Clinical Policy: Immunoglobulin for Vulgaris Reference Number: CP.CPA.91 Effective Date: 11.16.16 Last Review Date: 08.17 Revision Log Line of Business: Medicaid – Medi-Cal

See Important Reminder at the end of this policy for important regulatory and legal information.

Description The following are Immunoglobulins requiring prior authorization: Human Infusion (Bivigam™), Immune Globulin Intravenous (Carimune NF®), Immune Globulin Intravenous (Flebogamma®), Immune Globulin Infusion (Gammagard Liquid®), Immune Globulin Intravenous (Gammagard S/D®), Immune Globulin Injection (Gammaked™), Immune Globulin Intravenous (Gammaplex™), Immune Globulin Injection (Gamunex®-C), Immune Globulin Intravenous (Octagam®), Immune Globulin Intravenous (Privigen®), Immune Globulin Subcutaneous (Hizentra™), Immune Globulin Infusion with Recombinant Human Hyaluronidase (Hyqvia)

FDA approved indication Immune globulin intravenous: Bivigam, Carimune NF, Flebogamma, Gammaplex, Octagam, Privigen (including Gamunex-C, Gammaked and Gammagard S/D when used intravenously) are indicated: • Replacement therapy for primary immunodeficiency (PI) This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies • For the treatment of patients with idiopathic (ITP) to raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery. • Maintenance therapy to improve muscle strength and disability in adult patients with Multifocal Motor Neuropathy (MMN) • For prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia (CLL) • For prevention of coronary artery aneurysms associated with Kawasaki syndrome • For treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse

Immune globulin subcutaneous: Hizentra, Hyqvia (including Gamunex-C, Gammaked, Gammagard Liquid when used subcutaneously) are indicated: • For the treatment of/replacement therapy for patients with primary immunodeficiency (PI). This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies Limitation of use: • Hyqvia: safety and efficacy of chronic use of recombinant human hyaluronidase in Hyqvia have not been established in conditions other than PI.

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Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria.

It is the policy of health plans affiliated with Centene Corporation® that Bivigam, Carimune NF®, Flebogamma, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam, Privigen, Hizentra, Hyqvia are medically necessary when the following criteria are met:

I. Initial Approval Criteria A. Pemphigus Vulgaris, , Bullous , Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid), Acquisita (must meet all): 1. Diagnosis of one of the following: a. Pemphigus Vulgaris; b. Pemphigus Foliaceus; c. , Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid); d. Epidermolysis Bullosa Acquisita; 2. Diagnosis has been proven by biopsy and confirmed by pathology report; 3. The condition is rapidly progressing, extensive or debilitating; 4. Failure to and immunosuppressive agents (e.g., , , mycophenolate mofetil) unless contraindicated or clinically significant adverse effects are experienced; 5. Dose does not exceed: a. 2 gm/kg at four-week intervals; OR b. 400 mg/kg/day for 5 days, 1 cycle only (may repeat up to three times in a 6-month period; OR c. 300 mg/kg/day for 5 days at monthly intervals (3 cycles). Approval duration: 6 months or to member’s renewal period, whichever is longer

B. Other diagnoses/indications 1. Refer to CP.PHAR.57 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized).

II. Continued Therapy A. All- indications (must meet all): 1. Currently receiving medication via health plan benefit or member has previously met initial approval criteria; 2. Documentation of positive response to therapy; 3. The treatment is considered complete when the patient is free of disease after a 16- week interval between the last two infusion cycles; 4. Dose does not exceed: a. 2 gm/kg at four-week intervals; OR b. 400 mg/kg/day for 5 days, 1 cycle only (may repeat up to three times in a 6-month period; OR

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c. 300 mg/kg/day for 5 days at monthly intervals (3 cycles). Approval duration: 6 months or to member’s renewal period, whichever is longer.

B. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via health plan benefit and documentation supports positive response to therapy. Approval duration: Duration of request or 12 months (whichever is less); or 2. Refer to CP.PHAR.57 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized).

III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy – CP.PHAR.57 or evidence of coverage documents. B. A list of specific indications for which coverage is not authorized may be found in the PA guideline: Immune Globulin Conditions Not Medically Necessary – NATL.

IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key • PI: primary humoral immunodeficiency • CVID: common variable immunodeficiency • ITP: thrombocytopenic purpura • MMN: multifocal motor neuropathy • CLL: chronic lymphocytic leukemia (CLL) • CIDP: chronic inflammatory demyelinating polyneuropathy • IVIG: intravenous immunoglobulin

Appendix B: General Information • IVIG therapy for Pemphigus Vulgaris must be used only for short-term therapy and not as a maintenance therapy. • IVIG dose adjustments: i. Adjustment of the IVIG dose and time interval between doses should be based on trough levels measured every month for the first three months of therapy and again at six months ii. Adjustments to infusion rates and measuring of serum (immunoglobulin G) IgG levels may be needed during infections or in persons who have a high catabolism of infused IgG iii. To reduce infection frequency in immunodeficient patients, serum trough levels should be maintained at 670-730 mg/dl, a value close to the lower limit of normal. All IgG trough levels outside of the low normal range of 6.7-7.3 mg/dl require dosage adjustment. • The treatment is considered complete when the patient is free of disease after a 16-week interval between the last two infusion cycles. • Examples of clinically significant adverse effects to corticosteroids, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil) are diabetes or fractures from chronic steroid use.

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• Black Box Warning: Thrombosis, renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur.

Appendix C: Therapeutic Alternatives Drug Dosing Regimen Dose Limit/Maximum Dose systemic glucocorticoid Up to a maximum of an 2 mg/kg/day (up to 120 mg per (Various - , equivalent of 1.5 to 2 mg/kg per day) prednisolone, or day of prednisone methylprednisolone) cyclophosphamide Pulsed regimen of monthly This field intentionally left (Cytoxan®) infusion of dexamethasone 100 blank mg IV QD for 3 days and cyclophosphamide monthly infusion of 500 mg IV QD for 1 day plus cyclophosphamide 50 mg PO QD in between pulsed therapy OR cyclophosphamide 2 to 2.5 mg/kg of ideal body weight PO QD and prednisone 1 mg/kg of ideal body weight PO QD followed by a taper after two to three months azathioprine (Imuran®) Dosing of azathioprine is 2.5 mg/kg/day influenced by the level of activity thiopurine methyltransferase (TPMT) enzyme High TPMT activity: up to 2.5 mg/kg of ideal body weight PO QD Intermediate or low TPMT activity: up to 0.5 to 1.5 mg/kg PO QD Absent TPMT activity: should not be treated with azathioprine mycophenolate mofetil 2 g PO QD (taken as 1 g PO 3 g/day (Cellcept®) BID) added to systemic glucocorticoid therapy. Enteric- coated can be given as 720 mg PO BID

V. Dosage and Administration Bivigam, Gammaplex, Flebogamma, Gammagard, Gammagard

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S/D, Gammaked, Gamunex-C, Octagam, Cariumune NF, Privigen Indication Dosing Regimen Maximum Dose Pemphigus Vulgaris; Pemphigus 2 gm/kg IV at four-week 2 gm/kg at four- Foliaceus; Bullous Pemphigoid; intervals until are week intervals Mucous Membrane Pemphigoid healed. Frequency of (a.k.a. Cicatricial Pemphigoid); infusions can take place at Epidermolysis Bullosa Acquisita intervals of 6, 8, 10, 12, 14, and 16 weeks.

Other protocols that will be considered acceptable: 400 mg/kg/day IV for 5 days, 1 cycle only (may repeat up to three times in a 6-month period) OR 300 mg/kg/day for 5 days at monthly intervals (3 cycles)

VI. Product Availability Drug Availability Bivigam™ Vial, liquid solution, 10% (1 g/10 mL)): 50 mL, 100 mL Carimune NF® Vial, lyophilized powder: 3 g, 6 g, 12 g Flebogamma® 5% Vial, liquid preparation, 5% (50 mg/mL): 10mL, 50mL, 100mL, 200mL, 400mL Flebogamma® 10% Vial, liquid preparation, 10% (100 mg/mL): 50 mL, 100 mL, 200 mL Gammagard Liquid®, Vial, liquid solution, 10% (1 g/10 mL): 10 mL, 25 mL, 50 mL, 100 mL, 200 mL, 300 mL Gammagard S/D®, Bottle, solution, 5 g, 10 g Gammaked™ Vial, liquid solution, 10% (1 g/10 mL): 10 mL, 25 mL, 50mL, 100mL, 200mL Gammaplex™ Vial, liquid, 5% (50 mg/mL): 50 mL, 100 mL, 200 mL, 400 mL Gamunex®-C, Vial, solution, 10% (1 g/10 mL): 10 mL, 25 mL, 50 mL, 100 mL, 200 mL, 400 mL Octagam® 5% Bottle, liquid preparation, 5% (50 mg/mL): 20 mL, 50 mL, 100 mL, 200 mL, 500 mL Octagam® 10% Bottle, liquid preparation, 5% (100 mg/mL): 20 mL, 50 mL, 100 mL, 200 mL Privigen® Vial, liquid solution, 10% (100 mg/mL): 50 mL, 100 mL, 200 mL, 400 mL Hizentra™ Vial, liquid solution, 20% (0.2 g/mL): 5 mL, 10 mL, 20 mL, 50 mL Hyqvia Dual vial unit, solution:

