Immunoglobulin Therapy Standards of Practice by Amy E

Immunoglobulin Therapy Standards of Practice By Amy E. Clarke, RN IgCN, Joe DiStefano, RPh, and Luba Sobolevsky, PharmD

PHARMACISTS AND NURSES DIETITIANS PHARMACY TECHNICIANS Educational Review Systems is an Educational Review Systems (Provid- This INFUSION article is approved provider of continuing er number ED002) is a Continuing cosponsored by Educational nursing education by the Alabama Professional Education (CPE) Accred- Review Systems (ERS), which is State Nurses Association (ASNA), ited Provider with the Commission on accredited by the Accreditation an accredited approver of Dietetic Registration (CDR). Registered Council for Pharmacy Education continuing nursing education by dietitians (RDs) and dietetic technicians, (ACPE) as a provider of continuing the American Nurses Credentialing registered (DTRs) will receive 1.0 hour pharmacy education. ERS has Center (ANCC), Commission on or 0.1 continuing professional educa- assigned 1.0 contact hours (0.1 Accreditation. Program #_05-115- tion unit (CPEU) for completion of this CEU) of continuing education 18-021. Educational Review Systems program/material. Eligibility to receive credit to this article. Eligibility is also approved for nursing continuing education credit for this to receive continuing education continuing education by the state article begins September 26, 2018 and credit for this article begins of California, the state of Florida, expires September 26, 2021. September 26, 2018 and expires and the District of Columbia. This Dietitian Knowledge Level: 2 program is approved for 1.0 hours September 26, 2021. The universal Dietitian Learning Codes: activity numbers for this program of continuing nursing education. are: 0761-9999-18-323-H01-P _ and Eligibility to receive continuing • 5030 Home Care 0761-9999-18-323-H01-T__ Activity education credit for this article • 5410 Clinical guidelines Type: Knowledge-Based. begins September 26, 2018 and expires September 26, 2021.

September / October 2018 Approval as a provider refers to recognition of educational activities only and does not imply Accreditation Council for Pharmacy Education, ERS, or ANCC Commission on Accreditation, approval or endorsement of any product. This continuing education activity is intended for pharmacists, pharmacy technicians, nurses, and other alternate-site infusion professionals. In order to receive credit for this program activity, participants must complete the online post-test and subsequent evaluation questions available at www.nhia.org/CE_Infusion. Participants are allowed two attempts to receive a minimum passing score of 70 percent.

www.nhia.org/CE_Infusion 37 Learning Objectives: • Describe patient risk factors affecting Ig therapy • Identify Ig product formulation factors affecting Ig therapy • Review common IVIG adverse drug reactions and mitigation • Discuss common SCIG adverse drug reactions and mitigation

AUTHOR BIOS:

Amy E. Clarke, RN IgCN, is Joe DiStefano, RPh, is Luba Sobolevsky, PharmD, Director of Nursing Clinical Director of Clinical Programs is Executive Director, Program Services, Diplomat at NuFactor Specialty Immunoglobulin National Pharmacy, Specialty Infusion Pharmacy. He has thirty Society, the central health Group. She is a registered nurse years of home infusion, care organization in the field and has been in the specialty clinical, and pharmacy of Ig therapy. In this capacity, and home infusion arena since management experience she oversees all areas of IgNS, 1994. She has done over 2,000 and has specialized in including education, standards intravenous and subcutaneous immune globulin therapy of practice, certification, infusions to date. She has for more than ten years. professional resources, helped to educate nursing staff, He is responsible for development, advocacy, and pharmacists, payers, physicians, clinical program and tools alliances. She holds a Doctor among others through multiple development, policy and of Pharmacy degree from presentations on IVIG and procedure development, the University of Southern SCIG administration specifics, quality improvement, and California, and has expertise including continuing education accreditation. Joe holds across various sectors of presentations for the National a Bachelor of Science health care, including clinical, Home Infusion Association degree in Pharmacy from educational development, and (NHIA), Infusion Nursing Society Northeastern University in pharmaceutical industry. (INS), and the Immunoglobulin Boston, MA. National Society (IgNS). Amy is currently co-chair of the IgNS Education Commitee and is the IgNS president emeritus for the 2016-2018 term.

