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Evidence‐Based Care in Immunoglobulins: Individualizing Patient Treatment

Introduction

Immunoglobulin (Ig) therapy has long been used to increase plasma IgG levels in patients who lack sufficient antibodies or have impaired immune function, and in those who require additional protection against specific pathogens. Such Ig preparations aid in normalizing the immune response and neutralizing pathogens, thus accelerating disease recovery. Common uses of Ig span a wide variety of conditions including primary immune deficiency (PID), autoimmune and inflammatory conditions, and prophylaxis against selected pathogens. Ig is also used to treat secondary immunodeficiency resulting from conditions in which the humoral response is deficient due to nongenetic diseases such as leukemia, sepsis, and other infections, and in critically ill ICU patients.

Many Ig products, derived from pooled human plasma, have been approved by the Food & Drug Administration (FDA) for treatment of various disease states. The purpose of this monograph is to review the types of Ig products currently available and their approved indications, as well as their manufacturing process and physicochemical properties since these may impact efficacy and tolerability. The relative merits of intravenous and subcutaneous Ig products are discussed that can inform selection of the most appropriate agent, including the possible need to change to a different product or route of administration. Finally, common adverse effects are summarized, along with approaches for mitigating and managing such toxicities in order to maximize outcomes with Ig therapy.

History of Immunoglobulin Therapy

Modern human Ig therapy began in the 1940s following development of large-scale plasma purification methods. Central to this process was the use of cold ethanol precipitation, low temperature, reduced ionic strength, and low pH to separate and purify Ig from other plasma proteins and contaminants. In 1952, subcutaneous Ig (SCIG) was first used to successfully treat recurring sepsis in a boy with X-linked agammaglobulinemia.¹ Over the next two decades, various enzymatic cleavage steps were added to the purification process to reduce IgG aggregates, which can activate complement and cause anaphylaxis upon IV infusion. Intramuscular Ig (IMIG) was clinically evaluated in the early 1950s as an alternative to IV infusion therapy (IVIG). IMIG was deemed impractical, however, since it required injections at multiple sites to achieve the target dose and caused sterile abscesses, hematomas, and sciatic nerve injury, favoring development of IVIG. Initial commercial IVIG products became available in the 1970s and 1980s, which were further refined by additional purification methods and incorporation of stabilizers. The first SCIG products were introduced in the United States in the 1990s, and one IMIG product was approved in 2018. Recent innovations have included the addition of agents such as hyaluronidase to SCIG to improve its pharmacokinetics and pharmacodynamics. Currently a total of 20 IVIG, SCIG, and IMIG products are approved in this country, covering a variety of clinical indications (Table 1).

Immunoglobulin Manufacturing Process

IVIG is purified from human plasma by means of a multistep process. Plasma is obtained from a pool of more than 1000 healthy donors to ensure that the final IVIG product contains a large, diverse antibody repertoire.² IVIG is initially fractionated from other plasma proteins using ethanol precipitation to enrich for IgG. This is followed by various enzymatic treatments designed to reduce anticomplement activity, and purification steps such as anion-exchange chromatography to remove contaminants.³ A solvent/detergent process or octanoic acid is used to remove lipid-coated viruses, with nanofiltration to eliminate lipid-coated and non–lipid-coated viruses. These processes, along with low pH and heat inactivation, ensure that IVIG products are free of key pathogenic viruses including HIV, non-A non-B hepatitis, and SARS-CoV2. The final IVIG product may still contain minor contaminants such as IgA, IgM, complement proteins, plasminogen, plasmin, and prekallikrein activator, some of which may be important for certain patients (e.g., those with IgA subclass deficiencies who may have increased anti-IgA antibody titers).⁴ This plasma fractionation process also yields multiple fractions containing other useful therapeutic biologics such as albumin, Factor VIII, Factor IX, and alpha-1 antitrypsin.