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-10% IgG (1 g/10 mL): 25 mL, 50 mL, 100 mL, 200 mL, 300 mL -160 U/mL recombinant human hyaluronidase: 1.25 mL, 2.5 mL, 5 mL, 15 mL

VII. References 1. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed January 13, 2017. 2. Immune Globulin. American Hospital Formulary Service Drug Information. Available at: http://www.medicinescomplete.com/mc/ahfs/current/. Accessed January 13, 2017. 3. Gammagard S/D [Prescribing Information] Westlake Village, CA: Baxalta US Inc.; October 2016. 4. Gammaplex [Prescribing Information] Hertfordshire, United Kingdom: Bio Products Laboratory Limited: July 2015. 5. Gamunex-C [Prescribing Information] Research Triangle Park, NC. Grifolis Therapeutics Inc.: September 2016. 6. Hizentra [Prescribing Information] Bern, Switzerland: CSL Behring AG, October 2016. 7. Carimune NF [Prescribing Information] Bern, Switzerland: CSL Behring AG, November 2016. 8. Privigen [Prescribing Information] Bern, Switzerland: CSL Behring AG, October 2016. 9. Gammagard Liquid [Prescribing Information] Westlake Village, CA; Baxalta US Inc.: October 2016. 10. Ahmed A. IVIG therapy in the treatment of patients with bullous pemphigus unresponsive to conventional immunosuppressive treatment. J Am Acad. Derm. 2001;45:1. 11. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47(3):358-63. 12. Sami N, Qureshi A, Ruocco E, Ahmed AR. -sparing effect of intravenous in patients with pemphigus vulgaris. Arch Dermatol. 2002;138(9):1158-62. 13. Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol 2003 Nov;149(5):926-37. Available at: http://www.bad.org.uk/library- media%5Cdocuments%5CPemphigus_vulgaris_2003.pdf. Accessed January 13, 2017. 14. Goldstein BG, Goldstein AO. Pemphigus. UpToDate. December 2, 2011. Available at: http://www.uptodate.com/contents/pemphigus?source=search_result&search=IVIG+f or+pemphigus+vulgaris&selectedTitle=1%7E150 15. Hertl M, Geller S. Initial management of pemphigus vulgaris and pemphigus foliaceus. UpToDate. September 22, 2015. Available at: http://www.uptodate.com/contents/initial-management-of-pemphigus-vulgaris-and- pemphigus-foliaceus

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16. Ishii N, Hashimoto T, Zillikens D, et al. High-dose intravenous immunoglobulin (IVIG) therapy in autoimmune skin blistering diseases. Clin Rev Immunol 2010; 38:186. 17. Flebogamma 5% DIF [Prescribing Information] Barcelona, Spain: Institutio Grifols, S.A.; April 2015. 18. Flebogamma 10% DIF [Prescribing Information] Barcelona, Spain: Institutio Grifols, S.A.; January 2016.Gammaked [Prescribing Information] Research Triangle Park, NC: Grifolis Therapeutics Inc.; September 2016. 19. Octagam 5% [Prescribing Information] Hoboken, NJ; Octapharma USA Inc.: October 2014. 20. Bivigam [Prescribing Information] Boca Raton, FL: Biotest Pharmaceuticals Corporation; April 2014. 21. Octagam 10% [Prescribing Information] Hoboken, NJ; Octapharma USA: November 2015. 22. Hyqvia [Prescribing Information] Westlake Village, CA; : Baxalta US Inc.; April 2016. 23. Clinical Pharmacology Web site. Available at: http://www.clinicalpharmacology- ip.com/default.aspx. Accessed January 13, 2017.

Reviews, Revisions, and Approvals Date P&T Approval Date Converted to new template; minor changes to verbiage and grammar. 01.17.17 8.17 References updated.

Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.

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This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services.

Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

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