AUTHOR DISCLOSURES STATEMENT The authors have no conflicts of interest to disclose. September / October 2018

38 www.nhia.org/CE_Infusion Background administration protocol should be initiated for Since their first use in the 1950s, the first several infusions — until the patient’s immunoglobulin (Ig) preparations have individual tolerability of the new brand is evolved through sophisticated manufacturing established.(3) processes, resulting in effective and safe products used in a variety of clinical indications Site of care options include hospital, infusion and practice settings. Patient risk factors, suite, physician’s office, and the home setting. product differences, dosing, appropriate Considerations for safe at-home administration administration protocols, and emergency include a patient or caregiver’s ability and preparedness are among the factors that motivation to participate in care, provider’s and impact patient safety, tolerability, adherence, nurse’s specialized expertise and credentials, and treatment success.(1) Ig standards-based protocols and policies, immediate access to emergency medical Any specialized clinical field requires services, among other considerations.(3) standardization to ensure best clinical practice, assure health care professional Before initiating Ig therapy, the Ig clinician accountability, and protect patients, clinicians, should conduct a thorough assessment that and organizations. The Immunoglobulin includes outlining the outcome goals, patient’s National Society (IgNS) has recently published health status and vital signs, hydration status, the second edition of the Ig Therapy Standards disease-specific assessments, previous Ig of Practice, a set of guidelines that provide regimen, risk factors and co-morbidities, as a framework to support multidisciplinary well as any history of adverse drug reactions practices in defining and developing Ig (ADRs). Access to preferred Ig brand and issues policies, procedures, and data collection with insurance coverage and payer formulary strategies. IgNS is dedicated to advancing are important patient advocacy factors.(3) a multidisciplinary health care practice approach through comprehensive education Risk Factors and Considerations and professional certification for nurses (with A thorough risk assessment including a a pharmacist certification underway). The patient’s individual health risk factors, Ig brand organization promotes patient-centric advocacy risk factors, and other issues impacting success initiatives and provides critical practice of therapy must be conducted ahead of every resources to clinicians and organizations.(2, 3) infusion.

Ig therapy is used for replacement therapy Patient risk factors relevant to Ig therapy in immunodeficiency diseases and for selection include diabetes mellitus, fluid immunomodulatory effects in autoimmune and restriction, cardiac and pulmonary function, inflammatory disorders. Sixteen Ig therapy blood type, age (especially neonates and products are currently available in the U.S., geriatrics), obesity, history of thrombosis, and with multiple new products in various stages renal impairment/renal failure. of development.(4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 22,23) While all Ig brands have been shown to be Further, several class-labeled Boxed Warnings effective in respective clinical trials, formulation exist with Ig therapy. Renal dysfunction differences and routes of administration are and renal failure are class-labeled Boxed known to significantly impact tolerability on Warnings for intravenous immune globulin an individual patient level. Ig products are not (IVIG), and are most often associated with interchangeable, and specific Ig products need sucrose-containing Ig preparations. The last to be matched to specific patient characteristics Ig brand stabilized with sucrose (Carimune to ensure patient safety. It is thus inappropriate NF, CSL Behring) is no longer produced and to switch Ig products without careful and is not commercially available. Patients at risk September / October 2018 due consideration, and substitution should for renal dysfunction, renal failure, osmotic only occur with the active participation of the nephrosis, and death include those with pre- patient, prescriber, and the health care team. existing renal insufficiency, diabetes mellitus, In the event of a brand switch, an Ig-naive age greater than 65, volume depletion, sepsis,

