Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
 **History/Background and/or General Information  
  
** Immune globulin (also referred to as gamma globulin or immunoglobulin) is a
therapeutic compound prepared from pools of plasma obtained from several
thousand healthy blood donors that contains antibodies to a wide spectrum of
antigens. Immune globulin has been utilized for immune deficiencies identified
in individuals with inherited or acquired immunodeficiencies and is used for
its capacity in combating infection as a replacement therapy and for its anti-
inflammatory and immunomodulating effects. The appropriate use of immune
globulin can decrease morbidity and mortality and improve quality of life.1,2  
  
The focus of this LCD is the United States (U.S.) Food and Drug Administration
(FDA) approved indications and the off-label indications for immune globulin
where the evidence supports such use. Immune globulin products are not generic
drugs and products are not interchangeable. A specific product needs to be
matched to patient characteristics to ensure patient safety and a change of
product should occur only with the active participation of the prescribing
provider.3  
  
The overall coverage of drugs is addressed in the CMS IOM Publication 100-02,
_Medicare Benefit Policy Manual_ , Chapter 15, Sections 50.4.1 and 50.4.2 and
includes coverage for FDA-approved drugs and unlabeled use of a drug.  
  
 **Covered Indications  
  
** Immune globulin products will be considered medically reasonable and
necessary when administered for treatment of FDA-labeled indications
(https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/immune-
globulins4).  
  
 **Off-label indications for intravenous** **immune globulin** **(** **IVIG)
products will be considered medically reasonable and necessary in the
following situations:**

  1. Multiple myeloma for recurrent infections with hypogammaglobulinemia and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection1,3,5-7
  2. Following treatment of lymphoma utilizing B-cell depleting therapies for recurrent infections with hypogammaglobulinemia and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection3
  3. Recipients of hematopoietic stem cell transplants with severe combined immunodeficiency (SCID) or other primary immunodeficiencies who are functionally agammaglobulinemic because of weak B-cell engraftment3 
  4. Recipients of allogeneic hematopoietic stem cell transplantation with chronic graft versus host disease (GVHD), recurring bacterial infections, and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection3
  5. Human Leukocyte Antigen (HLA) and ABO desensitization protocols for the prevention of acute humoral rejection in renal transplantation3
  6. The treatment of antibody mediated solid organ transplant rejection in combination with rituximab and plasma exchange (PE)3,8
  7. Treatment of hypogammaglobulinemia in solid organ transplants3
  8. Autoimmune hemolytic anemia (AIHA) when other treatment approaches have failed9-10
  9. Systemic capillary leak syndrome (SCLS)11-13
  10. Guillain-Barre syndrome (GBS) in adults1,3,14-15
  11. Moderate to severe myasthenia gravis (MG)2-3,10,15-18
  12. Lambert-Eaton myasthenic syndrome (LEMS) in individuals who fail to respond or do not tolerate other treatments3
  13. Relapsing-remitting multiple sclerosis (MS)3,19-22
  14. Neuromyelitis optica (Devic syndrome) in individuals with severe relapses not responding to corticosteroids and who are not candidates for PE3
  15. Stiff-person syndrome (also referred to as stiff-man syndrome)2-3
  16. Treatment of autoimmune encephalitis, once infection is ruled out, as an alternative in patients who fail to respond or do not tolerate other treatments23-27
  17. Treatment of Susac syndrome in combination with high-dose intravenous corticosteroids28
  18. Severe forms of polymyositis resistant to treatment with glucocorticosteroids and immunosuppressants29-30
  19. Severe forms of inclusion body myositis with dysphagia and individuals are otherwise treatment-resistant3,29-33
  20. Immune mediated necrotizing myopathy resistant to treatment with glucocorticosteroids and immunosuppressants29-30
  21. Overlap syndrome with myositis including anti-synthetase syndrome resistant to treatment with glucocorticosteroids and immunosuppressants29-30
  22. Severe systemic lupus erythematosus (SLE) in individuals who fail to respond or do not tolerate other treatments10,30
  23. Biopsy-proven autoimmune mucocutaneous blistering diseases in individuals who fail to respond or do not tolerate other treatments and individuals with rapidly progressive disease requiring a faster response than conventional therapy (i.e., pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita)3,30,34-39
  24. Toxic epidermal necrolysis (TEN)3,30
  25. Stevens-Johnson syndrome3,30
  26. Severe scleromyxedema3,30,40-41
  27. Thyroid eye disease, also referred to as Graves' disease in patients who have failed treatment with teprotumumab or have contraindications to the use of teprotumumab3,42-45

