MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 1

Original Issue Date (Created): September 20, 2002

Most Recent Review Date (Revised): June 4, 2013

Effective Date: October 1, 2013

I. POLICY Intravenous Immune globulin (IVIg) Therapy

IVIg may be considered medically necessary for the following indications:

Primary immune deficiency syndromes, including combined immunodeficiencies.

X-linked agammaglobulinemia (Bruton’s)

X-linked hyper-IgM syndrome

Severe combined immunodeficiency (SCID)

Wiskott-Aldrich syndrome

Ataxia telangiectasia

Patients with primary immunodeficiency syndromes should meet all the following

criteria for treatment with immune globulin:

o Laboratory evidence of immunoglobulin deficiency (see Policy Guidelines)

o Documented inability to mount an adequate immunologic response to

inciting antigens (see Appendix)

o Persistent and severe infections despite treatment with prophylactic

antibiotics

Acute Humoral Rejection

Autoimmune Mucocutaneous Blistering Diseases in patients with severe, progressive

disease, despite treatment with conventional agents (corticosteroids, azathioprine,

cyclophosphamide, etc.)

pemphigus

pemphigoid

pemphigus vulgaris

pemphigus foliaceus

Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)

Autoimmune and inflammatory disorders

dermatomyositis refractory to treatment with corticosteroids; in combination with

other immunosuppressive agents

Kawasaki syndrome*;

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 2

Neuroimmunological

myasthenia gravis in patients with chronic debilitating disease in spite of treatment

with cholinesterase inhibitors, or complications from or failure of corticosteroids

and/or azathioprine.

myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) in patients

with contraindications to plasma exchange

Guillain-Barre 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.

Hematologic

idiopathic thrombocytopenic purpura (ITP)

treatment of acute, severe ITP (see policy guidelines)

treatment of chronic ITP*; in patients with at least 6 months’ duration of disease,

and with 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 antibody autoimmune hemolytic anemia, refractory to corticosteroids and

immunosuppressive agents

anti-phospholipid syndrome

severe anemia due to parvovirus B19

Infectious diseases

HIV [human immunodeficiency virus]-infected patients

toxic shock syndrome

patients with primary defective antibody synthesis

Transplantation

prior to solid 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

* FDA-labeled indications

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 3

IVIg is considered not medically necessary as a treatment of relapsing/remitting multiple

sclerosis.

Other applications of IVIg therapy are considered investigational, including, but not limited to,

the following conditions:

chronic progressive multiple sclerosis;

refractory rheumatoid arthritis and other connective tissue diseases, including systemic

lupus erythematosus;

recurrent spontaneous abortion (see below for related laboratory tests);

inclusion-body myositis;

polymyositis, including refractory polymyositis;

myasthenia gravis in patients responsive to immunosuppressive treatment;

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;

Behcet’s syndrome;

adrenoleukodystrophy;

stiff person syndrome;

organ transplant rejection;

uveitis;

demyelinating optic neuritis;

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 4

recent-onset dilated cardiomyopathy;

Fisher syndrome

pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections

(PANDAS);

autism

complex regional pain syndrome

Alzheimer’s disease

IGG sub-class deficiency

neonatal sepsis

Crohn’s disease

opsoclonus-myoclonus;

birdshot retinopathy;

epidermolysis bullosa acquisita;

necrotizing fasciitis;

polyradiculoneuropathy (other than CIDP).

Subcutaneous Immune Globulin (SCIg) Therapy

SCIg may be considered medically necessary for the treatment of primary

immunodeficiencies*, including congenital agammaglobulinemia, hypogammaglobulinemia,

common variable immunodeficiency (CVID), severe combined immunodeficiency, Wiskott-

Aldrich syndrome, and X-linked agammaglobulinemia (XLA).

Policy Guidelines

Primary Immunodeficiency Syndromes. The diagnosis of immunodeficiency and post

immunization titers must be taken in context with the clinical presentation of the patient and

may vary dependent on the type of vaccine given and the prior immunization history of the

patient. The following parameters are examples of criteria for diagnosis of the primary

immunodeficiency syndromes.

Laboratory evidence of immunoglobulin deficiency may include the following

definitions:

Agammaglobulinemia (total IgG less than 200 mg/dL)

Persistent hypogammaglobulinemia (total IgG less than 400 mg/dL, or at least

two standard deviations below normal, on at least two occasions)

Absence of B lymphocytes

Inability to mount an adequate antibody response to inciting antigens may include the

following definitions:

Lack of appropriate rise in antibody titer following provocation with a

polysaccharide antigen. For example, an adequate response to the pneumococcal

vaccine may be defined as at least a four-fold increase in titers for at least 50%

of serotypes tested.

