Off-Label Use of Intravenous Immune Globulin (IVIG)

Language quoted from Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCDs) and coverage provisions in interpretive manuals is italicized throughout the policy. NCDs and coverage provisions in interpretive manuals are not subject to the LCD Review Process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). In addition, an administrative law judge may not review an NCD. See Section 1869(f)(1)(A)(i) of the Social Security Act.

Unless otherwise specified, italicized text represents quotation from one or more of the following CMS sources:

Title XVIII of the Social Security Act (SSA):

Section 1862(a)(1)(A) excludes expenses incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Section 1833(e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

CMS Publications

CMS Publication Pub 100-02, Medicare Benefit Policy Manual, Chapter 15:

50 - Drugs and Biologicals

50.4.5 - Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 17:

10 - Payment Rules for Drugs and Biologicals

NGS Abstract:
Intravenous Immune Globulin (IVIG) is a blood product containing human immunoglobulins specifically prepared for intravenous infusion. IVIG is used in the treatment of primary immunodeficiency diseases featuring low or dysfunctional antibody levels to prevent infection and for certain inflammatory, autoimmune and other diseases featuring to interfere with harmful antibodies and/or for blocking damage from immune cells.

This LCD addresses off-label uses for IVIG. We define off-label as not in Medicare approved compendia or in the FDA label.

NGS has approved IVIG for the following off label uses:

• Stiff-person syndrome may be treated with IVIG when/if standard treatment with Diazepam is no longer effective. IVIG therapy is considered medically necessary for stiff-person syndrome when the following criteria are met:
  1. Diagnosis has been confirmed by anti-glutamic acid decarboxylase (GAD) antibody testing; and
  2. Member had an inadequate response to first-line treatment (benzodiazepines and/or baclofen).
• Autoimmune retinopathy (AIR) that is sight threatening and refractory to corticosteroid and immunosuppressant therapy
  • Induction Dose - 1.5g/kg in divided dose over 3 days.
  • Maintenance Dose - 0.4 to 1.5 g/kg in single or divided doses monthly.
  • The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
• Pure red cell aplasia related to human parvovirus B19 infection - IVIG therapy is considered medically necessary for severe, refractory anemia associated with bone marrow suppression, with parvovirus B19 viremia.
• Hematopoetic Stem Cell Transplantation (HSCT) - IVIG is indicated to prevent the risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic) and infections (e.g., cytomegalovirus infections [CMV], varicella-zoster virus infection, and recurrent bacterial infection) after HSCT in patients 20 years of age or older during the first 100 days after transplantation. It is not indicated in HSCT patients younger than 20 years of age, nor is it recommended for autologous transplants. The evidence is sufficient to conclude that the complications of stem cell transplantation are independent of the source of stem cells.

• • Dosage guideline is 500 mg/kg body weight given on days –7 and –2 pre-transplantation, then weekly through day 90 post-transplantation.
• Secondary hypogammaglobulinemia - there is an association between the administration of certain pharmaceuticals and the development of hypogammaglobulinemia.
• Chronic Graft versus Host Disease (GVHD) IVIG is indicated in patient with chronic GVHD who meet all of the following criteria:

• • Laboratory proven hypogammaglobulinemia with IgG levels <400 mg/dl.
  • At least one acute infection requiring hospitalization and/or parenteral antibiotics
  • Confirmed diagnosis of chronic GVHD
  • At least 100 days post transplant.
• Hypogammaglobulinemia for Graft vs. Host Disease (GVHD)-
  • there is sufficient evidence to conclude that patients who require ongoing immunosuppression for the treatment of chronic GVHD are at increased risk when compared to their peers who do not require such treatment.
  • There is sufficient evidence that such patients who are hypogammaglobulinemic (IgG < 400 mg/d) and have experienced one serious infection may benefit from treatment of IVIG
  • There is insufficient evidence that prophylactic treatment of HSCT patients with IVIG provides a benefit in the absence of hypogammaglobulinemia

• Systemic Lupus Erythematosus - The routine use of IVIG is not usually recommended. IVIG may be used in patients with severe active systemic lupus erythematosus for whom other interventions have been unsuccessful, have become intolerable or are contraindicated.
• Scleromyxedema -Systemic therapy is the treatment method of choice for patients with scleromyxedema. Intravenous immunoglobulin (IVIG) is our first choice for therapy based upon multiple case reports and case series that support its efficacy and the generally well-tolerated nature of this nonimmunosuppressive treatment.

The mechanism through which IVIG improves scleromyxedema is unclear. Suggested mechanisms focus on the immunomodulatory effects of IVIG, including neutralization of circulating autoantibodies by anti-idiotype antibodies, functional blockade of fragment crystallizable receptors on macrophages, and inhibition of fibrosis via modulation of the production of cytokines and cytokine antagonists.