www.nhia.org/CE_Infusion 39 paraproteinemia, or patients Therapy Standards of Practice Common Systemic ADRs receiving known nephrotoxic 2nd Edition, Ig Product Observed with IVIG drugs. Considerations section. The ADRs reported most often include headache, Thrombosis is another class- Intravenous fatigue, nausea, changes in labeled Boxed Warning Immunoglobulin (IVIG) blood pressure, myalgias, for all IVIG as well as IVIG is typically given via arthralgias, urticaria, pruritus, subcutaneous (SCIG) and a peripherally inserted rash, low-grade fever, chills, facilitated SCIG (fSCIG) angiocatheter (the most chest discomfort, and formulations. Risk factors common method) or a central tachycardia. General patient may include advanced age, line (such as an implanted counseling to help with these prolonged immobilization, port), and is administered includes staying orally well- hypercoagulable conditions, using an infusion pump which hydrated, pre-medication history of venous or allows controlled titration use and adherence, good arterial thrombosis, use of of rates and volumes. The rest, and compliance with estrogens, indwelling vascular pharmacokinetic profile medications used to treat catheters, hyperviscosity, and of the IV route allows fast chronic conditions such as cardiovascular risk factors. absorption and higher initial hypertension. (3,4, 8-16, 19-23) serum Ig peaks as compared A patient’s medical history to SCIG and fSCIG. The Many ADRs occurring during and health status must be IVIG serum concentration an infusion may be prevented evaluated to determine the continues to decline over a or decreased in severity by Ig product(s) that may be three-four week period, when lowering the infusion rate or most suitable on an individual the next dose is administered. temporarily discontinuing basis. Clinicians are advised Due to its complexity, adverse delivery and restarting at a to review the IgNS Ig Therapy event profile, risk factors, and lower rate after symptoms Standards of Practice 2nd potential for serious ADRs at resolve, and repeating Edition, Ig Treatment Planning every infusion, regardless of ordered premedication if section for further information. patient experience or brand, enough time has passed. (3-6, 8-24) IVIG must be administered Other ADRs may be treated by a clinician who, per the symptomatically. (3) Ig Product Risk Factors Ig Therapy Standards of Ig product formulations differ Practice, must remain with To mitigate and decrease in route of administration, the patient throughout the the severity of ADRs, concentration, osmolality, infusion. (3,4,8-16,19-24) premedication strategies may stabilizers, sodium, IgA be considered. Hydration is content, FXIa and PKA levels, IVIG infusion rates are recommended for all patients pH, and anti-A and anti-B determined based (unless volume-restricted due levels — characteristics on product-specific to specific risk factors) — taken that can impact safety and manufacturer’s guidelines, either orally or delivered via tolerability through a variety patient risk factors, and infusion. Other management of mechanisms. history of ADRs. Infusions may include slowing the should be initiated at a slow titration and/or maximum Understanding formulation rate and then titrated using infusion rates, splitting differences and at least three rate escalation the dose over more days, individualizing product steps, as tolerated, to the administering multiple day selection are critical to maximum rate. courses over non-consecutive appropriate and safe Ig days, as well as adding therapy management. ancillary medications such as September / October 2018 A thorough review of Ig IV hydration. In some cases, product parameters, and changing the brand and/or the corresponding concerns route of administration may and practice guidelines be necessary to achieve better can be found in the IgNS Ig tolerability. (3)

