Last Review Date: 08/01/2024

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, 11/2023, 02/2024, 08/2024

1. Length of Authorization

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

2. Dosing Limits

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

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

3. Initial Approval Criteria ^1-8,12,15,18

Coverage is provided in the following conditions:

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

Primary Immunodeficiency (PID) † ^{1-8,11,12,18,35}

Such as: Wiskott -Aldrich syndrome, 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 has an IgG level <200 mg/dL; OR
  • Patient meets 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, deep skin or organ abscesses
• Persistent thrush in the mouth or fungal infection on the skin
• Need for intravenous antibiotics to clear infections
• Two or more deep-seated infections including septicemia
• Family history of PID; 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 and HyQvia ONLY] † Ф ^3,4,21,36

• 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 (CLL)/ Small Lymphocytic Lymphoma (SLL) ‡ ^31,32,35

• Patient has an IgG level <200 mg/dL; OR
• Patient has an IgG level <500 mg/dL; AND
  • Patient has recurrent sinopulmonary infections requiring IV antibiotics or hospitalization; OR
• Patient meets 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, deep skin or organ abscesses
  • Persistent thrush in the mouth or fungal infection on the skin
  • 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 ^1-8,15,18,36

Coverage may be renewed based upon the following criteria:

• Patient continues to meet the 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)

• 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 and HyQvia 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 or HyQvia; AND
  • Patient improved and stabilized on IVIG treatment: AND
  • Patient was NOT receiving maximum dosing of Hizentra or HyQvia prior to relapse

Acquired Immune Deficiency secondary to Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) ^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

• Continued treatment is necessary to decrease the risk of infection

5. Dosage/Administration^{1-8,13-15,31-34}

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.

v 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.

6. Billing Code/Availability Information

HCPCS Code(s) & 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; July 2024. Accessed July 2024.
2. Cutaquig [package insert]. Vienna, Austria; Octapharma; November 2021. Accessed September 2023.
3. Hizentra [package insert]. Bern, Switzerland; CSL Behring AG; April 2023. Accessed September 2023.
4. HyQvia [package insert]. Lexington, MA; Baxalta US Inc.; January 2024. Accessed January 2024.
5. Cuvitru [package insert]. Lexington, MA; Baxalta US Inc.; March 2023. Accessed September 2023.
6. Gammagard Liquid [package insert]. Lexington, MA; Baxalta US Inc.; March 2023. Accessed September 2023.
7. Gamunex®-C [package insert]. Research Triangle Park, NC; Grifols Therapeutics, LLC; January 2020. Accessed September 2023.
8. Gammaked [package insert]. Research Triangle Park, NC; Grifols Therapeutics, LLC; January 2020. Accessed September 2023.
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 October, 2023
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 3.2023. National Comprehensive Cancer Network, 2023. 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 October 2023.
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.
33. Grindeland JW, Grindeland CJ, Moen C, Leedahl ND, Leedahl DD. Outcomes Associated With Standardized Ideal Body Weight Dosing of Intravenous Immune Globulin in Hospitalized Patients: A Multicenter Study. Ann Pharmacother. 2020 Mar;54(3):205-212. doi: 10.1177/1060028019880300. Epub 2019 Oct 3.
34. Epland, K., Suez, D. & Paris, K. A clinician’s guide for administration of high-concentration and facilitated subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency diseases. Allergy Asthma Clin Immunol 18, 87 (2022). https://doi.org/10.1186/s13223-022-00726-7
35. Jeffrey Modell Foundation Medical Advisory Board, 2021. 10 Warning Signs of Primary Immunodeficiency. Jeffrey Modell Foundation, New York, NY. https://res.cloudinary.com/info4pi/image/upload/v1662306262/JMF_10_Signs_Generic_082421_v2_dcadf429cc.pdf?updated_at=2022-09-04T15:44:23.120Z. Accessed October 2023.
36. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision. Eur J Neurol. 2021 Nov;28(11):3556-3583. Erratum in: Eur J Neurol. 2022 Apr;29(4):1288. PMID: 34327760.
37. Bril V, Hadden RDM, Brannagan TH 3rd, et al. Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial. J Peripher Nerv Syst. 2023 Sep;28(3):436-449. doi: 10.1111/jns.12573. Epub 2023 Jul 6. PMID: 37314318.
38. Hassan S, Duff K, Wisseh S, et al. Rationale and Design of a Phase 3b Study of the Long-Term Tolerability and Safety of HyQvia in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): ADVANCE-CIDP 3 (4331). Neurology 2020-04-14 94(15_supplement): 4331 https://doi.org/10.1212/WNL.94.15_supplement.4331.
39. First Coast Service Options, Inc. Local Coverage Article: Billing and Coding: Immune Globulin (A57778). Centers for Medicare & Medicaid Services, Inc. Updated on 07/14/2023 with effective date 07/01/2023. Accessed January 2024.
40. Novitas Solutions, Inc. Local Coverage Article: Billing and Coding: Immune Globulin (A56786). Centers for Medicare & Medicaid Services, Inc. Updated on 07/14/2023 with effective date 07/01/2023. Accessed January 2024.
41. Wisconsin Physicians Service Insurance Corporation. Local Coverage Article: Billing and Coding: Immune Globulins (A57554). Centers for Medicare & Medicaid Services, Inc. Updated on 11/22/2022 with effective date 12/01/2022. Accessed January 2024.

Appendix 1 – Covered Diagnosis Codes (All Products)

Additional covered diagnosis codes applicable to Hizentra and Hyqvia ONLY:

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

The preceding information is intended for non-Medicare coverage determinations. 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 Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.