IVIG is usually administered at the dose of 2 g/kg per month divided over two to four consecutive days per month according to the preparation and concentration of IVIG. Improvement in skin and extracutaneous symptoms, especially rheumatologic symptoms, often is evident after the first one or two cycles of IVIG. In our experience, almost all patients exhibit at least partial improvement within four to six cycles. Patients with an unsatisfactory response to IVIG after six cycles are typically transitioned to other therapies.

Lower doses of IVIG may also be effective. A patient with skin-limited disease who had failed to respond to systemic glucocorticoids, extracorporeal photophoresis, and interferon had a reduction in clinical findings within two cycles of IVIG given at a dose of 0.5 g/kg given over five days at four-week intervals.

Although remissions persisting for a few months to three years after cessation of IVIG infusions have been reported, the response to IVIG is usually transient. Maintenance IVIG cycles every six to eight weeks are generally required to maintain remission. We typically administer IVIG over two to four days at a dose of 2 g/kg of IVIG every six weeks or 1.5 g/kg of IVIG every four weeks.

• Systemic Capillary Leak Syndrome (SCLS) or Clarkson’s Disease-  Systemic Capillary Leak Syndrome is a rare illness of unknown origin which has been reported through registries, case studies and case series. Due to the rarity of the illness, large studies are not expected to be generated. Diagnosis in the most recent review and registry review is associated with monoclonal gammopathy. Prophylaxis with IVIG given on a routine monthly basis has been associated with increased survival. This monthly prophylaxis should be tapered to the lowest effective dose. Medicare is expanding coverage for this illness on a trial basis when associated with monoclonal gammopathy and used for prophylaxis but can be withdrawn or altered based on subsequent literature. All other claims will have the appeals process for potential coverage where medical documentation and submitted literature can be reviewed for individual consideration.

The dose used in most case reports has been 2 grams per kg intravenously per month and we would suggest using this dose, although 1 gram per kg per month was noted to be effective in another report.

Stiff person syndrome is a rare acquired neurologic disorder characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles, resulting in severely impaired ambulation. It is caused by increased muscle activity due to decreased inhibition of the central nervous system. If left untreated, stiff person syndrome can progress to cause difficulty walking and significantly impact a person's ability to perform routine, daily tasks. For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes a small, randomized crossover study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Autoimmune retinopathy - while there is little high level evidence conclusively demonstrating benefit of Ig therapy, autoimmune retinopathy (AIR) is a very rare condition and open label studies and case series do demonstrate some benefit including recent publications. It is important to acknowledge that AIR is sight threatening and when refractory to corticosteroid and immunosuppressant therapy, observational studies conclude that Ig therapy is well-tolerated and effective in arresting disease in some patients.

Pure red cell aplasia associated with Human Parvovirus B19 Human parvovirus B19 is a common single-stranded DNA virus. Infections are usually mild or asymptomatic, and do not require treatment. In some cases, the infection can lead to sufficiently severe complications such as transient aplastic crisis, in which case treatment is indicated and may be lifesaving. For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. Relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Hematopoetic Stem Cell Transplantation (HSCT) 

The Infectious Disease Society of America (IDSA) in their guideline for preventing infectious complications among HSCT recipients, defines HSCT to include any stem cell transplant, regardless of type or source. While there are differences in the risks and complications of HSCT between different sources, the effects on immune function are similar.

Secondary hypogammaglobulinemia - the literature reviewed shows the following evidence:

There is an association between the administration of certain pharmaceuticals and the development of hypogammaglobulinemia. Not all forms of secondary hypogammaglobulinemia confer an increased risk of infection. There is insufficient evidence to conclude that IVIG reduces the incidence or severity of infection in patients with drug induced secondary hypogammaglobulinemia.

Chronic Graft versus Host Disease (GVHD) 

The ISDA guidelines provides a summary of evidence which supports that risk of infection is, among other things, related to the presence or absence of GVHD. Patients with chronic GVHD, who require ongoing immunosuppressive therapy to prevent complications of GVHD, may have ongoing impaired immunity as demonstrated by any number of objective tests. This being said, the ISDA does not recommend routine administration of IVIG during the first 100 days post transplant and indicates that IVIG treatment as prophylaxis “may be considered” in patients with IgG levels <400 mg/dl. We note the quality of evidence on their scale (graded CIII) does not meet the reasonable and necessary criteria of 1862(a)(1)(A) which supports the decision not to add this indication as covered. The same applies to routine prophylaxis in the absence of confirmed hypogammaglobulinemia in patients >100 days post transplant. There is however, support for the use of IVIG in patients with chronic GVHD with confirmed hypogammaglobulinemia (IgG < 400 mg/dl) and who have experienced at least one serious infection.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease and follows a relapsing and remitting course. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. SLE can affect any organ system, but it mainly attacks the skin, joints, kidneys, blood cells, and nervous system. For individuals who have SLE who receive IVIG therapy, the evidence includes a systematic review of multiple studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are mainly retrospective. More RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Scleromyxedema 

Data on the efficacy and safety of IVIG are primarily limited to case reports and case series; no randomized trials have been performed. Examples of published reports that have offered support for the efficacy of IVIG for this disease include:

In a retrospective study, 13 of 31 patients (42 percent) with scleromyxedema (without features of dermato-neuro syndrome or mucinous cardiac involvement) treated with IVIG (2 g/kg monthly for the first six months) as a first- or second-line therapy achieved a complete clinical response. Patients were treated with IVIG for a median of 16 months.

