstrated inability to produce antibody normally following antigenic stimulation. Treatment with Ig will provide a decrease in severity and frequency of infections.


Primary Immunodeficiences
Ig is indicated for replacement therapy for patients with PID characterized by absent or deficient antibody production especially with recurrent or unusually severe infections. Agammaglobulinemia (no antibody production) can occur because of the absence of functionally mature B cells. Deficient antibody production is defined by decreased concentrations or the inability to respond to antigenic challenge with IgG production or both. This is often referred to as common variable immunodeficiency (CVID) which can be a result of several genetic abnormalities. Patients with CVID are predisposed to chronic lung disease and pulmonary deterioration. Replacement of Ig will prevent the progression of lung disease and reduce the incidence of pneumonia.


Hyper-IgM syndromes are characterized by hypogammaglobulinemia with severely impaired production of specific antibody. It can be caused by X-linked or autosomal recessive varieties. B cells are present, but there is an inability to generate specific antibodies and there will be decreased levels of IgG and IgA and increased/normal levels of IgM. Ig replacement decreases meningitis and pneumonia in these patients.  Ig therapy is appropriate for patients that show a well-documented “non-response” to polysaccharide challenge and show evidence of difficult to treat, recurrent severe infections.


Wiskott-Aldrich syndrome is another disease characterized by normal total IgG levels but has impaired specific antibody responses to polysaccharide and protein antigens.

 
There were no studies in the 1950’s comparing IMIg with placebo or another treatment arms as Ig replacement made intuitive good sense for patients with endogenous B cell failure. The first major randomized trials for replacement Ig therapy were in the 1970s when IVIg was developed and demonstrated that IVIg was as good or superior to IMIg in reducing infection frequency in patients with PID.  Studies continued comparing doses of IMIg to larger doses of IVIg. These studies established that IVIg was superior to IMIg. The dose needed to prevent symptoms is dependent upon the severity of the antibody defect and the catabolism of the IVIg. The benefits of IVIg can take up to 4 to 6 months to become apparent.

 
The National Advisory Committee on Blood and Blood Products and Canadian Blood Services published a guideline in 2010 on the use of immune globulin therapy for patients with primary immune deficiency.  The recommendations were based in systematic review of evidence.  Per the evidence of 19 observational studies, the panel agreed there was sufficient evidence do demonstrate that immunoglobulin therapy reduces the rate of infection and hospitalization in patients with PID, which likely leads to a lower mortality and improved quality of life, such that immune globulin therapy is medically necessary for treatment of PID.


Common Variable Immune Deficiency (CVID) diagnosis is not commonly made until patients are in their third or fourth decade of life, although 20% of the symptoms are noted during childhood. It usually presents as recurrent infections of the ears, sinuses and lungs. CVID patients have depressed antibody responses and low levels of immunoglobulins in their blood. Some of the antibodies that are produced may attack their own tissues (autoantibodies). These autoantibodies can often cause arthritis and endocrine disorders. Gastrointestinal issues are common with patients with CVID, possibly due to malabsorption issues, inflammatory bowel disease or parasitic issues. Polyarthritis can manifest in larger joints due to due to suboptimal treatment. Patients with CVID may also have an increased risk of lymphoid and gastrointestinal cancers. CVID patients will typically have low levels of serum immunoglobulins, IgG, often IgA and sometimes IgA. They will also have very low or absent response to antigen challenge. They normally have enough cells to produce B lymphocytes, but these cells do not fully mature to plasma cells to make immunoglobulins and antibodies for the blood stream and secretions. In the absence of a significant T-lymphocyte defect or organ damage, Ig therapy will almost always bring improvement of symptoms. The goal of treatment is to keep the patient infection-free and prevent chronic inflammatory changes in the tissues.


X-linked agammaglobulinemmia (Bruton’s or XLA) and ARA (autosomal recessive agammoglobulinemia), are genetic diseases with the basic defect being the inability to produce antibodies, due to an underlying failure of B-lymphocyte precursors to mature into B-cells. These patients will develop infections that are usually mucous membrane-related (sinus, ears and lungs) but can also have blood borne infections usually caused by pneumococcus, streptococcus, staphylococcus and Haemophilus influenza. Infections do not usually appear until six to 18 months after birth (loss of mother’s acquired immunity). Gastrointestinal symptoms/disorders are common. Recurrent infections in a small child with abnormally small tonsils or lymph nodes should cause consideration for the diagnosis of agammaglobulinemia. Immunoglobulins will be markedly reduced or absent although occasionally IgG and IgM are present. As babies only make small amounts of immunoglobulins in the first months of life it is difficult to determine true immunodeficiency. A low percentage of B-cells in peripheral blood is the most reliable lab finding to determine XLA or ARA.


