Last Review Date: 05/04/2023

Date of Origin: 7/20/2010

Dates Reviewed: 09/2010, 12/2010, 03/2011, 06/2011, 09/2011, 12/2011, 03/2012, 06/2012, 09/2012, 12/2012, 03/2013, 06/2013, 09/2013, 12/2013, 03/2014, 09/2014, 12/2014, 03/2015, 06/2015, 09/2015, 12/2015, 03/2016, 06/2016, 09/2016, 12/2016, 03/2017, 06/2017, 09/2017, 12/2017, 03/2018, 04/2018, 06/2018, 10/2018, 01/2019, 08/2019, 10/2019, 10/2020, 10/2021, 12/2021, 07/2022, 10/2022, 05/2023

1. Length of Authorization

Initial coverage will be provided for 6 months and may be renewed annually thereafter.

2. Dosing Limits

A. Quantity Limit (max daily dose) [NDC Unit]:

B. Max Units (per dose and over time) [HCPCS Unit]:

3. Initial Approval Criteria ^1-8,15,18

Coverage is provided in the following conditions:

• Baseline values for BUN and serum creatinine obtained within 30 days of request; AND

Primary immunodeficiency (PID)/Wiskott -Aldrich syndrome †

Such as: 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) [list not all inclusive]

• Patient is at least 2 years of age; AND
• Patient’s IgG level is <200 mg/dL OR both of the following:
  • Patient has a history of multiple hard to treat infections as indicated by at least one of the following:

• • Four or more ear infections within 1 year
  • Two or more serious sinus infections within 1 year
  • Two or more months of antibiotics with little effect
  • Two or more pneumonias within 1 year
  • Recurrent or deep skin abscesses
  • Need for intravenous antibiotics to clear infections
  • Two or more deep-seated infections including septicemia; AND

• • The patient has a deficiency in producing antibodies in response to vaccination; AND

• • Titers were drawn before challenging with vaccination; AND
  • Titers were drawn between 4 and 8 weeks of vaccination

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [Hizentra ONLY] † Ф

• Patient is at least 18 years of age; AND
• Physician 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
  • Used as initial maintenance therapy for prevention of disease relapses after treatment and stabilization with intravenous immunoglobulin (IVIG)§; OR
  • Used for re-initiation of maintenance therapy after experiencing a relapse and requiring re-induction therapy with IVIG (see Section IV for criteria)

Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia ‡ ^31,32

• Patient’s IgG level is <200 mg/dL OR both of the following:
  • Patient has a history of multiple hard to treat infections as indicated by at least one of the following:
    • Four or more ear infections within 1 year
    • Two or more serious sinus infections within 1 year
    • Two or more months of antibiotics with little effect
    • Two or more pneumonias within 1 year
    • Recurrent or deep skin abscesses
    • Need for intravenous antibiotics to clear infections
    • Two or more deep-seated infections including septicemia; AND
  • The patient has a deficiency in producing antibodies in response to vaccination; AND
    • Titers were drawn before challenging with vaccination; AND
    • Titers were drawn between 4 and 8 weeks of vaccination

Note: other secondary immunodeficiencies resulting in hypogammaglobulinemia and/or B-cell     aplasia will be evaluated on a case-by-case basis

§ Refer to the Immune Globulins medical necessity criteria (Document Number: IC-0071) for the relevant intravenous criteria requirements

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ^1-8,15,18

Coverage may be renewed based upon the following criteria:

• Patient continues to meet the universal and other indication-specific relevant criteria identified in section III; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: severe hypersensitivity/anaphylaxis, thrombosis, aseptic meningitis syndrome, hemolytic anemia, hyperproteinemia, acute lung injury, etc.; AND
• BUN and serum creatinine obtained within the last 6 months and the concentration and rate of infusion have been adjusted accordingly; AND

Primary immunodeficiency (PID)/Wiskott -Aldrich syndrome

• Disease response as evidenced by one or more of the following:
  • Decrease in the frequency of infection
  • Decrease in the severity of infection

     Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [Hizentra ONLY]

• Renewals will be authorized for patients that have 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
• Patient is re-initiating maintenance therapy after experiencing a relapse while on Hizentra; AND
  • Patient improved and stabilized on IVIG treatment: AND
  • Patient was NOT receiving maximum dosing of Hizentra prior to relapse

Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia ^31,32

• Disease response as evidenced by one or more of the following:
  • Decrease in the frequency of infection
  • Decrease in the severity of infection; AND

• Patient is at a decreased risk of infection as a result of treatment necessitating continued therapy

5. Dosage/Administration

Dosing should be calculated using adjusted body weight if one or more of the following criteria are met:

• Patient’s body mass index (BMI) is 30 kg/m² or more; OR
• Patient’s actual body weight is 20% higher than his or her ideal body weight (IBW)

This information is not meant to replace clinical decision making when initiating or modifying medication therapy and should only be used as a guide. Patient-specific variables should be taken into account.

Dosing for immunoglobulin products is highly variable depending on numerous patient specific factors, indication(s), and the specific product selected. For specific dosing regimens refer to current prescribing literature.