Lack of appropriate rise in antibody titer following provocation with a protein

antigen. For example, an adequate response to tetanus/diphtheria vaccine may

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 5

be defined as less than a four-fold rise in titers 3-4 weeks after vaccine

administration.

According to a 2010 national guideline from Canada on immune globulin for primary immune

deficiency, although higher trough levels of IVIg may be associated with clinical response; the

goal of IVIg dose increases should be to improve clinical effectiveness and not merely to

increase trough levels.

Acute, severe ITP may be defined by the following parameters:

acute ITP with major bleeding, e.g., life-threatening bleeding and/or clinically important

mucocutaneous bleeding

acute ITP with severe thrombocytopenia and at high risk for bleeding complications

acute ITP with severe thrombocytopenia and a slow or inadequate response to

corticosteroids

acute ITP with severe thrombocytopenia and a predictable risk of bleeding in the future,

e.g., a procedure or surgery with a high bleeding risk.

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) should meet the

diagnostic criteria established by the American Academy of Neurology, particularly if the patient

also is diagnosed with chronic fatigue syndrome. (See Appendix A for the diagnostic criteria.) In

addition, by intravenous immunoglobulin infusion (IVIg), treatment should be limited to CIDP

patients who do not respond to initial therapy with prednisone and are experiencing serious

clinical worsening. In patients treated for chronic diseases, such as CIDP, multifocal motor

neuropathy, and dermatomyositis, the effect of IVIg is transitory and therefore periodic infusions

of IVIg are needed to maintain treatment effect. The frequency of transfusions is titrated to the

treatment response; typically, biweekly or monthly infusions are needed.

Patients with multifocal motor neuropathy should meet established diagnostic criteria such as

those published by Van Asseldonk and colleagues in Lancet Neurology in 2005 (See Appendix B

for the diagnostic criteria).

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 6

The following is an adaptation of recommendations that have been made for IVIg dosing in a

consensus report from the IVIg advisory committee:

Disorder Dose

Primary immunodeficiency disorders 0.4-0.6 g/kg every 28 days

Chronic inflammatory demyelinating polyneuropathy (CIDP) 0.4 g/kg for 5 doses

Guillain-Barré syndrome 0.25-0.4 g/kg × 5 doses

Dermatomyositis 0.4 g/kg for 5 doses

Idiopathic thrombocytopenia 0.4 g/kg/d × 5 days

Acute humoral rejection 1 g/kg/d for 2 doses

Cross-reference:

MP-7.006 Pregnancy-Related Testing for Genetic, Chromosomal, Metabolic, and

Immunologic Abnormalities

MP-2.304 Pervasive Developmental Disorders

MP-4.031 Plasma Exchange

MP-2.068 Extracorporeal Photophoresis after Solid-Organ Translplant and for Graft-Versus

Host Disease, and Cutaneous T-Cell Lymphoma

II. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated

[Y] = Standard product coverage varies from application of this policy, see below

[N] Capital Cares 4 Kids [N] Indemnity

[N] PPO [N] SpecialCare

[N] HMO [N] POS

[Y] SeniorBlue HMO* [Y] FEP PPO**

[Y] SeniorBlue PPO*

* For treatment of Autoimmune Mucotaneous Blistering Diseases, refer to Centers for Medicare and

Medicaid (CMS) National Coverage Determination (NCD) 250.3 Intravenous Immune Globulin

for the Treatment of Autoimmune Mucocutaneous Blistering Diseases. For IVIG given in the home

for treatment of primary immunodeficiency, refer to NHIC LCD 27260 Intravenous Immune Globulin

and Local Coverage Article for Intravenous Immune Globulin effective January 2011 (A46761). For the

treatment of second-line therapy in acute relapse of relapsing multiple sclerosis (MS), refer to Novitas

Solutions Local Coverage Determination LCD L32937 - Intravenous Immune Globulin (IVIG).

Also, for off-label uses of drugs and biologicals, refer to the following Medicare Benefit Policy Manual

sections: “FDA approved drugs used for indications other than what is indicated on the official label may

be covered under Medicare if determined that the use is medically accepted, taking into consideration the

major drug compendia, authoritative medical literature and/or accepted standards of medical practice.”