Severe Combined Immune Deficiency (SCID) is a genetic defect characterized by the combined absence of B lymphocyte and T lymphocyte function and is potentially fatal. SCID is considered the most serious of the PIDs and there are at least 13 genetic defects that have been identified to cause SCID, thus causing laboratory findings to vary. The most common form of SCID affecting 45% of all cases is X-SCID, a mutation in the X-chromosome. X-SCID is characterized by very low T-lymphophocytes and high B-lymphocytes. The B-lymphocytes are nonfunctional however due to the abnormal receptors of growth factors on their cell surfaces. Adenosine Deaminase Deficiency (ADD), Deficiency of the Alpha Chain of the IL-7 Receptor, Deficiency of Janus Kinase 3, Deficiencies of CD3 chains and Deficiencies of CD45 are examples of other forms of SCID. Combined Immune Deficiency (CID) are less severe although not an easily distinguishable form of SCID. Due to increased rates of successful stem cell transplantation, particularly in patients without an HLA-matching sibling donor, this has become a more acceptable treatment in patients with CID. Patients with SCID are depicted with severe infections and life-threatening illnesses that normally children would not have, such as pneumonia or meningitis. Live-virus vaccines pose a threat to children with SCID as well as fungal infections that can be difficult to treat. Diarrhea due to malabsorption and skin rashes are common. Immune globulin levels of all classes are very low with these patients, although IgG may be present from the mother for a few months. Positive family history may prompt screening at birth (or prior if the gene defect has been identified) and some states perform routine screening on all newborns. Diagnosis is often made with peripheral blood lymphocyte counts (complete and differential) to identify the absolute lymphocyte count. (SCID average is 1500 per cubic millimeter while normal is considered 4000 per cubic millimeter).


Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder characterized in children with a wobbly, staggering gait. There is a progressive decline in motor function. Respiratory infections can be life-threatening. Diagnosis is usually made by common clinical features with supporting lab tests. Elevated alpha-feroprotein is usually seen after age 18 to 24 months in 95% of patients. Other confirmatory laboratory tests are available, e.g. elevated blood protein of CA125 and absence of the ATM protein on a Western blot.


Dosing and intervals should be based on patients’ response and adjusted for optimal clinical results. Once deficient antibody production has been documented, infusions are administered every three to four weeks (initial dose is usually is usually 400-600 mg/kg). Doses and intervals are titrated to achieve trough IgG levels. Usually a trough greater than 500 mg/dL is used for agammaglobulinemic patients, many practitioners use the pretreatment level plus 300 mg/dL for patients with CVID. Higher doses may be more useful in patients with chronic lung disease (greater than 800 mg/dL). Due to the variability among patients, a given dose of Ig will result in a different trough level in patients with similar body mass. Monitoring trough levels should be used to optimize therapy for agammaglobulinemic and hypogammaglobulinemic patients. In patients with deficient but partial IgG production such as CVID, troughs should be used as guidance and not as the primary benchmark for guiding therapy and the dose must be individualized to achieve clinical effect.

 

AUTOIMMUNE DISEASES
Immune thrombocytopenic purpura (ITP) affects both children and adults. Children can recover spontaneously from the disorder. Regardless, treatment is usually provided for children at the greatest risk for bleeding complications. Steroids remain the drug of choice for initial treatment of acute ITP. Several studies in adult ITP suggest that steroids alone can increase the platelet count unless clinical features of hemorrhage have developed. IVIg has been considered second-line therapy for many years with rituximab as third-line therapy. If after 6 months of medical management there is a failure to increase the platelet count to a safe range of about 30,000/m3, a splenectomy should be considered. The mechanism of action for Ig is believed to be mediated by the immunomodulatory capacity exerted by Fc receptor blockade and potentially through ligation of inhibitory Fc receptors.


KAWASAKI DISEASE (KD) is an acute febrile childhood vasculitis of medium–sized vessels commonly affecting the coronary arteries. The origin is unknown but it is felt to be infectious or post-infectious in nature. Ig with aspirin is the standard of care for children for the first 10 days of the syndrome to prevent the development of coronary aneurysms. All patients should be given a 2g/kg dose as soon as diagnosed. Usually reductions in fever, neutrophil counts occur within 24 hours. It is theorized that the Ig neutralizes bacterial super antigen toxins that lead to vascular endothelial inflammation.