IVIG was initially developed as a lyophilized product to maximize its shelf life. It was subsequently discovered that lowering the pH to 4.25 during the purification process or in the final container allows IVIG to remain stable in a liquid state, avoiding the need for lyophilization. Like all drugs, however, these products have a finite shelf-life and should not be used after their expiration date.

Pharmacoeconomic Impact of Immunoglobulin

In 2019, IVIG was ranked as the fifteenth highest drug expenditure in the United States with an estimated cost of approximately $4.7 billion, a 6.6% increase over the previous year. Use of IVIG for treatment of PID in Medicare beneficiaries grew 60% from 2010 to 2014, reflecting a rise in the number of patients diagnosed and treated with Ig for on- and off-label uses.⁵ In 2016, Ig cost was the fourth highest drug expense for Medicare Advantage plans, and Ig was one of the top five specialty home health care drugs in 2018.⁶ For patients with severe primary antibody deficiencies, lifelong Ig therapy represents a significant expense when the costs of drug, administration, and supportive care are considered. Optimizing the use and clinical benefits of IVIG through improved provider education and stewardship could therefore result in cost savings to individual patients and to the healthcare system overall.

The cost of Ig therapy depends on the delivery method and site of care. Most pharmacoeconomic studies have found that home-based SCIG delivery is associated with significant cost savings compared with hospital-based IVIG therapy.^7,8,9,10,11 Yet even changing the administration site for IVIG from a hospital setting to home-based delivery can significantly lower health care costs, with mean cost per infusion decreasing in one study from $4745 to $3293 (2010 dollars), and hospitalization and pharmacy costs trending lower.¹² Individualized IVIG dosing may result in further cost savings compared with standard regimens, without significantly affecting efficacy. (One real-world database study in patients with PID, however, reported significantly higher treatment-related costs with SCIG vs IVIG, which was attributed to the higher cost of SCIG versus IVIG and to drug price increases over time.¹³) A health economic modeling study found that early initiation of Ig therapy in patients with PID was more cost effective compared with either delayed therapy or no treatment.¹⁴ These results and others indicate that home-based therapy, particularly with SCIG, can realize substantial cost savings, and that prompt initiation of Ig therapy can result in both pharmacoeconomic and clinical benefits.¹⁵

Evidence‐based Use of Immunoglobulin

Appropriate, evidence-based use of IVIG is essential since such treatment can be associated with the risk of adverse events. IVIG treatment also increases health care costs and can present challenges for insurance coverage, and its use may further strain the limited availability of Ig (due to the broad range of off-label uses and occasional shortages of human plasma).¹⁶ To this end, the American Academy of Allergy, Asthma & Immunology (AAAAI) reviewed data that provided the basis for FDA-approved indications of IVIG, as well as for off-label use in other selected disease states, to develop updated evidence-based recommendations regarding appropriate usage (Table 2).¹⁷ The data were reviewed, categorized, and ranked to assess type of study, strength of the data, and the expected benefits of IVIG for specific disease states. Supporting data were rated as strong, moderate, weak, or no recommendation. The strength of each recommendation (rated A–F) was based on the evidence category, ranging from the strongest evidence level (based on meta-analysis of randomized controlled trials) to the lowest (laboratory-based studies only). Such an evidence-based approach can aid clinicians in clinical decision-making regarding use of and probable benefit from IVIG for specific patients. The AAAAI and American College of Allergy, Asthma & Immunology (ACAAI) also issued practice parameters to aid clinicians in the diagnosis, screening, and management of PID. More than 200 summary statements were developed for various immunodeficiencies in which IVIG therapy may be indicated, covering clinical and laboratory diagnosis and disease management.¹⁸

