Effective Date

Date of Origin 

10-01-2024            

Cutaquig^® 16.5%

Subcutaneous injection

● Treatment of primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older

Cuvitru™ 20%

Subcutaneous injection

● Replacement therapy for primary humoral immunodeficiency (PI) in adult and pediatric patients two years of age and older

Gammagard™ Liquid 10%

Subcutaneous injection

● Replacement therapy for primary humoral immunodeficiency (PI) in adult and pediatric patients two years of age or older

● Maintenance therapy to improve muscle strength and disability in adult patients with multifocal motor neuropathy (MMN)

Gammaked™ 10%

Subcutaneous injection

● Treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older

● Treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in adults

Gamunex-C^® 10%

Subcutaneous injection

● Treatment of primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older

● Treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in adults

Hizentra^® 20%

Subcutaneous injection

● Treatment of primary immunodeficiency (PI) in adults and pediatric patients two years of age or older

● Maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy (CIDP)

HyQvia™ 10%

Subcutaneous injection

● Treatment of primary immunodeficiency (PI) in adults

Xembify^® 20% 

Subcutaneous injection

● Treatment of Primary Humoral Immunodeficiency (PI) in patients 2 years of age and older

Immune Globulins

Immunoglobulin is used to treat a wide variety of diseases, including primary and secondary immunodeficiency states and hematologic and autoimmune disorders. Immunoglobulin is increasingly recognized as a treatment of a variety of medical conditions, not only for its ability to fight infection as a replacement therapy but also for its anti-inflammatory and immunomodulating effects. The appropriate use of immunoglobulin can be life-saving. However, its administration can lead to numerous adverse events and potential additional adverse consequences. Due to finite supply, possible adverse events, and the need for further research in some applications of therapeutic immunoglobulin, it is important for clinicians prescribing immunoglobulin to be familiar with current clinical indications and levels of evidence in support of its use in these conditions.(15)

Primary Immunodeficiency

Immunoglobulin replacement therapy via the IV or SQ route is required in patients with certain primary immunodeficiency (PI) diseases characterized by absent or deficient antibody production and, in most cases, recurrent or unusually severe infection. Replacement therapy for agammaglobulinemia and hypogammaglobulinemia in well-described immunodeficiencies such as X-linked agammaglobulinemia (XLA) or common variable immunodeficiency (CVID) is necessary and life-saving. Other more genetically complex PIs, however, may also involve defects in antibody function that contribute to an increased susceptibility to infections.(24) Over 300 distinct primary immunodeficiencies have been described to date with new primary immunodeficiencies being discovered at a rapid rate.(23)

Immune globulin is the current mainstay of therapy for patients with PI. Immune globulin protects against infection by providing protective antibodies and humoral immunity. A study in 31 children with X-linked agammaglobulinemia showed that immune globulin reduced the incidence of infection from 0.4 per patient year to 0.06 per patient year (p<0.001). In a study of adults with common variable immunodeficiency (CVID), immune globulin reduced the incidence of bacterial pneumonia from 84% before treatment to 11% after treatment with immune globulin.(11)

The prevalence of primary immunodeficiencies in the United States is as many as 1:2000 live births.(16) A 20-year survival rate is 64%-67% for males and females respectively. Important signs that may indicate a primary immunodeficiency disease include recurrent, unusual or difficult to treat infections, poor growth or loss of weight, recurrent pneumonia, ear infections or sinusitis, multiple courses of antibiotics or IV antibiotics necessary to clear infections, recurrent deep abscesses of the organs or skin, a family history of primary immunodeficiency disease, swollen lymph glands or an enlarged spleen, autoimmune disease. Diagnosis of primary immunodeficiencies involves laboratory evaluations (Serum IgA, IgG, and IgM levels, circulating T and B lymphocytes and T cell function), measurement of specific antibodies to vaccines, imaging (CT scan of chest detecting pulmonary abnormalities), histology of lymph nodes (reactive follicular or atypical hyperplasia, and granulomatous inflammation), bronchoscopy (infectious processes), and lymph node biopsy.(17)