 

NEUROLOGIC DISEASES
IVIg has been used successfully patients diagnosed with Stiff-Person Syndrome (Moersch-Woltman Syndrome). These patients are characterized by high levels of anti-GAD antibodies and symmetric muscle rigidity and spasms. It is often associated with other autoimmune diseases such as diabetes mellitus and thyroiditis. In a small randomized study, 16 patients were treated with 1 gram/kg/day for 2 consecutive days or placebo for 3 months. After a washout period of one month, patients were then crossed over to the alternative therapy for another 3 months and then followed for 3 months after treatment. The results demonstrated a decline in stiffness for the patients that were treated with IVIg in the first part of the trial, but rebounded when using placebo after the cross over. The placebo group maintained the same level of stiffness, but showed significant improvement when using the IVIg after cross over. Benefits varied in the patients, but 11 of the 16 were able to walk unassisted after receiving the IVIg and serum titers of anti-GAD antibodies declined after administration of IVIg.

 

OTHER USES
Autoimmune blistering disease
Pemphigoid is an autoimmune, vesiculobullous erosive disease affecting the mucosa and despite long doses of immunosupressives, 25% of patients with bullous pemphigoid do not respond. Pemphigus is a group of autoimmune blistering diseases that involve the skin and mucous membranes. Conventional therapy is commonly corticosteroids, immunosuppressive agents such as azathioprine and mycophenolate and anti-inflammatories alone or in combination, but not all patients respond. Pemphigus vulgaris is an autoimmune blistering disease that causes antibodies to bind to desmoglein in the skin interfering with normal skin function. Per 158 patients followed that received high-dose immune globulin therapy, 92% had overall improvement, Adjunctive therapy was slightly better with 97% showing improvement. These studies were largely uncontrolled and heterogeneous. In patients that are treatment-resistant to conventional therapy, addition of high dose immune globulin therapy might be considered.  After remission is attained, many patients can reduce and discontinue IVIg.





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Procedure Codes and Billing Guidelines: 

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes
  • J1557 Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g., liquid), 500 mg
  • J1559 Injection, immune globulin (Hizentra), 100 mg
  • J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), 500 mg
  • J1568 Injection, immune globulin, (Octagam), intravenous, non-lyophilized, (e.g. liquid), 500 mg
  • J1569 Injection, immune globulin, (Gammagard liquid), intravenous, non-lyophilized, (e.g. liquid), 500 mg
  • J1572 Injection, immune globulin, (Flebogamma), intravenous, non-lyophilized, (e.g. liquid), 500 mg
  • J1561 Injection, immune globulin, (Gamunex), intravenous, non-lyophilized, (e.g. liquid), 500 mg
  • J1556 Injection, immune globulin (Bivigam), 500 mg
  • J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
  • J3490/J3590 Injection, immune globulin (HyQvia), subcutaneous, human immunoglobulin G and Hyaluronidase (human recombinant)
  • 90283 Immune globulin (IgIV), human, for intravenous use
  • 90284 Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
  • 96369 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to 1 hour, including pump set-up and establishment of subcutaneous infusion site(s)
  • 96370 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
  • 96371 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); additional pump set-up with establishment of new subcutaneous infusion site(s) (List separately in addition to code for primary procedure)   

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Selected References: 