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 7

Refer to Medicare Benefit Policy Manual (100-2, Chapter 15, Section 50.4.2- Unlabeled Use of Drug).”

http://www.cms.gov/manuals/Downloads/bp102c15.pdf

Off-label use of FDA approved drugs and biologicals used in an anti-cancer chemotherapeutic regimen

for medically accepted indications may be covered under Medicare if the indications are supported in

either one or more Medicare recognized compendia or in peer-reviewed literature. Refer to Medicare

Benefit Policy Manual (100-2, Chapter 15, Section 50.4.5- Off-Label Use of Drugs and Biologicals in an

Anti-Cancer Chemotherapeutic Regimen) for the compendia list.

http://www.cms.gov/manuals/Downloads/bp102c15.pdf

**Refer to the FEP Medical Policy Manual MP-10.04.03 IVIG / IGSC Immune Globulin. The

FEP Medical Policy manual can be found at:

http://bluewebportal.bcbs.com/landingpagelevel3/504100?docId=23980

III. DESCRIPTION/BACKGROUND This policy addresses the use of human immune globulin therapy for preventing and/or treating

a wide variety of disorders in the outpatient setting. Both intravenous infusion (IVIg) and

subcutaneous infusion (SCIg) of immune globulin are addressed. However, the policy only

considers nonspecific pooled preparations of IVIg, not other preparations used for passive

immunization to specific antigens.

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. Three

formulations of human IgG are available for delivery by intravenous infusion (IVIg), by

subcutaneous infusion (SCIg), or by intramuscular (IMIg) depot injections. IMIg has been

largely abandoned in the United States because volume constraints and pain preclude delivery

of sufficient product weekly into each buttock to yield therapeutic serum levels of IgG, leaving

recipients susceptible to infections. Thus, this policy focuses on IVIg and SCIg for conditions

that typically would be treated in an outpatient setting.

Intravenous infusion immune globulin is an antibody-containing solution obtained from the

pooled plasma of healthy blood donors that contains antibodies to greater than 10 million

antigens. IVIg has been used to correct immune deficiencies in patients with either inherited or

acquired immunodeficiencies and has also been investigated as an immunomodulator in

diseases thought to have an autoimmune basis. Several IVIg products are available for clinical

use in the United States. The labeled indications approved by the U.S. Food and Drug

Administration (FDA) for IVIg are listed in the Policy section. A variety of off-label indications

have been investigated; some of the most common are inflammatory myopathies, neuropathies

(e.g., Guillain-Barre syndrome), myasthenia gravis, multiple sclerosis, and solid organ

transplantation.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 8

This policy only addresses nonspecific pooled preparations of IVIg; it does not address other

immunoglobulin preparations that are specifically used for passive immunization to prevent or

attenuate infection with specific viral diseases such as respiratory syncytial virus,

cytomegalovirus, or hepatitis B.

Subcutaneous infusion immune globulin is used for treating patients with primary

immunodeficiencies (PID). A genetic basis for more than 80 different types of PID has been

discovered, the most common being primary antibody deficiency (PAD) that is associated with

low levels or total lack of normal circulating immunoglobulins. The first FDA-approved SCIg

product, Vivaglobin, is a pasteurized, polyvalent human normal immune globulin product that is

manufactured from large pools of human plasma by cold alcohol fractionation with no chemical

or enzymatic alterations. Vivaglobin administration produces relatively stable steady-state serum

levels of IgG that are representative of those seen in a normal human population.

Applications of this product for conditions other than primary immunodeficiencies are

considered off-label in the United States and are not addressed in this policy. In recent years,

other SCIg products have also received FDA-marketing approval.

Regulatory Status Several IVIg have been approved by the FDA. These include Carimune (ZLB Bioplasma),

Flebogamma (Grifols), Gammagard (Baxter), Gamunex (Talecris Biotherapeutics), Octagam

(Octapharma), Polygam S/D (Baxter) Privigen (CSL Behring LLC).

Several SCIg products have received FDA marketing approval for primary immunodeficiencies.

These include Vivaglobin® (ZLB Behring LLC, Kankakee, IL), Hizentra® (ZLB Behring LLC,

Kankakee, IL), Gamunex-C® (Talecris Biotherapeutics, Inc., Research Triangle Park, NC), and

Gammaked® (Kedrion Biopharma, Cambridge, MA).

IV. DEFINITIONS ANTIBODY is a protein substance produced in response to a unique antigen. The substance

developed combines with a specific antigen to destroy or control it.

IMMUNE GLOBULIN is a drug created from serum containing antibodies. It is used to supply

necessary antibodies to patients with immunoglobulin deficiencies and to provide passive

immunity against common viral infections (e.g., hepatitis A and measles).

INTRAVENOUS refers to within or into a vein.

OFF LABEL refers to the use of a drug to treat a condition for which it has not been approved by

the U.S. Food and Drug Administration (FDA), especially when such may relieve unpleasant

symptoms or prove compassionate. Drug effects that have been observed but not specifically

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 9

proven (and for which no application has been made) may be exploited for unproven or "off-

label" uses by licensed medical practitioners.