Diagnostic criteria discussed by the American Academy of Allergy and Immunology (AAAI) for hypogammaglobulinemia include low IgG level (< 700 mg/dL or more than two standard deviations below the mean) or an inability to mount a significant response to antigenic challenge or both in patients with recurrent bacterial infections coupled with a lack of response to protein or polysaccharide vaccine challenges (i.e., patients who cannot make IgG antibody against diphtheria and tetanus toxoids, pneumococcal polysaccharide vaccine, or both).(14) The European and Pan-American Guidelines, state that, the first criterion for CVID requires IgG levels to be two standard deviations below the mean [for the patient's age]. For most laboratories, the lower limit of normal for IgG is 7 - 8 g/L (700 – 800 mg/dL). Impaired vaccine response is the second and most contentious criterion. The last criterion requiring exclusion of secondary causes is the least contentious. Secondary hypogammaglobulinemia can be caused by a variety of conditions, including gut or renal loss, adverse reactions to drugs, etc.(13) These patients are recommended for immune globulin replacement. The European Society of Immune Deficiencies (ESID) registry has published a working definition for several primary immunodeficiencies including agammaglobulinemia, severe combined immunodeficiency, and CVID. The working definition also includes both laboratory values and clinical symptoms. The working definition is based on more recent registry information than the diagnostic requirements discussed by AAAI and is being used by the ESID however neither definition has been validated.(13)

Treatment guidelines published in 2010 from the National Advisory Committee on Blood and Blood Products and Canadian Blood Services concluded there is sufficient evidence that immunoglobulin therapy reduces the rate of infection and hospitalization in patients with primary immune deficiency, which likely leads to a lower mortality and improved quality of life. These guidelines also recommend when considering primary immune deficiency in patients with autoimmune hematological diseases that quantitative IgA, IgG, and IgM levels be drawn and evaluated prior to beginning therapy with immune globulin. Primary immune deficiency may require indefinite therapy.(19)

Chronic Inflammatory Demyelinating Polyneuropathy(18)

Chronic inflammatory demyelinating polyneuropathy (CIDP, also known as chronic inflammatory demyelinating polyradiculoneuropathy) is an acquired disorder of peripheral nerves and nerve roots. The diagnosis of CIDP should be considered in patients with symmetric or asymmetric polyneuropathy who have a progressive or relapsing-remitting clinical course for more than two months, particularly if the clinical features include positive sensory symptoms, proximal weakness, or areflexia.

Electrophysiologic testing developed by the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) is necessary to confirm the diagnosis. Definitive CIDP diagnosis has at least one of the following criteria based on electrodiagnostic findings:

• Motor distal latency prolongation in 2 nerves

• Reduction of motor conduction velocity in 2 nerves

• Prolongation of F-wave latency in 2 nerves

• Absence of F-wave latency in at least 1 nerve

• Partial motor conduction block of at least 1 motor nerve

• Abnormal temporal dispersion in at least 2 nerves

• Distal CMAP duration increase in at least 1 nerve

EFNS/PNS diagnostic criteria for CIDP also recommends exclusion of other conditions that include:

• Lyme disease, diphtheria, or drug or toxin exposure likely caused the neuropathy

• Hereditary demyelinating neuropathy

• Prominent sphincter disturbance

• Diagnosis of multifocal motor neuropathy

• Other causes of demyelinating neuropathy (e.g., POEMS syndrome, osteosclerotic myeloma, diabetic and nondiabetic lumbosacral radiculoplexus neuropathy)

Initial treatment for CIDP is immune modulating therapy with IVIG, glucocorticoids, or plasma exchange. Considerations that drive the selection of initial therapy include disease severity, comorbid disorders, venous access, potential adverse effects, availability, and cost. Guidelines recommend the use of a corticosteroid or IVIg for patients with moderate to severe CIDP. IVIg should be considered instead of a corticosteroid for patients with pure motor CIDP based on evidence of deterioration in these patients soon after initiation of a corticosteroid.

Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia(29)

Chronic lymphocytic leukemia (CLL) is associated with immunosuppression and an increased risk of infection. Infectious complications are influenced by the progressive reduction in immunoglobulin levels (hypogammaglobulinemia) and are common in patients with previously treated CLL. Immune globulin can provide additional protection against infection by supplementing humoral immunity and is associated with a significant decrease in the occurrence of infections, but with no improvement in overall survival outcome. In patients with recurrent sinopulmonary infections requiring intravenous antibiotics or hospitalization, SCIG therapy may be used.

Safety(1-6, 20, 21)

All immune globulins contain a boxed warning for thrombosis. Risk factors include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

There is a boxed warning for renal dysfunction and acute renal failure in all intravenous immune globulins (IVIG). Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or in patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. Bivigam, Flebogamma DIF, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam 5%, Octagam 10%, and Privigen do NOT contain sucrose.

Adverse events of immune globulin therapy can be difficult to classify due to the diversity of components in the formulation. Mild adverse events are common and may include low grade fever, headache, nausea, malaise, and myalgia. Infusion related reactions such as urticaria and fever can be prevented by pre-medicating patients with diphenhydramine and acetaminophen. Tension headache is the most common adverse event associated with immune globulin use and ranges in frequency from 26%-61%. Migraine headaches also occur and are more common in patients with a history of migraines.

Aseptic meningitis has been reported in patients receiving high dose immune globulin, with the majority of patients recovering within five days of symptom onset. Anaphylaxis has rarely occurred with immune globulin. Because immune globulin products are derived from donor plasma, the transmission of infectious particles is possible.

1

Cuvitru prescribing information. Baxalta. September 2021.

2

Gammagard Liquid prescribing information. Baxalta US Inc. March 2021.

3

Gammaked prescribing information. Kedrion USA. January 2020.

4

Gamunex-C prescribing information. Grifols Therapeutics Inc. January 2020.

5

Hizentra prescribing information. CSL Behring. April 2022.

6

HyQvia prescribing information. Baxalta US Inc. March 2021.

7

Jolles S, Sewell W, Misbah S. Clinical uses of intravenous immunoglobulin. Clin Exper Immunol. 2005;142:1-11.

8

El-Shanawany T, Sewell W, Misbah S, et al. Current clinical uses of intravenous immunoglobulin. Clin Med. 2006;6(4):356-359.

9

Orange J, Hossny E, Weiler C, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol. 2006;117(4):S525-S553.

10

Pierce L, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med. Rev. 2003;17(4):241-251.

11

Hamrock D. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharmacol. 2006;6:535-542.

12

Gerald K. McEvoy, Pharm.D. ed. 2014. Immunoglobulins. AHFS Drug Information® - 56th Ed. Bethesda, MD. American Society of Health-System Pharmacists.

13

ESID registry. Working definitions for clinical diagnosis of PID. Available at: http://esid.org/Working-Parties/Registry/Diagnosis-criteria.

14

Ameratunga R, Woon ST, Gills D, et al. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clinical and Experimental Immunology. July 2013;174:203-211.

15

Perez EE, Orange JS, Bonilla F, et al. Update on the use of immune globulin in human disease: a review of evidence. J Allergy Clin Immunol 2017;139(3):s1-46.

16

Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 2015;136(5):1186-1205,1205e1-1205e78.

17

Immune Deficiency Foundation Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases Third Edition. 2015.

18

Ryan, M, Ryan SJ. Chronic Inflammatory Demyelinating Polyneuropathy: Considerations for Diagnosis, Management, and Population Health. AJMC journals supplement 2018. Accessed at https://www.ajmc.com/journals/supplement/2018/examining-therapies-cidp/chronic-infammatory-demyelinating-polyneuropathy-considerations-for-diagnosis-management-and-population-health?p=4

19

Shehata N, Palda V, Bowen T, et al. The Use of Immunoglobulin Therapy for Patients with Primary Immune Deficiency: An Evidence-Based Practice Guideline. Transfusion Medicine Reviews 2010;24(1) Suppl 1:S28-S50.

20

Cutaquig Prescribing information. Octapharma. November 2021.

21

Xembify Prescribing information. Grifols. August 2020.