  • Bivigam (immune globulin intravenous) [prescribing information]. Biotest Pharmaceuticals Co: Boca Raton, FL; August 2013.
  • Carimune NF (immune globulin intravenous) [prescribing information]. CSL Behring LLC: Kankakee, IL; August 2013.
  •  Flebogamma DIF (immune globulin intravenous) [prescribing information]. Grifols Biologicals Inc: Los Angeles, CA; August 2013.
  • Gammagard Liquid (immune globulin infusion) [prescribing information]. Baxter Healthcare Corporation: Westlake Village, CA; September 2013.
  • Gammagard S/D (immune globulin intravenous) [prescribing information]. Baxter Healthcare Corporation: Westlake Village, CA; September 2013.
  • Gammaked (immune globulin injection) [prescribing information]. Talecris Biotherapeutics Inc: Research Triangle Park, NC; September 2013.
  • Gammaplex (immune globulin intravenous) [prescribing information]. Bio Products Laboratory: Elstree, Hertfordshire UK: September 2013.
  • Gamunex-C (immune globulin injection) [prescribing information]. Talecris Biotherapeutics Inc: Research Triangle Park, NC; September 2013.
  • Octagam (immune globulin intravenous) [prescribing information].  Octapharma USA Inc: Centreville, VA; September 2013.
  • Privigen (immune globulin intravenous) [prescribing information].  CSL Behring LLC: Kankakee, IL; August 2013.
  • Hizentra (immune globulin subcutaneous) [prescribing information].  CSL Behring LLC: Kankakee, IL; September 2013.
  • Orange JS, Hossny EM, 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 Apr;117(4 Suppl):S525-53.
  • Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol 2008; 101(2):114-21.
  • Hoffmann F, Grimbacher B, Thiel J et al. Home-based subcutaneous immunoglobulin G replacement under real-life condition in children and adults with antibody deficiency. Eur J Med Res 2010; 15(6):238-45.
  • 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):1728-36.
  • Goebel A, Baranowski A, Maurer K et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome. Ann Intern Med 2010; 152(3):152-8.
  • Gurcan HM, Jeph S, Ahmed AR. Intravenous immunoglobulin therapy in autoimmune mucocutaneous blistering diseases: a review of the evidence for its efficacy and safety. Am J Clin Dermatol 2010; 11(5):315-26.
  • Feasby T, Banwell B, Benstead T et al. Guidelines on the ise on intravenous immune globulin for neurologic conditions. Transfus Med Rev 2007; 21(2 Suppl 1): S57-107
  • 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):S7-27.
  • Bucuvalas JC, Anand R. treatment with immunoglobulin improves outcome for pediatric liver transplant recipients. Liver Transpl 2009; 15(1):1594-9.
  • Anderson D, Ali K, Blanchette V et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfuse Med Rev 2007; 21(2 Suppl 1): S9-56.
  • Hughes RA, Swan AV, Raphael JC et al. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain 2007; 130(Pt 9):2245-57.
  • Cordonnier C, Chevret S, Legrand M et al. Should immunoglobulin therapy be used in allogeneic stem cell transplantation? A randomized, double-blind, dose effect, placebo-controlled multicenter trial. Ann Intern Med 2003; 139(1):8-18.
  • Shehata N, Palda V, Bowen T et al. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev 2010; 24(Suppl 1): S28-50.
  • Tichy E. Immune Globulin Treatment: What Every Pharmacist Should Know. https://www.pharmqd.com/. Release date 3/29/13. Accessed August 10, 2014.
  • Tonkovic B, Rutishauser L. Descriptive Reviw and Analysis of Immunoglbulin Utilization Management from 2,548 Prior Authorization Requests. www.amcp.org. JMCP Vol 20, No.4. April 2014.
  • Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. Ann Allergy Asthma Immunol Sept 2007; 99(3): 281-283. doi: 10.1016/S1081-1206(10)-60665-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099256/. Accessed October 24, 2014.
  • AAAAI (American Academy of Allergy, Asthma & Immunology). Eight Guiding Principles for Effective Use of IVIG for Patients with Immunodeficiency. http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20Resources/IVIG-guiding-principles.pdf. Accessed October 28, 2014.
  • Haeney M. Intravenous immune globulin in primary immunodeficiency. Clin Exp Immunol 1994; 97 (Suppi 1):l1-15.
  • Jolles S, Sewell W, and Misbah S. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. doi:10.1111/j.1365-2249.2005.02834.x
  • Immune Thrombocytopenic Purpura. http://emedicine.medscape.com/article/202158-overview. Accessed October 28, 2014.
  •  Immune Deficiency Foundation (IDF). http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/. Accessed October 30, 2014.
  • Shehata N, Palda V, etal. The Use of Immunoglobulin Therapy for Patients With Primary
  • Immune Deficiency: An Evidence-Based Practice Guideline. Transfus Med Rev 2010; 24(Suppl 1):S28-50.
  • Jolles S. High-dose intravenous immune globulin (hdIVIg) in the treatment of autoimmune blistering disorders. Clin Exp Immunol. Sep 2002; 129(3): 385–389. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906471/. Accessed November 19, 2014.
  • Todman D, Stiff-Person Syndrome (Moersch-Woltman Syndrome). Internet Scientific Publications. The Internet Journal of Neurology, Volume 7, no 1. https://ispub.com/IJN/7/1/5243 Accessed November 20, 2014.
  • Elovara I, Apolstoski S, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases. European Journal of Neurology 2008, 15: 893–908. http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2008.02246.x/pdf. Accessed November 20, 2014.
  • Wassernan R, Irani A-M, etal. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease. Clin Exp Immunol. Sep 2010; 161(3): 518–526.
  • HyQvia (immune globulin subcutaneous) [prescribing information]. Baxter Healthcare Corporation. Westlake Village, CA. September 2014.

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Policy History: 

 

Date                                        Reason                               Action

September 2010                     Annual review                     Policy renewed

November 2011                      Annual review                     Policy revised

November 2012                     Annual review                      Policy renewed

April 2013                             Interim review                      Policy revised

November 2013                     Annual review                      Policy revised

November 2014                     Annual review                      Policy revised


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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.

 
Contact Information
New information or technology that would be relevant for Wellmark to consider when this policy is next reviewed may be submitted to:
  Wellmark Blue Cross and Blue Shield
  Medical Policy Analyst
  P.O. Box 9232
  Des Moines, IA 50306-9232
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