In light of the complexity of many rare diseases and their high clinical variability, a seven-member panel of multispecialty physicians was surveyed regarding IVIG use in 50 disease states to further improve upon evidence-based recommendations.¹⁶ Data were rated according to their level of agreement with AAAAI evidence-based medicine ratings, and disease states reaching consensus were ranked to determine priority for IVIG use. Following discussion and resurvey, the panel was able to reach consensus on 86% of disease states for which IVIG therapy could be appropriate. This approach, using a 3-axis prioritization algorithm, may aid in reaching consensus on the efficacy of IVIG and other therapeutic options for several clinical conditions. Additionally, numerous national and international guidelines are available to provide further direction on the optimal use of IVIG in various disease states such as neuromuscular disorders, hematologic conditions, dermatologic disorders, pregnancy, and solid organ transplantation.^{19,20,21,22,23} These resources, in addition to the AAAAI’s eight guiding principles for appropriate use of IVIG in patients with PID (Table 3), can help clinicians better evaluate the strength of clinical evidence and expert recommendations when deciding whether use of IVIG is well supported in specific disease states and conditions.²⁴

Approved Uses of IVIG

Immunoglobulins are now considered as a cornerstone of essential treatment for a variety of immune and inflammatory diseases, most notably for various immunodeficiencies in which patients have higher susceptibility to viral, bacterial, or fungal infections. Available data supporting approved uses of Ig, based on level of evidence, have been reviewed by the AAAAI Work Group.¹⁷ Categories for which IVIG therapy is considered to “definitely benefit” include:

• Primary humoral immunodeficiencies, a heterogenous group of disorders in which the immune response is absent or dysfunctional, increasing risk of infection. Examples include agammaglobulinemia; hypogammaglobulinemia; selective antibody deficiency (SAD), with recurrent bacterial infections; hyper IgM syndrome; and recurrent infections due to an undefined immune mechanism.
• Secondary humoral immunodeficiencies arising due to nongenetic factors. These can be associated with certain hematologic malignancies like B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma, or result from environmental factors such as burns, diabetes, malnutrition; selected therapies like steroids, chemotherapy, and radiation; and many other conditions including AIDS, trauma, uremia, tuberculosis, and cytomegalovirus infection. IVIG is also used for prevention and treatment of certain types of rejection in solid organ transplantation recipients.
• Autoimmune disorders and inflammatory conditions including autoimmune thrombocytopenia; Kawasaki disease; chronic inflammatory demyelinating polyneuropathy (CIDP); and multifocal motor neuropathy (MMN).

Additionally, many off-label uses of IVIG (up to 150) have been explored, including but not limited to treatment of other autoimmune and inflammatory conditions; sepsis, septic shock, and toxic shock syndrome; neuropathic pain; various hematologic conditions; chimeric antigen receptor T-cell therapy; and viral pneumonia.^{25,26,27,28,29,30,31} For some of these conditions, such as Guillain-Barré syndrome, IVIG is accepted as appropriate and effective therapy and is commonly used (although not FDA-approved). Discussion of off-label uses of Ig and supporting data are beyond the scope of this monograph but have been reviewed by AAAAI and others.¹⁷

Factors Influencing Product Selection

Many factors should be considered when choosing an Ig product or considering a switch in IVIG products or to a different administration route. Selection should be based on product characteristics as well as patient comorbidities and risk factors to optimize clinical efficacy and minimize toxicity. Providers should consider a product’s adverse event profile, administration site, dosing and frequency, pharmacokinetics, venous access, number of infusions required, and infusion rate and duration. Patient preference and cost/insurance must also be taken into account.³²

Product Formulation

Differences in Ig product formulation exist that affect their pharmacodynamics, tolerability, and safety. For example, variations in the amounts of salt, sugar, osmolarity, and stabilizers can alter tolerability. Even slight changes in formulation for the same product have been shown to increase the incidence of adverse reactions.³³ Additionally, tolerability varies among patients, based on their comorbidities and individual pharmacokinetics/pharmacodynamics. All product characteristics that affect tolerability and adverse event risk therefore should be considered during the formulary review process.³⁴ Health care professionals (HCPs) should strive to match patient-specific factors to Ig product characteristics in order to minimize risk of adverse events and reduce the cost of product switching.