22

Jeffrey Modell Foundation Medical Advisory Board, 2013. 10 Warning Signs of Primary Immunodeficiency. Jeffrey Modell Foundation, New York, NY

23

American Academy of Allergy Asthma & Immunology. Primary Immunodeficiency. Accessed at https://www.aaaai.org/conditions-and-treatments/primary-immunodeficiency-disease

24

Orange JS, Ballow M, Stiehm, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol Vol 130 (3).

25

Emerson GG, Herndon CN, Sreih AG. Thrombotic complications after intravenous immunoglobulin therapy in two patients. Pharmacotherapy. 2002;22:1638-1641.

26

Department of Health (London). Clinical Guidelines for Immunoglobulin Use: Update to Second Edition. August, 2011.

27

Provan, Drew, et al. "Clinical guidelines for immunoglobulin use." Department of Health Publication, London (2008).

28

Dantal J. Intravenous Immunoglobulins: In-Depth Review of Excipients and Acute Kidney Injury Risk. Am J Nephrol 2013;38:275-284.

29

NCCN Drugs & Biologics Compendium. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2022. National Comprehensive Cancer Network, 2022. Accessed October 2022.

Hyqvia

immun glob inj

10 GM/100ML ; 2.5 GM/25ML ; 20 GM/200ML ; 30 GM/300ML ; 5 GM/50ML

M ; N ; O ; Y

N

Gammagard liquid ; Gammaked ; Gamunex-c

immune globulin (human) iv or subcutaneous soln

1 GM/10ML ; 10 GM/100ML ; 2.5 GM/25ML ; 20 GM/200ML ; 30 GM/300ML ; 40 GM/400ML ; 5 GM/50ML

M ; N ; O ; Y

N

Cuvitru ; Hizentra

immune globulin (human) subcutaneous inj

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML ; 8 GM/40ML

M ; N ; O ; Y

N

Hizentra

immune globulin (human) subcutaneous inj  ; immune globulin (human) subcutaneous soln pref syr

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML

M ; N ; O ; Y

N

Cutaquig

immune globulin (human)-hipp subcutaneous inj

1 GM/6ML ; 1.65 GM/10ML ; 2 GM/12ML ; 3.3 GM/20ML ; 4 GM/24ML ; 8 GM/48ML

M ; N ; O ; Y

N

Xembify

immune globulin (human)-klhw subcutaneous inj

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML

M ; N ; O ; Y

N

Cutaquig

immune globulin (human)-hipp subcutaneous inj

1 GM/6ML ; 1.65 GM/10ML ; 2 GM/12ML ; 3.3 GM/20ML ; 4 GM/24ML ; 8 GM/48ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Cuvitru ; Hizentra

immune globulin (human) subcutaneous inj

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML ; 8 GM/40ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Gammagard liquid ; Gammaked ; Gamunex-c

immune globulin (human) iv or subcutaneous soln

1 GM/10ML ; 10 GM/100ML ; 2.5 GM/25ML ; 20 GM/200ML ; 30 GM/300ML ; 40 GM/400ML ; 5 GM/50ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Hizentra

immune globulin (human) subcutaneous inj  ; immune globulin (human) subcutaneous soln pref syr

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Hyqvia

immun glob inj

10 GM/100ML ; 2.5 GM/25ML ; 20 GM/200ML ; 30 GM/300ML ; 5 GM/50ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Xembify

immune globulin (human)-klhw subcutaneous inj

1 GM/5ML ; 10 GM/50ML ; 2 GM/10ML ; 4 GM/20ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ONE of the following is met:

1. The patient has a diagnosis of Primary Immunodeficiency (PID)/Wiskott-Aldrich syndrome [e.g., x-linked agammaglobulinemia, common variable immunodeficiency, transient hypogammaglobulinemia of infancy, IgG subclass deficiency with or without IgA deficiency, antibody deficiency with near normal immunoglobulin levels) and combined deficiencies (severe combined immunodeficiencies, ataxia-telangiectasia, x-linked lymphoproliferative syndrome)] AND BOTH of the following:
   1. ONE of the following:
      1. If the requested agent is Cutaquig or HyQvia, the patient is 18 years of age or older OR
      2. If the requested agent is Cuvitru, Gammagard Liquid, Gammaked Liquid, Gamunex-C, Hizentra or Xembify, the patient is 2 years of age or older AND
   2. ONE of the following:
      1. The patient’s IgG level is less than 200 mg/dL OR
      2. BOTH of the following:
         1. The patient has a history of multiple hard to treat infections as indicated by at least ONE of the following:
            1. Four or more ear infections within 1 year
            2. Two or more serious sinus infections within 1 year
            3. Two or more months of antibiotics with little effect
            4. Two or more pneumonias within 1 year
            5. Recurrent or deep skin abscesses
            6. Need for intravenous antibiotics to clear infections
            7. Two or more deep-seated infections including septicemia AND
         2. The patient has a deficiency in producing antibodies in response to vaccination and BOTH of the following:
            1. Titers were drawn before challenging with vaccination AND
            2. Titers were drawn between 4 and 8 weeks of vaccination OR
2. The patient has a diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) AND ALL of the following:
   1. The requested agent is Hizentra AND
   2. The patient is 18 years of age or older AND
   3. BOTH of the following:
      1. The prescriber has assessed baseline disease severity utilizing an objective measure/tool (e.g., INCAT, Medical Research Council (MRC) muscle strength, 6-MWT, Rankin, Modified Rankin, etc.) AND
      2. ONE of the following:
         1. The requested agent will be used as initial maintenance therapy for prevention of disease relapses after treatment and stabilization with intravenous immunoglobulin (IVIG) OR
         2. The requested agent will be used for re-initiation of maintenance therapy after experiencing a relapse and requiring re-induction therapy with IVIG OR
3. The patient has a diagnosis of Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia AND ONE of the following:
   1. The patient’s IgG level is less than 200 mg/dL OR
   2. BOTH of the following:
      1. The patient has a history of multiple hard to treat infections as indicated by at least ONE of the following:
         1. Four or more ear infections within 1 year
         2. Two or more serious sinus infections within 1 year
         3. Two or more months of antibiotics with little effect
         4. Two or more pneumonias within 1 year
         5. Recurrent or deep skin abscesses
         6. Need for intravenous antibiotics to clear infections
         7. Two or more deep-seated infections including septicemia AND
      2. The patient has a deficiency in producing antibodies in response to vaccination and BOTH of the following:
         1. Titers were drawn before challenging with vaccination AND
         2. Titers were drawn between 4 and 8 weeks of vaccination

Length of Approval: 6 months

Renewal Evaluation

Target Agent(s) will be approved when BOTH of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
2. ONE of the following:
   1. The patient has a diagnosis of Primary Immunodeficiency (PID)/Wiskott-Aldrich syndrome [e.g., x-linked agammaglobulinemia, common variable immunodeficiency, transient hypogammaglobulinemia of infancy, IgG subclass deficiency with or without IgA deficiency, antibody deficiency with near normal immunoglobulin levels) and combined deficiencies (severe combined immunodeficiencies, ataxia-telangiectasia, x-linked lymphoproliferative syndrome)] AND the prescriber has provided information showing disease response as evidence by ONE or more of the following:
      1. Decrease in the frequency of infection OR
      2. Decrease in the severity of infection OR
   2. The patient has a diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) AND ONE of the following:
      1. The prescriber has provided information indicating the patient has demonstrated a beneficial clinical response to maintenance therapy, without relapses, based on an objective clinical measuring tool (e.g., INCAT, Medical Research Council (MRC) muscle strength, 6-MWT, Rankin, Modified Rankin, etc.) OR
      2. The patient is re-initiating maintenance therapy after experiencing a relapse while on Hizentra AND BOTH of the following:
         1. The patient improved and is stabilized on IVIG treatment AND
         2. The patient was NOT receiving maximum dosing of Hizentra prior to relapse OR
   3. The patient has a diagnosis of Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia AND the prescriber has provided information showing disease response as evidence by BOTH of the following:
      1. ONE of the following:
         1. Decrease in frequency of infection OR
         2. Decrease in the severity of infection AND
      2. The patient is at a decreased risk of infection as a result of treatment necessitating continued therapy

Length of Approval: 12 months