*HyQvia initial treatment interval/dosage ramp-up schedule

6. Billing Code/Availability Information

HCPCS Code & NDC(s):

*90284 – immune globulin (SCIg), human, for use in subcutaneous infusions

7. References

1. Xembify [package insert]. Research Triangle Park, NC; Grifols Therapeutics, LLC; August 2020. Accessed August 2022.
2. Cutaquig [package insert]. Vienna, Austria; Octapharma; November 2021. Accessed August 2022.
3. Hizentra [package insert]. Bern, Switzerland; CSL Behring AG; April 2022. Accessed August 2022.
4. HyQvia [package insert]. Lexington, MA; Baxalta US Inc.; April 2023. Accessed April 2023.
5. Cuvitru [package insert]. Lexington, MA; Baxalta US Inc.; September 2021. Accessed August 2022.
6. Gammagard Liquid [package insert]. Lexington, MA; Baxalta US Inc.; March 2021. Accessed August 2022.
7. Gamunex®-C [package insert]. Research Triangle Park, NC; Grifols Therapeutics, LLC; January 2020. Accessed August 2022.
8. Gammaked [package insert]. Research Triangle Park, NC; Grifols Therapeutics, LLC; January 2020. Accessed August 2022.
9. Jeffrey Modell Foundation Medical Advisory Board, 2013. 10 Warning Signs of Primary Immunodeficiency. Jeffrey Modell Foundation, New York, NY
10. 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 Suppl): S525-53.
11. 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).
12. Bonilla FA, Khan DA, Ballas ZK, et al. Practice Parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 2015 Nov;136(5):1186-205.e1-78.
13. Emerson GG, Herndon CN, Sreih AG. Thrombotic complications after intravenous immunoglobulin therapy in two patients. Pharmacotherapy. 2002;22:1638-1641.
14. Department of Health (London). Clinical Guidelines for Immunoglobulin Use: Update to Second Edition. August, 2011.
15. Provan, Drew, et al. "Clinical guidelines for immunoglobulin use." Department of Health Publication, London (2008).
16. Dantal J. Intravenous Immunoglobulins: In-Depth Review of Excipients and Acute Kidney Injury Risk. Am J Nephrol 2013;38:275-284.
17. Immune Deficiency Foundation. Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases. 3^rd Ed. 2015. Avail at: https://primaryimmune.org/sites/default/files/publications/2015-Diagnostic-and-Clinical-Care-Guidelines-for-PI_1.pdf.
18. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
19. Alonso W, Vandeberg P, Lang J, et al. Immune globulin subcutaneous, human 20% solution (Xembify®), a new high concentration immunoglobulin product for subcutaneous administration. Biologicals. 2020;64:34-40.
20. Kobayashi RH, Gupta S, Melamed I, et al. Clinical Efficacy, Safety and Tolerability of a New Subcutaneous Immunoglobulin 16.5% (octanorm [cutaquig®]) in the Treatment of Patients with Primary Immunodeficiencies. Front Immunol. February 2019 | Volume 10 | Article 40.
21. van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP), a multicenter randomised double-blind placebo-controlled trial: the PATH Study. Lancet Neurol. 2017;17(1):35-46.
22. Hagan JB, Fasano MB, Spector S, et al. Efficacy and safety of a new 20% immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. J Clin Immunol. 2010;30(5):734-745.
23. Jolles S, Borte M, Nelson R, et al. Long-term efficacy, safety, and tolerability of Hizentra for treatment of primary immunodeficiency disease. Clin Immunol. 2014;150(2):161-169.
24. Wasserman RL, Melamed I, Nelson RP Jr, et al. Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. Clin Pharmacokinet. 2011;50(6):405-414.
25. Wasserman RL, Melamed I, Kobrynski L, et al. Efficacy, Safety, and Pharmacokinetics of a 10% Liquid Immune Globulin Preparation (GAMMAGARD LIQUID, 10%) Administered Subcutaneously in Subjects with Primary Immunodeficiency Disease. J Clin Immunol. 2011 Mar 22. [Epub ahead of print]
26. Food and Drug Administration. Safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-efficacy-and-pharmacokinetic-studies-support-marketing-immune-globulin-intravenous-human. Accessed May 28, 2019
27. Wasserman RL, Melamed I, Stein MR, et al; and IGSC, 10% with rHuPH20 Study Group. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol. 2012;130(4):951-957.
28. Suez D, Stein M, Gupta S, et al. Efficacy, safety, and pharmacokinetics of a novel human immune globulin subcutaneous, 20% in patients with primary immunodeficiency diseases in North America. J Clin Immunol. 2016;36(7):700-712.
29. Roifman CM, Schroeder H, Berger M, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial. Int Immunopharmacol. 2003;3(9):1325-1333.
30. Roifman CM, Schroeder H, Berger M, et al, and the IGIV-C in PID Study Group. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial. Int Immunopharmacol. 2003;3:1325-1333.
31. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2022. National Comprehensive Cancer Network, 2021. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed September 2021.
32. Chapel H, Dicato M, Gamm H, et al. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. Br J Haematol 1994 Sep;88(1):209-12. doi: 10.1111/j.1365-2141.1994.tb05002.x.

Appendix 1 – Covered Diagnosis Codes (All Products)

Additional covered diagnosis codes applicable to Hizentra ONLY:

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA): N/A