Products vary by Ig content and composition including gamma globulin content, subclass composition (IgA, IgM, IgG), and percent monomers versus dimers.³⁵ Ig products also differ with respect to IgG subclass composition, which can affect complement activation, placental transfer, and possibly half-life, and these factors may need to be considered in certain patients. Some patients with selective IgA subclass deficiency, for instance, have anti-IgA antibodies; in such individuals, low levels of IgA present in an Ig product can trigger anaphylaxis. While IgA content varies by product, all Ig agents are contraindicated in patients with IgA deficiency who have antibodies to IgA in order to avoid anaphylactic reactions.⁴ (Commercial production of a low-IgA [<1 µg/mL] IVIG, Gammagard S/D 5%, has been limited but is available by special request.)

Immunoglobulin preparations often include various excipients such as carbohydrates, amino acids, and other chemicals. These are designed to stabilize the product and to prevent aggregation and dimer formation but could inhibit IgG function and increase side effects.³³ Commonly used carbohydrate stabilizers include D-sorbitol, sucrose, glucose, and maltose. The amino acids glycine and L-proline are also used for Ig stabilization, as well as the excipient polysorbate 80. In addition to IgG stabilization, use of glycine and L-proline also allows for subcutaneous Ig delivery in a smaller volume, facilitating SCIG infusion. The possible effects of these stabilizers in certain patient populations should be recognized since some individuals (e.g., those with renal dysfunction, diabetes, and the elderly) may be at increased risk of renal failure, particularly with sucrose-stabilized IVIG. Hyperprolinemia is a risk factor with L-proline–stabilized products, while for patients with hereditary fructose intolerance the presence of D-sorbitol is a risk factor since it is metabolized to fructose. Glucose is a risk factor for patients with diabetes mellitus, and maltose could be a risk factor since it can cause false positives for glucose with certain glucometers.

Igs differ in other physicochemical properties that may be clinically relevant for some patients. IVIG products typically have an osmolality of 240 to 370 mOsm/kg. Agents with a higher osmolality can cause increased serum viscosity, adding to the risk of thromboembolic events.33 Patients at risk of thrombosis or those with renal insufficiency may therefore require a reduction in infusion rate with such preparations. To prevent Ig aggregation, the pH of the final liquid product following reconstitution usually ranges from 4.0 to 4.5. More basic products require the addition of stabilizing sugars that, as previously noted, could adversely affect some patients. Conversely, infusion of a large volume of a low pH product could be problematic for neonates since it can cause metabolic acidosis. IVIG products also differ with respect to polyethylene glycol (PEG) and albumin content, half-life, diphtheria toxin titer, and methodology used to remove or inactivate a particular virus or surrogate virus marker. Pharmacists should refer to published guidelines and resources to compare all Ig properties when selecting a product.

IVIG Infusion Rate

The maximum tolerated infusion rate for IVIG differs for each patient, especially if comorbidities are present. Recommended initial, maintenance, and maximum infusion rates also vary among products. In general, more concentrated IVIG products allow for shorter infusion times and lower total fluid volume. The infusion rate may need to be tailored for each patient; a slow rate is typically used initially and titrated up based on tolerability. For selected patients, such as those with cardiac or renal conditions who are at risk for volume overload, slow infusion using a more concentrated product is indicated.³³ Rapid infusion rates can result in “rate-related” toxicities such as fever, headache, rash, nausea, malaise, arthralgia, myalgia, chest pain, and hypotension that may decrease tolerability. If infusion-related adverse events occur, administration should be slowed to the minimum infusion rate practicable or else halted. HCPs should refer to prescribing information for product-specific recommendations regarding initial, maintenance, and maximum infusion rates.

