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Supplements Examining the Application of Immunoglobulin in Multiple Disease States: A Review of Evidence
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Elena E. Perez, MD, PhD
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Intravenous and Subcutaneous Immunoglobulin Treatment Options
Stacy Ness, Pharm D, RPh, CSP, MSCS, AAHIVP
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Intravenous and Subcutaneous Immunoglobulin Treatment Options

Stacy Ness, Pharm D, RPh, CSP, MSCS, AAHIVP
Clinicians have a range of options for treating patients with disease states that require the use of immunoglobulin (Ig). Traditionally, intravenous immunoglobulin (IVIG) administration has provided effective therapy for a variety of disease states. More recently, subcutaneous immunoglobulin (SCIG) administration has become available for patients with primary immunodeficiencies and chronic inflammatory demyelinating polyneuropathy (CIDP). Ig is used as replacement therapy in patients with primary or secondary immunodeficiencies and has been shown to reduce morbidity due to bacterial infections associated with antibody deficiency. The mechanism of action for use of Ig in the treatment of autoimmune disorders is complex and partially understood, but immunomodulatory effects have been suggested in CIDP and multifocal motor neuropathy. The available IVIG and SCIG products differ in their pharmaceutical properties (eg, pH, osmolality, IgA content, sodium content, and stabilizer), which can affect safety and tolerability in some patients. The pharmacokinetics of Ig also differ based on the route of administration. With IVIG administration every 3 or 4 weeks, peak concentrations are greater and trough concentrations are lower, which can increase the propensity of systemic adverse effects (AEs) and impact tolerability of therapy. SCIG infusions are typically administered more frequently (ie, biweekly, weekly, and even daily based on patient need), resulting in steady state concentrations with fewer fluctuations in Ig plasma levels. The route of administration plays a major role in the types of AEs seen in patients receiving Ig therapy, with systemic AEs associated with IV administration and local reactions more commonly seen with SC administration. By understanding the differences in IVIG and SCIG products, which are not interchangeable, and the patient characteristics that guide product selection, clinicians and managed care providers can better serve patients with immunodeficiency disorders and other disease states.

Am J Manag Care. 2019;25:-S0
Intravenous and Subcutaneous Immunoglobulin Treatment Options

Immunoglobulin (Ig) has provided lifesaving therapy for a range of primary immunodeficiency diseases. With the introduction of subcutaneous immunoglobulin (SCIG) products, treatment options have expanded for patients with several conditions, such as primary immunodeficiency diseases or chronic inflammatory demyelinating polyneuropathy (CIDP), that require Ig therapy. In addition, recombinant human hyaluronidase-facilitated SCIG (fSCIG) is an option with primary immunodeficiency diseases, which allows for easier entry of large volumes of fluid through the extracellular matrix.1 Table 12-9 lists the currently available intravenous immunoglobulin (IVIG) and SCIG products. IVIG and SCIG products are manufactured from the plasma of healthy donors. Plasma pools are derived from a minimum of 1000 donors as mandated by the FDA but typically include a larger number.10 Generally, a batch of Ig will include plasma from approximately 15,000 donors.11 The volume of the plasma pools in production typically ranges from 2000 kg to 4000 kg.12 Ig products sold in the United States are derived solely from US donor plasma, although the final Ig product may be manufactured in FDA-approved facilities outside of the United States.2 These supply factors impose an inherent limit of source material that can cause supply chain issues, such as frequent product shortages, and is reflected in the product cost. The limited supply of product puts a premium on the importance of clinically appropriate therapy, including the decision to use the intravenous (IV) or the subcutaneous (SC) route of administration. SCIG products are currently only approved for the treatment of primary immunodeficiency, with the exception of immunoglobulin subcutaneous (Hizentra), which is also approved for CIDP13; IVIG products are indicated for several other disease states (Table 12-9).2,14 Clinicians and managed care professionals should also be aware that physicians often prescribe Ig products, particularly IVIG, for off-label uses, and payers do reimburse (often denied, and need appeal) for such uses.15 Although those off-label uses, which may number more than 150,16,17 are outside the scope of this paper, they represent a very important component of Ig therapy; readers are encouraged to refer to the findings of a work group of the American Academy of Allergy, Asthma, and Immunology (AAAAI) for their review and categorization of the evidence for the use of Ig for a wide range of disorders.14

Choosing the Right Patient for the IV and SC Routes of Administration

The AAAAI established a list of 8 guiding principles to help clinicians make quality decisions regarding IVIG for patients with primary immunodeficiency.18 These principles provide a framework for the clinically appropriate use of IVIG. Although the AAAAI’s principles are directed at IVIG for primary immunodeficiency, many points also translate to SCIG therapy and other FDA-approved indications, such as CIDP or multifocal motor neuropathy. Site of care, route of administration, and product characteristics are principles that apply globally when considering the effective use of Ig. The AAAAI states that the decision to infuse Ig in a hospital, hospital outpatient, community office, or home-based setting must be based on clinical characteristics of the patient and a discussion between the healthcare providers and the patient. Ultimately, the route of administration of Ig should be based on patient characteristics, as the IV and SC routes have demonstrated efficacy based on appropriate dosing regimens.19 Lastly, Ig is not a generic drug, and Ig products are not interchangeable based on the variability of key components in each product. When making the clinical decision regarding an Ig product, clinicians should be aware that some products may be designed for a single route of administration, whereas others may be approved for multiple routes of administration (refer to Table 12-9). For example, immune globulin (Flebogamma DIF) is approved only for IV administration,4,5 and immune globulin with recombinant human hyaluronidase (HyQvia) is approved only for SC administration.20 Other products, such as immune globulin (Gammagard Liquid 10%) and immune globulin injection, caprylate/chromatography purified (Gamunex-C 10%), are approved for IV and SC administration.21,22

It is recommended that payers and institutions keep an open Ig formulary because a patient may not tolerate a certain product and may require options based on product and patient characteristics. Specific Ig products need to match with patient characteristics to ensure patient safety; a change of Ig product should only occur with the active participation of the clinicians and other members of the healthcare team.