**Limitations  
  
** The following are considered not medically reasonable and necessary:

  1. The off-label use of subcutaneous immune globulin
  2. The off-label use of intravenous immune globulin not listed above in the covered indications

**  
AND  
  
** Immune globulin for the following:

  3. Routine use in the immediate peri-transplantation period for the prevention of infection or GVHD following marrow or peripheral blood allogeneic transplantation3,46
  4. Acute GVHD with hematopoietic stem cell transplantation in the immediate post-transplantation phase3
  5. Hematopoietic stem cell transplantation in the immediate post-transplantation phase with a history of sinusoidal obstructive syndrome3,46
  6. Cord blood stem cell transplantation for children or adults3
  7. Polyneuropathy associated with IgM monoclonal gammopathy10
  8. Idiopathic neuropathies10
  9. Brachial plexopathy10
  10. Adrenoleukodystrophy10
  11. Amyotrophic lateral sclerosis10
  12. Critical illness polyneuropathy10
  13. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)10

Please refer to the CMS IOM Publication 100-03, _Medicare National Coverage
Determinations (NCD) Manual,_ Chapter 1, Part 4, Section 250.3 Intravenous
Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering
Diseases for additional limitations.  
  
 **Provider Qualifications  
  
** Services will be considered medically reasonable and necessary when all
aspects of care are within the scope of practice of the provider's
professional licensure; and when all procedures are performed by appropriately
trained providers in the appropriate setting.  
  
 **Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

For more than 20 years, IVIG has been used in the treatment of a wide range of
primary and secondary immunodeficiencies. Utilization of IVIG now represents a
standard therapeutic option for many antibody deficiencies. Immune globulin is
progressively identified as a therapy for an assortment of disorders for its
capacity in combating infection as a replacement therapy and for its anti-
inflammatory and immunomodulating effects. The proper utilization of
immunoglobulin can be lifesaving.  
  
The prudent and efficient utilization of IVIG involves consideration of
several concerns associated to both the IVIG product and the patient. The
administration of IVIG, the diagnosis, and management of adverse events are
complex and require expert practice. It is vital for the prescribing provider
to carefully evaluate and monitor patients receiving IVIG for therapy to be
optimized.  
  
Most IVIG adverse reactions are rate-related, are mild, and occur in only
5-15% of infusions. They are normally described as back or abdominal pain,
nausea, breathing difficulties, chills, flushing, rash, anxiety, low-grade
fever, arthralgia, myalgias, and/or headache. More serious adverse events
include acute renal failure, neurodegeneration, and thromboembolic events,
such as myocardial infarction (MI), stroke, deep vein thrombosis, and
pulmonary embolism. These adverse reactions are very rare and are more likely
to occur in individuals receiving larger doses of IVIG but have been reported
in patients with PIs. Rare but potentially serious or life-threatening adverse
events are reported during or within days following IVIG infusions,
particularly thromboembolic events (including transient ischemic attack [TIA],
stroke and MI), acute renal dysfunction and/or failure, and acute hemolysis.
While certain causes and risk factors have been identified in specific
products at specific times, FDA requires a "Black Box Warning" about potential
thromboembolic and renal adverse effects on all pooled, plasma-derived IgG
products.47 Risk factors for these reactions include preexisting
cardiovascular disease, diabetes mellitus, dehydration, age > 65 years,
sepsis, paraproteinemia, increased blood viscosity, hypercholesterolemia, and
hypertension.  
  
To date, immune globulin has been licensed by the FDA for the following
indications: 1) treatment of primary immunodeficiencies (PIs); 2) prevention
of bacterial infections in patients with hypogammaglobulinemia and recurrent
bacterial infection due to B-cell chronic lymphocytic leukemia (CLL); 3)
prevention of coronary artery aneurysms in Kawasaki disease; 4) increasing
platelet count in idiopathic thrombocytopenic purpura (ITP) to prevent or
control bleeding; 5) treatment of chronic inflammatory demyelinating
polyneuropathy (CIDP); 6) multifocal motor neuropathy (MMN); and 7)
dermatomyositis (DM). For specific details relating to a given indication,
providers should refer to the prescriber information for the specific immune
globulin product4: <https://www.fda.gov/vaccines-blood-biologics/approved-
blood-products/immune-globulins>.  
  