Dosing

The goal of IVIG therapy is to maintain Ig blood levels above a certain threshold to ensure adequate humoral immunity. This can be challenging due to variations in peaks and troughs resulting from intermittent dosing, and because of variable pharmacokinetics and pharmacodynamics. Excessive Ig levels can also increase the risk of systemic adverse events. Once steady-state levels are achieved (generally between the fourth and sixth IVIG infusion), Ig trough levels can be monitored by pharmacokinetic analysis but such data are specific for given indications.³⁶ Patients receiving IVIG on a 3- or 4-week injection cycle may experience a “wear-off’’ effect due to a decline in Ig levels below trough values and thus be at increased risk of infection and clinical symptoms such as fatigue.³⁷ In general, however, HCPs should base dosing decisions on both clinical response and trough levels, and not trough levels alone.³⁸

With SCIG, total injection volume is also a consideration for dosing. The injection volume is determined by how much can be comfortably injected by the patient, which in turn is dictated by the concentration, dose, and duration of infusion.³⁹ Larger volumes often require multiple injection sites (generally up to four sites for most patients, but higher in some). These factors may influence choice of product as well as selection of SCIG versus IVIG.

Both IVIG and SCIG are dosed based on a patient’s body weight, which also must be considered when measuring Ig trough levels to determine the target dose. In light of the small volume of distribution of IVIG, dosing strategies using ideal body weight or adjusted body weight may be more appropriate. A comparison of IVIG dosing for hematologic malignancies or hematopoietic stem cell transplant, based on actual, ideal, or adjusted body weight, found no difference in infection rate or treatment response rate, although use of the latter two methods resulted in significant institutional cost savings.⁴⁰ Currently, however, no consensus guidelines exist regarding the ideal strategy, so all three weight-based dosing methods have been used.⁴¹

IVIG doses may need to be tailored in patients with a very low or very high body mass index (BMI), and adjustments may be required due to significant weight changes (e.g., in growing children and adolescents).^42,43 Weight-based dose adjustments vary by product and indication, so providers should refer to prescribing information for details.

Administration Setting

IVIG is usually administered in a hospital or clinic setting every 2 to 4 weeks, requiring 2 to 4 hours per infusion (depending on dose and patient tolerance). IVIG maintains higher Ig serum levels compared with SCIG, allowing for less frequent dosing. SCIG is usually administered at home and thus may be more convenient for patients. However, SCIG requires a larger number of injections to achieve target Ig levels due to the smaller infusion volumes used. As noted previously, home-based administration typically is associated with cost savings compared with hospital-based or office infusion of IVIG.

AAAAI has issued guidelines regarding site of care for IVIG administration.⁴⁴ IVIG may be administered in a hospital setting (inpatient or outpatient), with infusion supervised by a physician or nurse; in an office setting, with physician/nurse supervision; or by home-based infusion, with or without nurse supervision. Choice of administration site is influenced by clinical factors such as comorbidities and by patient preference. Risk of nosocomial infection may also be a consideration when deciding whether a patient could receive outpatient IVIG or home therapy rather than in a hospital setting.

All initial IVIG infusions and any changes to a new product should be supervised by a physician in case of acute or severe complications such as thromboembolism, hypotension, or anaphylaxis.⁴⁴ Certain patients require continued higher-level supervision during infusions due to risk of infusion-related reactions or subsequent serious adverse reactions. Conversely, those who have tolerated prior therapy without any adverse events (approximately half of all patients receiving IVIG) may be candidates for lower levels of supervision. HCPs should discuss with their patients all potential benefits and risks related to site of administration.

Tolerability Profiles

The incidence of adverse events associated with Ig therapy varies by product, infusion rate, and patient comorbidities. In general, more systemic adverse events are seen with IVIG administration, whereas local reactions are more common with SCIG. Adverse systemic reactions with IVIG occur in 20% to 50% of patients (5% to 15% of all IVIG infusions) but are rare with SCIG. In general, 60% of adverse events occurring with IVIG are immediate (within 6 hours of infusion), 40% are delayed (up to 1 week), and less than 1% occur late (weeks to months after).⁴⁵ Local adverse events such as persistent pain, bruising, swelling, and erythema are common (~75%) with SCIG infusions but rare with IVIG.⁴⁶

Mild infusion reactions occurring with IVIG include headache, fever, chills, fatigue, lethargy, and malaise. Serious adverse events are less common, although thromboembolism, hypotension, seizures, aseptic meningitis syndrome, anaphylaxis, acute respiratory distress syndrome, pulmonary edema, apnea, and transfusion-related acute lung injury (TRALI) have been reported.⁴⁷ In patient surveys, over 6% of respondents had experienced an infusion-related adverse event with IVIG.^48,49 Because some adverse events are related to infusion rate, IVIG should be administered at a minimum dose and infusion rate to reduce risk of adverse reactions such as thrombosis and renal dysfunction. The absence of an adverse event following initial IVIG infusion does not guarantee safety with subsequent treatments, however. A survey of patients with PID found that 23% experienced an adverse reaction to a product they had previously received without any issue.