V. BENEFIT VARIATIONS The existence of this medical policy does not mean that this service is a covered benefit under

the member's contract. Benefit determinations should be based in all cases on the applicable

contract language. Medical policies do not constitute a description of benefits. A member’s

individual or group customer benefits govern which services are covered, which are excluded,

and which are subject to benefit limits and which require preauthorization. Members and

providers should consult the member’s benefit information or contact Capital for benefit

information.

VI. DISCLAIMER Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical

advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of

members. Members should discuss any medical policy related to their coverage or condition with their provider

and consult their benefit information to determine if the service is covered. If there is a discrepancy between this

medical policy and a member’s benefit information, the benefit information will govern. Capital considers the

information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law.

VII. REFERENCES A phase III study evaluating safety and effectiveness of immune globulin intravenous (IGIV

10%) for the treatment of mild to moderate Alzheimer’s disease. Sponsored by Baxter

Healthcare Corporation. Last updated March 30, 2010. Available online at

ClinicalTrials.gov. Last accessed February 27, 2013.

Berger M, Murphy E, Riley P et al. Improved quality of life, immunoglobulin G levels and

infection rates in patients with primary immunodeficiency diseases during self-treatment with

subcutaneous immunoglobulin G. South Med J 2010; 103(9):856-63.

Bucuvalas JC, Anand R. Treatment with immunoglobulin improves outcome for pediatric liver

transplant recipients. Liver Transpl 2009 15(11):1564-9.

Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.

Publication 100-02. Chapter 15. Sections 50, 50.4.1, 50.4.3. Drugs and Biologicals. Effective

10/01/03. [Website]: . http://www.cms.gov/Regulations-and-

Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013..

Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.

Publication 100-02. Chapter 15. Section 50.4.5. Off-Label Use of Anti-Cancer Drugs and

Biologicals. [Website]: http://www.cms.gov/Regulations-and-

Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013.

Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.

Publication 100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective 10/01/03.

[Website]: http://www.cms.gov/Regulations-and-

Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 10

Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD)

250.3 Intravenous Immune Globulin for the Treatment of Autoimmune Mucotaneous

Blistering Diseases. Effective 10/01/02. CMS [Website]: https://www.cms.gov Accessed

February 27, 2013.

Centers for Medicare and Medicaid Services (CMS) Intravenous Immune Globulin Local

Coverage Article for Intravenous Immune Globulin - Policy Article - Effective January 2011

(A46761) Effective 01/01/1. [Website]: http://www.cms.gov/medicare-coverage-

database/details/article-

details.aspx?articleId=46761&ver=10&ContrId=137&ContrVer=1&LCDId=27260&Cntrc

trSelected=137*1&Cntrctr=137&name=NHIC%2c%2bCorp.%2b(16003%2c%2bDME%2b

MAC)&LCntrctr=137*1&kq=1829415601&ua=highwire&IsPopup=y& Accessed

February 27, 2013.Chuhjo T, Nakao S, Matsuda T. Successful treatment of persistent

erythroid aplasia caused by parvovirus B19 infection in a patient with common variable

immunodeficiency with low-dose immunoglobulin. Am J Hematol 1999; 60(3):222-4.

Crabol Y, Terrier B, Rozenberg F et al. Intravenous Immunoglobulin Therapy for Pure Red

Cell Aplasia Related to Human Parvovirus B19 Infection: A Retrospective Study of 10

Patients and Review of the Literature. Clin Infect Dis 2013 [Epub ahead of print].

Durable Medical Equipment Regional Carrier (DMERC) Region A Local Coverage

Determination (LCD) L5044. External Infusion Pumps. Effective 2/4/2011. [Website]:

http://www.medicarenhic.com/dme/medical_review/mr_lcds/mr_lcd_current/L5044_2011-

07-22_rev_2013-02_PA_2013-01.pdf Accessed February 27, 2013.

Durable Medical Equipment Regional Carrier (DMERC) Region A Local Coverage

Determination (LCD) 27260 Intravenous Immune Globulin Effective 01/01/12. [Website]:

http://www.cms.gov/medicare-coverage-database/details/article-

details.aspx?articleId=46761&ver=10&ContrId=137&ContrVer=1&LCDId=27260&Cntrc

trSelected=137*1&Cntrctr=137&name=NHIC%2c%2bCorp.%2b(16003%2c%2bDME%2b

MAC)&LCntrctr=137*1&kq=1829415601&ua=highwire&IsPopup=y& Accessed

February 27, 2013.