Evidence-based guidelines show that IVIG replacement therapy has been
beneficial and is recommended in the following conditions/situations that lead
to a secondary humoral deficiency: 1) Multiple myeloma and after lymphoma
treatment with B cell-depleting therapies for recurrent infections with
hypogammaglobulinemia and subprotective antibody levels following immunization
against diphtheria, tetanus or pneumococcal infections, 2) Recipients of
hematopoietic stem cell transplants for SCID or other primary immunodeficiency
conditions who are functionally agammaglobulinemic because of weak B-cell
engraftment, 3) Recipients of allogeneic hematopoietic stem cell transplants
with chronic graft versus host disease, recurring bacterial infections, and
subprotective antibody levels following immunization against diphtheria,
tetanus or pneumococcal infections, 4) HLA and ABO desensitization protocols
for the prevention of acute humoral rejection in renal transplantation, 5) The
treatment of antibody mediated solid organ transplant rejection in combination
with rituximab and plasma exchange, and 6) The treatment of
hypogammaglobulinemia in solid organ transplants.  
  
Evidence-based guidelines demonstrate support for immune globulin replacement
therapy and recommend IVIG in the following autoimmune disorders: 1) Guillain-
Barre syndrome (GBS) in adults, 2) Autoimmune hemolytic anemia (AIHA) when
other treatment approaches have failed, 3) Systemic capillary leak syndrome
(SCLS), 4) Moderate to severe myasthenia gravis (MG), 5) Lambert-Eaton
myasthenic syndrome (LEMS) in individuals who fail to respond or do not
tolerate other treatments, 6) Relapsing-remitting multiple sclerosis (MS), 7)
Neuromyelitis optica in individuals with severe relapses not responding to
corticosteroids and are not candidates for PE, 8) Stiff-person syndrome, 9)
Severe forms of polymyositis resistant to treatment with glucocorticosteroids
and immunosuppressants, 10) Severe forms of inclusion body myositis with
dysphagia and individuals are otherwise treatment-resistant, 11) Immune
mediated necrotizing myopathy resistant to treatment with glucocorticosteroids
and immunosuppressants, 12) Overlap syndrome with myositis including anti-
synthetase syndrome resistant to treatment with glucocorticosteroids and
immunosuppressants, 13) Severe systemic lupus erythematosus (SLE) in
individuals who fail to respond or do not tolerate other treatments, and 14)
Biopsy-proven autoimmune mucocutaneous blistering diseases in individuals who
fail to respond or do not tolerate other treatments and individuals with
rapidly progressive disease requiring a quicker response than conventional
therapy (i.e., pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid,
mucous membrane pemphigoid (also referred to as cicatricial pemphigoid), and
epidermolysis bullosa acquisita).  
  
Evidence-based guidelines also recommend IVIG replacement therapy for the
following rare conditions: 1) Toxic epidermal necrolysis, 2) Stevens-Johnson
syndrome, 3) Severe scleromyxedema, and 4) Thyroid eye disease in patients who
have failed treatment with teprotumumab or have contraindications to the use
of teprotumumab.  
  
Peer-reviewed medical literature lends support for IVIG replacement therapy
for the following rare conditions: 1) Treatment of autoimmune encephalitis,
once infection is ruled out, as an alternative in patients who fail to respond
or do not tolerate other treatments and 2) Treatment of Susac syndrome in
combination with high-dose intravenous corticosteroids.  
  
Coverage has been extended for the above conditions consistent with FDA
approvals, current evidence-based guidelines, and peer-reviewed medical
literature.  
  
The quality of evidence in the literature is insufficient to support IVIG for
the following conditions: 1) Routine use in the immediate peri-transplantation
period for the prevention of infection or GVHD following marrow or peripheral
blood allogeneic transplantation,3,46 2) Acute GVHD with hematopoietic stem
cell transplantation in the immediate post-transplant phase,3 3) Hematopoietic
stem cell transplantation in the immediate post-transplantation phase with a
history of sinusoidal obstructive syndrome,3,46 4) Cord blood stem cell
transplantation for children or adults,3 5) Polyneuropathy associated with IgM
monoclonal gammopathy,10 6) Idiopathic neuropathies,10 7) Brachial
plexopathy,10 8) Adrenoleukodystrophy,10 9) Amyotrophic lateral sclerosis,10
10) Critical illness polyneuropathy,10 and 11) POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).10  
  
As in IVIG therapy, subcutaneous immunoglobulin (SCIG) administration should
be individualized for each patient. Currently, SCIG therapy is FDA-approved
for use in the treatment of PI diseases only; with the exception of one SCIG
product that is also approved for maintenance therapy in CIDP. Currently, data
is lacking in the literature for more widespread use of SCIG. Thus, the use of
SCIG for off-label conditions cannot be recommended at this time.