All Ig products are associated with an increased risk of thromboembolic events, as stated in their accompanying boxed warnings. Risk of such adverse events may be increased by patient-specific factors such as comorbidities, overweight, dehydration, immobility, and history of hypertension, cardiovascular disease, or thrombotic disorders. The elderly (>65 years of age) also have an increased risk of acute renal failure and arterial and venous thrombosis.⁵⁰ All products are associated with an increased risk of renal dysfunction, acute renal failure, osmotic nephrosis, and related death, especially in patients with specific risk factors.⁵¹ HCPs must ensure adequate patient hydration and monitor renal function during therapy since renal dysfunction can be irreversible. Use of an Ig product with a lower sucrose concentration may be indicated for patients at risk of renal toxicity. A lower incidence of severe adverse drug reactions, including a significantly lower rate of renal impairment, has been seen with sucrose-free IVIG compared with products containing sucrose. In contrast, a higher incidence of hemolysis-related adverse drug reactions was noted with glycine- and L-proline-stabilized IVIGs.⁵²

Hemolytic anemia (hemolysis) can occur due to the presence of antibodies against blood group proteins (e.g., anti-A, anti-B) in IVIG products, although at a low (~0.1%) incidence. Risk factors for hemolysis include use of high-dose IVIG (>0.5 g/kg); non-O blood group recipients; certain comorbidities (inflammatory or autoimmune disorders); and use of certain concomitant medications. All patients who receive IVIG should be carefully monitored for hemolysis.

Some conditions requiring Ig therapy are associated with comorbidities that can also increase morbidity and mortality. Patients with PID who receive IVIG or SCIG, for instance, have a significantly higher incidence of comorbidities including asthma or chronic obstructive pulmonary disease (COPD), rheumatoid disease, hypothyroidism, lymphoma, and neurologic disorders.⁵³ Knowledge and increased awareness of such comorbidities, in addition to the risk of treatment-related adverse events with Ig therapy, can improve coordination of care, reduce toxicity, and enhance outcomes.

Recommendations have been developed for pharmacists to aid in mitigating toxicities associated with Ig administration, including premedication for IVIG-related adverse events and management of injection site reactions with SCIG (Table 4).³⁷

Route of Administration

Multiple IVIG and SCIG products have been approved by the FDA, covering various indications, with some approved for both IV and SC administration. The advantages and limitations of IVIG and SCIG use are compared and contrasted in Table 5. IVIG allows for monthly injections, with less pain and discomfort for patients. This approach requires good venous access, though, which may be a limitation in the elderly and infants. The need for routine HCP visits required with IVIG infusions might be counterbalanced by improved patient care and early identification of any problems achieved with more frequent visits, thus improving overall outcomes. Use of an infusion pump allows for rapid delivery of IVIG, leading to its preferred use by many providers and patients. On the other hand, SCIG has certain advantages over IVIG since there is no need for venous access, and patient convenience is greater due to self-administration. It does require patients to be more self-sufficient for their care and willing to be educated on proper technique. There are also differences in the types of adverse events associated with IVIG versus SCIG (systemic versus local). Providers should consider these factors and discuss the advantages and challenges of both approaches with their patients when deciding which route to use.

Intramuscular Ig formulations are used in certain circumstances. Use of IMIG therapy is limited to post-exposure prophylaxis following exposure to measles, chickenpox, rubella, and other pathogens, and for prevention of hepatitis A.^54,55,56 Currently, only one IMIG product (GamaSTAN) is marketed. IMIG is not typically used for replacement therapy since intramuscular injections are more painful, so patient compliance may be lower.