40 www.nhia.org/CE_Infusion Patient counseling and Local site reactions are the Facilitated Subcutaneous education on Ig therapy more common side effect with Immunoglobulin (fSCIG) management includes hydration SCIG therapy and include local Facilitated-subcutaneous and rest prior to infusion; swelling, redness, and irritation. infusion of Ig 10% and adherence to concomitant Successful SCIG administration recombinant human medication regimen — depends on the effectiveness hyaluronidase improves particularly for conditions of initial patient education absorption (vs. SCIG), is infused that may impact safety and/ and training by a nurse or less frequently, and minimizes or tolerability of Ig, such prescriber, patient and/or the need for multiple infusion as hypertension, migraine, caregiver comfort; proper sites. Of note, swelling at the congestive heart failure, technique including insertion; infusion site usually presents thromboembolic conditions, and ensuring that the tubing as diffuse and soft, rather than and other risk factors. (3,4,8-16,19-24) is primed to just short of the raised and nodular as compared needle (“dry-priming”) to to those commonly observed Subcutaneous minimize a localized response, with SCIG. Local site reactions Immunoglobulin (SCIG) as well as appropriate needle and management of fSCIG SCIG is typically administered length and gauge; SC tissue are similar to SCIG. Facilitated- through a pump or a syringe and infusion site; and needle SCIG is approved in adults with driver infusion device phobia. Further, appropriate PID; during the clinical trial, simultaneously through multiple interventions and trouble- some patients developed non- SC sites. SCIG is available as a shooting can be instrumental neutralizing antibodies to the 10% (1 g/10 mL) or 20% (1 g/5 in improving tolerability and a hyaluronidase component. The mL) solution. The choice of patient’s experience. (3, 4, 10, 12, 14, 15) clinical significance is unknown concentration may depend on and may be a consideration in patient tolerability of Ig therapy reproduction. (3,16) as well as the volume infused. Treatment Success Factors 11. Gammagard S/D IgA<1μ/mL[package insert]. Westlake There are multiple factors that contribute to Village, CA: Baxter Healthcare Corporation; 2014. patient tolerability, adherence, and response 12. Gammaked [package insert]. Research Triangle Park, NC: to therapy. Appropriate product selection, Grifols Therapeutics, Inc.; 2016. healthcare professionals’ expertise in 13. Gammaplex 5%[package insert]. Durham, NC: BPL Inc; 2009. administration, and education provide key 14. Gamunex-C [package insert]. Research Triangle Park, NC: opportunities to ensure success. Additional Grifols Therapeutics, Inc.; 2017. considerations influencing a positive patient 15. Hizentra [package insert]. Kankakee, IL: CSL Behring LLC; outcome may include psychosocial issues, 2016. caregiver support, nursing resources, insurance coverage, and financial impact.(3) 16. Hyqvia [package insert]. Cambridge, MA: Shire US, Inc.; 2016 Conclusion 17. Caress JB, Kennedy BL, Eickman KD. Safety of intravenous immunoglobulin treatment. Expert Opin Drug Saf. Ig therapy requires a high degree of specialized 2010;9(6):971-979. education and advanced, standardized clinical practice to ensure safety and good clinical 18. Lin RY, Rodriguez-Baez G, Bhargave GA,et al. Intravenous gammaglobulin-associated renal impairment reported to outcomes. Adherence to the Ig Therapy the FDA: 2004 - 2009. Clin Nephrol. 2011;76(5):365-372. Standards of Practice is critical, as it guides all major aspects of practice, including appropriate 19. Octagam 5% [package insert]. Hoboken, NJ: Octapharma USA, Inc.; 2015. product selection and dosing, route and method of administration, mitigation of risks, 20. Octagam 10% [package insert]. Hoboken, NJ: Octapharma management of adverse events administration USA, Inc.; 2015. protocols, and other aspects. The standards 21. Privigen [package insert]. Kankakee, IL: CSL Behring LLC; facilitate collaboration of care, serve as a 2017. foundation to organizational policies, support 22. Panzyga [package insert]. Hoboken, NJ. Octapharma USA clinicians, and most importantly, help protect the Inc.; 2018. patients. 23. Gammaplex 10% [package insert]. Durham, NC: BPL 2017 24. Siegel J. Immune globulins. Therapeutic, pharmaceutical References cost, and administration considerations. Pharmacy Practice 1. Gelfand EW. Differences between IGIV products: impact on News. February 6, 2018. clinical outcome. Int 2. Immunoglobulin National Society. www.ig-ns.org. Accessed March 12, 2018 3. Immunoglobulin Therapy: Standards of Practice, 2nd Edition (IgNS 2018) 4. Cuvitru [package insert] Westlake Village, CA: Baxalta US; 2016. 5. Dalakas MC, Clark WM. Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record. Neurology. 2003;60(11):1736-1737. 6. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44(2):223-226. 7. Epstein JS, Zoon KC. Important drug warning: immune globulin intravenous (human) (IGIV) products. Neonatal Netw. 2000;19(2):60-62. 8. Flebogamma 5% DIF [package insert]. Barcelona, Spain: Grifols Biologicals, Inc.; 2017. September / October 2018 9. Flebogamma 10% DIF [package insert]. Barcelona, Spain: Grifols Biologicals, Inc.; 2018. 10. Gammagard Liquid [package insert]. Westlake Village, CA: Baxalta US; 2016.

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