Franco AC, Torrico AC, Moreira FT et al. Adjuvant use of intravenous immunoglobulin in the

treatment of neonatal sepsis: a systematic review with a meta-analysis. J Pediatr (Rio J)

2012; 88(5):377-83.

Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane

Database Syst Rev 2012; 12:CD002277.

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.

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.

Hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database

Syst Rev 2008; (4):CD006501.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 11

Hoffmann F, Grimbacher B, Thiel J et al. Home-based subcutaneous immunoglobulin G

replacement under real-life conditions in children and adults with antibody deficiency. Eur J

Med Res 2010; 15(6):238-45.

Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of

toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol 2012;

167(2):424-32.

Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre

syndrome. Cochrane Database Syst Rev 2012; 7:CD002063.

Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre

syndrome. Cochrane Database Syst Rev 2010; (6):CD002063.

INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N

Engl J Med 2011; 365(13):1201-11.

Ito S, Oyake T, Uchiyama T et al. Successful treatment with cyclosporine and high-dose gamma

immunoglobulin for persistent parvovirus B19 infection in a patient with refractory

autoimmune hemolytic anemia. Int J Hematol 2004; 80(3):250-3.

Koduri PR, Kumapley R, Khokha ND et al. Red cell aplasia caused by parvovirus B19 in AIDS:

use of i.v. immunoglobulin. Ann Hematol 1997; 75(1-2):67-8.

Miyasaka N, Hara M, Koike T et al. Effects of intravenous immunoglobulin therapy in Japanese

patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized

double-blind placebo-controlled trial. Mod Rheumatol 2012; 22(3):382-93.

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. Nobile-Orazio E, Cocito D, Jann S et al. Intravenous immunoglobulin versus

intravenous methylprednisolone for chronic inflammatory demyelinating

polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012; 11(6):493-502.

Novitas Solutions. Local Coverage Determination (LCD) L32937. Intravenous Immune

Globulin. Effective 04/04/13. [Website]: https://www.novitas-solutions.com/policy/mac-

ab/l32937.html Accessed February 27, 2013.

Patwa HS, Chaudhry V, Katzberg H et al. Evidence-based guideline: intravenous

immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and

Technology Assessment Subcommittee of the American Academy of Neurology. Neurology

2012; 78(13):1009-15.

Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane

Database Syst Rev 2006; (2):CD000112.

Raanani P, Gafter-Gvili A, Paul M et al. Immunoglobulin prophylaxis in hematological

malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev

2008; (4):CD006501.

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.

Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn's

disease. Autoimmun Rev 2012 [Epub ahead of print].

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 12

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.

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.

Silvergleid AJ, Berger M. General principles in the use of immune globulin. In UpToDate

Online Journal [serial online]. Waltham, MA: UpToDate. Updated December 14,

2012..[Website]: www.uptodate.com. Accessed February 27, 2013.

Taber’s Cyclopedic Medical Dictionary, 19th edition.

Wang DX, Shu XM, Tian XL et al. Intravenous immunoglobulin therapy in adult patients with

polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol 2012;

31(5):801-6.

VIII. CODING INFORMATION Note: This list of codes may not be all-inclusive, and codes are subject to change at any time.

The identification of a code in this section does not denote coverage as coverage is

determined by the terms of member benefit information. In addition, not all covered

services are eligible for separate reimbursement.

Covered when medically necessary:

CPT Codes® 90283 90284 96365 96366 96369 96370 96371

Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.

HCPCS

Code Description

J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg

J1556 Injection, immune globulin (bivigam), 500 mg

J1557 Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg

J1559 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg

J1561 Injection, immune globulin (Gamunex/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

J1568 Injection, immune globulin (Octagam) intravenous, non-lyophilized (e.g., liquid), 500 mg

J1569 Injection, immune globulin (Gammagard) intravenous, 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, non-lyophilized (e.g., liquid), not otherwise specified, 500