Product Selection and Transitioning

Product Selection

The Immunoglobulin National Society and AAAAI have published guidelines to support multidisciplinary practices on the optimal use of Ig (Table 3). These recommendations are designed to aid HCPs in product selection, route of administration, dosing, risk assessment, and common adverse reactions and their management. Adherence to these guidelines can help pharmacists ensure appropriate, effective, and safe use of IVIG. Choice of route and site of care is based on the patient’s clinical characteristics, patient preference, and product being considered. As noted earlier, although IgG trough levels may help guide treatment decisions, they are not useful in many circumstances and should not be a deciding factor in whether to use IVIG. Treatment should not be interrupted, nor should the dose or frequency be reduced once treatment is started and a definitive diagnosis established. It is important to keep in mind that Ig products are not generic and must not be considered as interchangeable. Any changes in product, including a switch to a different route, should be directed by the prescribing physician.

Recombinant human hyaluronidase has been used to enhance subcutaneous absorption and increase dispersion of SCIG. Hyaluronidase depolymerizes hyaluronan present in the skin extracellular matrix and thus increases SCIG bioavailability. This approach, known as facilitated SCIG (fSCIG), allows for a reduction in the number of infusion sites and dosing frequency (to every 3–4 weeks) compared with conventional SCIG and results in more stable steady-state plasma levels.⁵⁷ Currently, fSCIG is used in one SCIG product (HyQvia), which has been shown to prevent infections and have good tolerability. Facilitated SCIG thus represents an additional subcutaneous treatment option for patients with PID.

Product Transitioning

Some patients may need to transition to a different Ig product, using the same or a different route of administration. Possible reasons to switch to a different IVIG product include safety and tolerability; product availability; patient preference and convenience; cost; and insurance or contracting issues (Table 4). Switching from one IVIG product to another may be appropriate if repeated adverse events to one agent occur despite preinfusion medications and infusion rate adjustments. Differences in product composition or manufacturing could affect the tolerability of the new agent, however, especially in patients with comorbidities, and the maximum tolerated infusion rate may differ for each patient and product. Consequently, when switching to another IVIG is necessary, to minimize risk of toxicity practitioners should consider the patient naïve to Ig (i.e., use conservative initial infusion times, dose titration, and increased monitoring).

Switching from IVIG to SCIG may be appropriate for some patients. Factors favoring the use of SCIG include poor venous access, patient stability and self-reliance, a need for low maintenance doses, low risk of systemic adverse events, and patient preference and convenience (Table 4). In a survey of over 1600 patients who were receiving IVIG for PID, reasons cited for changing to SCIG included greater convenience (55%), physician recommendation (43%), adverse reaction to IVIG (41%), and poor venous access (35%).⁵⁸ A switch from IVIG to SCIG may be considered for patients receiving IVIG every 28 days but experience malaise or upper respiratory symptoms in the week prior to their next infusion (i.e., ‘‘wear-off’’ effect due to a decline in Ig below trough values).17 In a small study of patients who were switched from hospital-based IVIG to home-based SCIG, greater patient satisfaction was noted for SCIG compared with IVIG.⁵⁹ Yet some patients may resist transitioning from IVIG to SCIG for various reasons including disease stability, a belief that self-administration is too difficult or complicated, uncertainty regarding proper dosing, concerns over cost or insurance, and a preference for administration by an infusion nurse.