Another pertinent resource for clinicians is the Immunoglobulin Therapy Standards of Practice published by the Immunoglobulin National Society (IgNS), which is in its second edition.2 The IgNS document comprehensively covers many aspects of Ig therapy, with practice criteria accompanying each standard. Recognizing the collaborative approach that is necessary to properly treat patients who are receiving Ig therapy, IgNS emphasizes the interdisciplinary aspects of patient care that includes prescribers, pharmacists, nurses, and many other healthcare professionals.2

Patient Factors and Formulation Factors

The primary and active component of Ig products is immunoglobulin G (IgG). However, formulations of Ig can vary in many different respects: IgG monomer, dimer, and aggregate concentrations; IgA and IgM content; stabilizers; additives; and levels of impurities.2 When multiple products are being considered for a specific patient, clinicians must weigh the impact of these pharmaceutical formulation factors, as they contribute to differences in safety and tolerability.23-27

Osmolality of IVIG, IV/SCIG, and SCIG products ranges from 208 mOsm/kg to 1250 mOsm/kg. Most of the products are within the range of physiologic osmolality of approximately 290 mOsm/kg (Table 22,6-8). Products that deviate substantially from physiologic osmolality levels may put the patient at risk for various infusion-related adverse effects (AEs), such as thrombotic events and aseptic meningitis, particularly in elderly or neonatal patients, patients with cardiometabolic impairment, and patients with renal dysfunction.2,24 Similarly, the same patient populations may be sensitive to the sodium content of Ig products, which is reported in a variety of units (eg, mmol/L, mEq/mL, mg/mL). If the pH of an injectable product is substantially below physiologic levels, localized reactions at the site of injection may result. With the pH of Ig products ranging from a low of 4 to 7.2 (see Table 22,6-8), a slow infusion time may be advisable for products with pH levels toward the lower end of the range.

Although Ig products primarily contain IgG, they also contain varying amounts of IgA (<1 mcg/mL to ≤200 mcg/mL for IVIG products and 37 mcg/mL to 80 mcg/mL for SCIG products).2 Early research indicated that rare but severe anaphylactic reactions to Ig products were most likely to occur in patients who were severely deficient in IgA and also had IgE-type anti-IgA antibodies present. However, the administration of a low-IgA product has been shown to be effective in preventing severe allergic reactions in a small number of IgA-deficient patients who have previously experienced such reactions. Because SCIG therapy has a slower release of product into the general circulation, there are also a number of reports in the literature suggesting that SCIG therapy may be used successfully in IgA-deficient patients who experience adverse drug reactions (ADRs) to IVIG products.2  

Stabilizers are included in the product formulations to prevent IgG aggregation, which may increase the risk of certain AEs, such as anaphylaxis.19 Glycine is the most commonly used stabilizer, whereas D-sorbitol, glucose, maltose, L-proline, and polysorbate 80 are included in some formulations. Ig products containing glucose should be avoided in patients with diabetes when it is feasible as they can potentially raise serum glucose levels. Furthermore, products that contain maltose as a stabilizer should be used cautiously in patients with diabetes as some blood glucose monitoring systems (glucometers) may return falsely elevated glucose levels, which could lead to the unnecessary administration of insulin and result in hypoglycemia. Fortunately, most glucometers exhibiting this interference have been phased out of the market.19

Volume is also a significant consideration when choosing an Ig product, whether it is IV or SC. IVIG products are available as 5% or 10% solutions. One product is available as a lyophilized powder that can be reconstituted into a 5% or 10% solution using sterile water. When considering an IVIG product to select for a patient based on volume, it is very important to keep the clinical picture of the patient in mind. Extra volume could be beneficial in those patients who do not maintain adequate oral hydration and could also help minimize ADRs. In contrast, the extra volume could worsen underlying clinical conditions, such as congestive heart failure, hypertension, and renal dysfunction. Furthermore, the additional volume of low concentrated products may take longer to infuse and increase nursing time. SCIG products are commercially available as 10%, 16.5%, and 20% solutions. Although a 10% product may be better tolerated in some patients, the greater volume of product that needs to be infused means more SC infusion sites and frequent administrations. The rate of infusion and volume per site is individualized for each product and must be taken into consideration, in addition to patient tolerability.2-8 

When writing a prescription for Ig, some prescribers may specify a brand, and some payers impose limited formularies that require the use of a specific Ig product. If the prescribed or reimbursed product is not ideal for the patient based on these clinical characteristics, it is incumbent upon the Ig clinician to advocate for other options with the prescriber or payer if warranted.2 The potential interactions between patient factors and pharmaceutical formulation factors must be considered by clinicians when making IVIG or SCIG product choices and must be assessed on an ongoing basis.

Individual Patient Ability and Preference

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