In a review of eight adults with scleromyxedema who were treated with monthly cycles of IVIG (2 g/kg per cycle divided over two to five days), two achieved a complete response and six achieved a partial response after up to six cycles of IVIG. Treatment was followed by maintenance therapy every 6 to 12 weeks as needed.

?In a multicenter, retrospective study of 30 patients with scleromyxedema, three of the six patients treated with IVIG (2 g/kg per monthly cycle) achieved complete clinical remissions. The three remaining patients achieved partial responses.

In the first study, a complete clinical response was defined as complete clinical improvement from baseline. In the latter two studies, complete responses were defined as an absence of systemic symptoms or skin findings of scleromyxedema, and partial responses consisted of a decrease in skin changes and improvement in systemic symptoms. In these and other reports, responders to IVIG have included both patients who received IVIG as initial treatment and patients who had previously failed other therapies.

Systemic Capillary Leak Syndrome (SCLS) or Clarkson’s Disease 

In the last decade, multiple case reports have described apparently successful use of monthly infusions of IVIG to reduce the frequency of attacks in some patients.

In a series of 28 patients followed for a median of 55 months (range 1 to 161 months), all five of the patients who did not receive prophylactic IVIG therapy died, compared with only 3 out of the 23 patients who received prophylactic IVIG therapy. Eight of the patients receiving IVIG had no new attacks over multiple years of follow-up. Doses ranged from 0.4 grams to 2 grams per kg per month.

In a case-series of 69 patients with monoclonal gammopathy-associated systemic capillary leak syndrome (Clarkson disease) in whom several preventative agents were used, prophylactic treatment with IVIG (48 patients) was an independent predictor of survival (hazard ratio 0.27, 95% CI 0.1 to 0.7 and 0.35 95% CI 0.13 to 0.96, respectively). Five- and 10-year survival rates in patients treated with IVIG were 91 and 77 percent, respectively, compared with 47 and 37 in patients not treated with IVIG. In addition, compared with no IVIG treatment, IVIG reduced the rate of recurrence and severity of attacks and severity of attacks.

However, a few case reports have described treatment failures.

Autoimmune retinopathy

While there is little high level evidence conclusively demonstrating benefit of Ig therapy, autoimmune retinopathy (AIR) is a very rare condition and open label studies and case series do demonstrate some benefit including recent publications. It is important to acknowledge that AIR is sight threatening and when refractory to corticosteroid and immunosuppressant therapy, observational studies conclude that Ig therapy is well-tolerated and effective in arresting disease in some patients

Use of IVIG for the treatment of secondary hypogammaglobulinemia induced by various medications.

While evidence from the peer reviewed medical literature documents an association between various agents which suppress the immune system and low immunoglobulin levels, the literature does not address whether this finding equates to a higher incidence of serious and/or life threatening infections or that the administration of immune globulin offers a beneficial effect by reducing either the frequency of said infections, or the morbidity/mortality associated with them

Use of IVIG for hypogammaglobulinemia associated with hematopoetic stem cell transplant (HSCT).

The Infectious Disease Society of America (IDSA) in their guideline for preventing infectious complications among HSCT recipients, defines HSCT to include any stem cell transplant, regardless of type or source. While there are differences in the risks and complications of HSCT between different sources, the effects on immune function are similar. In light of this, NGS will no longer cover indications for bone marrow transplant (BMT) recipients only, but will extend the same coverage currently in place of BMT recipients, to all HSCT recipients.

The ISDA guidelines provides a summary of evidence which supports that risk of infection is, among other things, related to the presence or absence of GVHD. Patients with chronic GVHD, who require ongoing immunosuppressive therapy to prevent complications of GVHD, may have ongoing impaired immunity as demonstrated by any number of objective tests. This being said, the ISDA does not recommend routine administration of IVIG during the first 100 days post transplant and indicates that IVIG treatment as prophylaxis “may be considered” in patients with IgG levels <400 mg/dl. We note the quality of evidence on their scale (graded CIII) does not meet the reasonable and necessary criteria of 1862(a)(1)(A) which supports the decision not to add this indication as covered. The same applies to routine prophylaxis in the absence of confirmed hypogammaglobulinemia in patients >100 days post transplant. There is however, support for the use of IVIG in patients with chronic GVHD with confirmed hypogammaglobulinemia (IgG < 400 mg/dl) and who have experienced at least one serious infection.

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