mg

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 13

ICD-9-CM

Diagnosis

Code*

Description

040.82 Streptococcus infection in conditions classified elsewhere and of unspecified site

041.00 – 041.9 Bacterial infection, code range

042.0 Human immunodeficiency virus (HIV) disease

204.10 Chronic lymphoid leukemia, without mention of having achieved remission

204.11 Chronic lymphoid leukemia in remission

279.00 Unspecified hypogammaglobulinemia

279.2 Combined immunity deficiency

279.3 Other selective immunoglobulin deficiencies

279.04 Congenital hypogammaglobulinemia

279.05 Immunodeficiency with increased igm

279.06 Common variable immunodeficiency

279.12 Wiskott-aldrich syndrome

279.2 Combined immunity deficiency

279.3 Unspecified immunity deficiency

287.3 – 287.39 Primary thrombocytopenia

287.4 – 287.49 Secondary thrombocytopenia

287.5 Unspecified thrombocytopenia

289.81 Primary hypercoagulable state

334.8 Spinocerebellar disease

354.0 -355.9 Mononeuritis, code range

356.4 356.9 Idiopathic peripheral neuropathy, code range

357.0 Acute infective polyneuritis

357.81 Chronic inflammatory demyelinating polyneuritis

358.01 Myasthenia gravis with (acute) exacerbation

358.1 Myasthenic syndromes in diseases classified elsewhere

4260-4269 Conduction disorders, code range

695.14 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome

694.4 – 694.5 Pemphigus/pemphigoid code range

446.1 Acute febrile mucocutaneous lymph node syndrome (Kawasaki disease)

710.3 Dermatomyositis

757.39 Other specified congenital anomaly of skin

776.1 Transient neonatal thrombocytopenia

V42.81 Status post-bone marrow transplant

*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 14

The following ICD-10 diagnosis codes will be effective October 1, 2014:

ICD-10-CM

Diagnosis

Code*

Description

A48.3 Toxic shock syndrome

B95.0-B95.8 Streptococcus, staphylococcus and enterococcus as the cause of diseases classified elsewhere

code range

B20 Human immunodeficiency virus [HIV] disease

C91.10-C91.12 Chronic lymphocytic leukemia of b-cell type code range

D59.1 Other autoimmune hemolytic anemias (includes warm type)

D68.61 Anticardiolipin syndrome (includes antiphospholipid syndrome)

D80.0-D80.9 Immunodeficiency with predominantly antibody defects code range

D83.0-D83.9 Common variable immunodeficiency code range

G35 Multiple sclerosis

G60.0 –G60.9 Hereditary and idiopathic neuropathy

G61.0 Guillain-Barre syndrome

G70.01 Myasthenia gravis with (acute) exacerbation

G73.3 Myasthenic syndromes in other diseases classified elsewhere

I 44.0 – I45.9 Other conduction disorders

L10.0 – L10.9 Pemphigus code range

L12.0 – L12.9 Pemphigoid code range

L51.3 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome

M30.0 Mucocutaneous lymph node syndrome

M33.90 – M33.99 Dermatopolymyositis unspecified

P61.0 Transient neonatal thrombocytopenia

Z94.81 Bone marrow transplant status

*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.

IX. POLICY HISTORY MP 2.023 CAC 5/27/03

CAC 1/25/05

CAC 1/31/06

CAC 9/26/06

CAC 9/25/07

CAC 7/29/08

7/1/09 Administrative Change Cross-reference added for Pervasive Developmental

Disorders

CAC 9/29/09 Gamunex added to list of IVIG preparations in

background/description. References updated.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 15

CAC 9/28/10 Consensus review.

CAC 10/25/11 Consensus review

CAC 4/24/12 Adopt BCBSA.The following were added as medically necessary:

Primary immune deficiency syndromes, including combined immunodeficiencies

X-linked hyper-IgM syndrome

Ataxia telangiectasia

Autoimmune Mucocutaneous Blistering Diseases, in patients with severe,

progressive disease despite treatment with conventional agents (corticosteroids,

azathioprine, cyclophosphamide, etc.)

Pemphigus

pemphigoid*

pemphigus vulgaris

pemphigus foliaceus

Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)

Neuroimmunological

Eaton-Lambert myasthenic syndrome; in patients who have failed to respond

to anticholinesterase medications and/or corticosteroids

Infectious diseases

toxic shock syndrome

IVIg is considered not medically necessary as a treatment of relapsing/remitting

multiple sclerosis. Previously this indication was listed as investigational.

The following indications were added as investigational:

Fisher syndrome

pediatric autoimmune neuropsychiatric disorders associated with

streptococcal infections (PANDAS);

autism

complex regional pain syndrome

Alzheimer’s disease

IgG sub-class deficiency

Sepsis

FEP variation updated.

CAC 6/4/13 Minor revision. “Neonatal”added to bullet point on sepsis in the

investigational statement. Crohn’s disease, opsoclonus-myoclonus, birdshot

retinopathy;, epidermolysis bullosa acquisita , necrotizing fasciitis and

polyradiculoneuropathy (other than CIDP) were all added as examples of

investigational indications. Severe anemia associated with parvovirus B19

was added as a medically necessary indication under hematologic indications.

12/19/2013- New 2014 Code updates made. Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company®,

Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross BlueShield Association.

Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 16

X. APPENDIX

Appendix A:

Diagnostic Criteria for Diagnosis of Chronic Inflammatory Demyelinating

Polyneuropathy (CIDP) The following criteria are adapted from the Task Force Report of the Ad Hoc Subcommittee

of the American Academy of Neurology AIDS Task Force. (Neurology 1991; 41(5):617-8)

The report included mandatory, supportive, and exclusionary diagnostic criteria. Only the

mandatory criteria are excerpted here. The criteria are based on a combination of clinical

observations, physiologic studies, pathologic features (i.e., nerve biopsy), and studies of the

cerebrospinal fluid (CSF).

I. Clinical

Mandatory 1.Progressive or relapsing motor and sensory, rarely only motor or sensory, dysfunction of

more than 1 limb or a peripheral nerve nature, developing over at least 2 months.

2.Hypo- or areflexia. This will usually involve all 4 limbs.

II. Physiologic Studies

Mandatory Nerve conduction studies including studies of proximal nerve segments in which the

predominant process is demyelination.

Must have 3 of 4:

1. Reduction in conduction velocity (CV) in 2 or more motor nerves:

a. <80% of lower limit of normal (LLN) is amplitude >80% of LLN

b.<70% of LLN is amplitude <80% of LLN

2. Partial conduction block or abnormal temporal dispersion in 1 or more motor nerves:

either peroneal nerve between ankle and below fibular head, median nerve between wrist

and elbow, or ulnar nerve between wrist and below elbow.

Criteria suggestive of partial conduction block: <15% change in duration between proximal

and distal sites and >20% drop in negative peak (p) area or peak to peak (p-p) amplitude

between proximal and distal sites.

Criteria for abnormal temporal dispersion and possible conduction block: >15% change in

duration between proximal and distal sites and >20% drop in p area or p-p amplitude

between proximal and distal sites and >20% drop in p or p-p amplitude between proximal

and distal sites.

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 17

These criteria are only suggestive of partial conduction block as they are derived from

studies of normal individuals. Additional studies, such as stimulation across short segments

or recording of individual motor unit potentials, are required for confirmation.

3. Prolonged distal latencies in 2 or more nerves:

a. >125% of upper limit of normal (LEN) is amplitude >80% of LLN

b.>150% of LEN if amplitude <80% of LLN.

4. Absent F waves or prolonged minimum

a. >120% of ULN if amplitude >80% of LLN

b.>150% of ULN if amplitude <80% of LLN.

III. Pathologic Features

Mandatory Nerve biopsy showing unequivocal evidence of demyelination and remyelination.

Demyelination by either electron microscopy (>5 fibers) or teased fiber studies >12% of 50

fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination.

IV. CSF Studies

Mandatory 1. Cell count <10 per cubic mm if HIV-seronegative or <50 per cubic mm is HIV

seropositive

2. Negative VDRL

The following criteria are adapted from the Joint Task Force of the EFNS and the PNS.

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. J Peripher Nerv Syst. 2005;10:220-228. The EFNS/PNS diagnostic criteria were

designed to balance specificity and sensitivity.

V. Inclusion Criteria

1. Typical CIDP – Chronically progressive, stepwise, or recurrent symmetric proximal

and distal weakness and sensory dysfunction of all extremities, developing over at least

2 months; cranial nerves may be affected; and absent or reduced tendon reflexes in all

extremities

2. Atypical CIDP

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 18

One of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in

unaffected limbs):

Predominantly distal weakness (distal acquired demyelinating symmetric, DADS)

Pure motor or sensory presentations, including chronic sensory immune

polyradiculoneuropathy affecting the central process of the primary sensory neuron

Asymmetric presentations (multifocal acquired demyelinating sensory and motor,

MADSAM, Lewis-Sumner syndrome

Focal presentations (e.g., involvement of the brachial plexus or of one or more

peripheral nerves in one upper limb

Central nervous system involvement (may occur with otherwise typical or other forms

of atypical CIDP)

VI. Exclusion Criteria Diphtheria, drug or toxin exposure likely to have caused the neuropathy

Hereditary demyelinating neuropathy, known or likely because of family history, foot

deformity, mutilation of hands or feet, retinitis pigmentosa, ichthyosis, liability to

pressure palsy

Presence of sphincter disturbance

Multifocal motor neuropathy

Antibodies to myelin-associated glycoprotein

VII. Electrodiagnostic Criteria

1. Definite

At least one of the following:

At least 50% prolongation of motor distal latency above the upper limit of normal

values in two nerves, or

At least 30% reduction of motor conduction velocity below the lower limit of normal

values in two nerves, or

At least 20% prolongation of F-wave latency above the upper limit of normal values in

two nerves (>50% if amplitude of distal negative peak CMAP, 80% of lower limit of

normal values), or

Absence of F-waves in two nerves if these nerves have amplitudes of distal negative

peak CMAPs at least 20% of lower limit of normal values + at least one other

demyelinating parameter* in at least one other nerve, or

Partial motor conduction block: at least 50% amplitude reduction of the proximal

negative peak CMAP relative to distal, if distal negative peak CMAP at least 20% of

lower limit of normal values, in two nerves, or in one nerve + at least one other

demyelinating parameter* in at least one other nerve, or

Abnormal temporal dispersion (>30% duration increase between the proximal and

distal negative peak CMAP) in at least two nerves, or

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 19

Distal CMAP duration (interval between onset of the first negative peak and return to

baseline of the last negative peak) of at least 9 ms in at least one nerve + at least one

other demyelinating parameter* in at least one other nerve

2. Probable At least 30% amplitude reduction of the proximal negative peak CMAP relative to

distal, excluding posterior tibial nerve, if distal negative peak CMAP at least 20% of

lower limit of normal values, in two nerves, or in one nerve + at least one other

demyelinating parameter* in at least one other nerve

3. Possible As in (1) but in only one nerve

CMAP, compound muscle action potential. To apply these criteria, the median, ulnar

(stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial

nerves on one side are tested. Temperatures should be maintained at least 33° C at the

palm and 30° C at the external malleolus (good practice points).

* Any nerve meeting any of the criteria

VIII. Supportive Criteria

Elevated cerebrospinal fluid protein with leukocyte <10/mm3 (level A recommendation)

Magnetic resonance imaging showing gadonlinium enhancement and /or hypertrophy of

the cauda equine, lumbosacral or cervical nerve roots, or the brachial or lumbosacral

plexus (level C recommendation)

Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination in >5

fibers by electron microscopy or in >6 of 50 teased fibers

Clinical improvement following immunomodulatory treatment (level A recommendation)

Appendix B:

Diagnostic Criteria for Diagnosis of Multifocal Motor Neuropathy (MMN) The following are proposed diagnostic criteria adapted from a 2005 article by Van Asseldonk

and colleagues (Lancet Neurology; 4: 309-319)

I. Clinical criteria 1. Slow or stepwise progressive limb weakness

2. Asymmetrical limb weakness

MEDICAL POLICY

POLICY TITLE IMMUNE GLOBULIN

POLICY NUMBER MP-2.023

Page 20

3. Fewer than seven affected limb regions (on each side: upper arm, lower arm, upper leg,

or lower leg)

4. Tendon reflexes in affected limbs are decreased or absent

5. Signs and symptoms more pronounced in arms than in legs

6. 20–65 years old at disease onset

7. No objective sensory abnormalities except for vibration sense

8. No bulbar signs or symptoms

9. No upper-motor-neuron features

10. No other neuropathies

11. No myopathy (e.g., dystrophy, inclusion-body myositis)

II. Laboratory criteria 1. CSF protein less than 1 g/L

2. High anti-GM1 titre

3. High signal intensity on T2-weighted MRI of the brachial plexus

III. Electrodiagnostic criteria 1. Definite motor conduction block: Compound muscle action potential (CMAP) area

reduction on proximal versus distal stimulation of at least 50% over a long segment

(between erb and axilla, upper arm, lower arm, lower leg), or a CMAP amplitude

reduction on proximal versus distal stimulation of at least 30% over a short distance (2·5

cm) detected by inching. CMAP amplitude on stimulation of the distal part of the

segment with motor conduction block of at least 1 mV

2. Probable motor conduction block: CMAP amplitude reduction on proximal versus distal

stimulation of at least 30% over a long segment of an arm nerve. CMAP amplitude on

stimulation of the distal part of the segment with motor conduction block of at least 1 mV

3. Slowing of conduction compatible with demyelination: Motor conduction velocity

(MCV) <75% of the lower limit of normal; DML or shortest F wave latency 130% of the

upper limit of normal or absence of F waves all after 16–20 stimuli. CMAP amplitude on

distal stimulation of at least 0·5 mV

4. Normal sensory-nerve conduction in arm segments with motor conduction block. Normal

sensory nerve action potential (SNAP) amplitudes on distal stimulation.

Definite MMN: 1–11 on clinical criteria, 1 on laboratory criteria, and 1 and 4 on

electrodiagnostic criteria

Probable MMN: 1–3 and 6–11 on clinical criteria, 1 on laboratory criteria, and 2 and 4 on

electrodiagnostic criteria

Possible MMN: 1 and 7–11 on clinical criteria, 2 or 3 on laboratory criteria, and 3 and 4 on

electrodiagnostic criteria