An algorithm has been proposed to help guide decision making regarding use of IVIG or SCIG based on patient-related factors, clinical outcomes, and tolerability.³⁹ A switch from IVIG to SCIG may be appropriate, for instance, if a patient has poor venous access, tolerability issues, or prefers to avoid repeated provider visits for infusions. It should be noted that SCIG may not be appropriate in all cases. In a survey of patients with PID who were receiving IVIG but had previously been on SCIG, reasons for reverting back to IVIG included adverse events with SCIG (47%), inadequate control of their disease (25%), and too frequent dosing (23%).⁵⁸

Adjustments to dose and/or volume may be necessary when transitioning from an IVIG product to SCIG in order to individualize therapy. Such changes are calculated based on patient weight and desired change in IgG trough level. For example, an IVIG: SCIG dose-adjustment coefficient (DAC) of 1.37 to 1.53 may be required in patients with PID to maintain appropriate pharmacokinetics, according to the formula17:

SCIG dose = IVIG dose (g) x DAC/number of weeks between doses

These calculations were derived for patients with PID; to date, no similar dose adjustment guidelines exist for neuromuscular or other diseases. Dose adjustments in non-PID patients should therefore be made on case-by-case basis, usually relying on a 1:1 conversion from the prior weekly IVIG dose.³⁷ Practitioners should refer to product inserts for specific dose adjustment information.

Pharmacist Opportunities

Many opportunities are available to pharmacists to support patients and the health care team with ongoing Ig therapy. Pharmacists routinely work with physicians and nurses to coordinate care and support dosing including calculation of dose, volume, and any adjustments required due to changes in patient weight or treatment-related adverse events. Pharmacists can also help determine whether a change in product or administration route is indicated and provide recommendations to the physician. Since they can regularly monitor patient status, pharmacists are able to promptly assess any changes in patient clinical status or quality of life. Importantly, pharmacists can assist with identification and management of treatment-related adverse events through in-person visits, standardized patient assessment tools and questionnaires, and phone or online support. Through education and counseling, they are uniquely positioned to support patients and/or caregivers on proper administration techniques and site rotation to minimize the risk of adverse events and aid in their mitigation. Pharmacists can support patient adherence to treatment, either to maintain self-administration of SCIG or keep regular infusion appointments, thus improving patient empowerment and optimizing disease management.

Immunoglobulin Stewardship

Supplies of IVIG are limited, shortages are common, and IVIG products are often used off-label and sometimes inappropriately. This has led to concerns that inappropriate use of IVIG that is not supported by high-level evidence-based data could deplete lifesaving IVIG resources.²⁴ Stewardship programs thus could be helpful with utilization management and reducing treatment costs. In one study, an IVIG stewardship program (ISP) was implemented for patients with hypogammaglobulinemia caused by hematologic malignancies. Patients who stopped receiving IVIG after ISP implementation had a lower nadir IgG, fewer infections per patient-months, reduced antibiotic usage, and less hospitalizations for infection compared with previous IVIG usage, with cost savings realized.⁶⁰ Pharmacist-driven IVIG stewardship programs may also help ensure guideline compliance regarding appropriate indication and dose. Use of a computerized provider order entry system was found to optimize use of IVIG: the automated order set and its implementation was associated with a significantly reduced dosage variation, which could result in greater adherence to evidence‐based care and possibly reduce costs.⁶¹ Such an approach might also minimize pharmacists’ time required for order configuration, allowing them to attend to other duties.

Conclusion

Ig therapy has been valuable as a therapeutic modality for nearly 75 years. For the past 40 years, the use of Ig has vastly improved the lives of patients with primary immune deficiencies by means of high-dose replacement therapies to normalize Ig levels in those who are unable to produce IgG on their own. For patients with autoimmune disorders, the use of Ig therapies to modulate the immune system has had a remarkable impact on neurological disorders such as CIDP and inflammatory disease like MMN and Kawasaki disease. With over 150 different disorders in which Ig therapies have been utilized, it is imperative that evidence-based approaches be utilized to separate science from urban legend. The demand for Ig has steadily risen and is expected to increase at a rate of 8% or more over the next decade. Ig stewardship therefore will be essential to maintain appropriate supplies of Ig for those therapies known to have evidence support while still allowing research on new methodologies for dosing strategies, new disease states, special patient populations, and patient settings as we face an ever-changing environment and new microbiological challenges.

References

1. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722-728.
2. Perez EE. Immunoglobulin use in immune deficiency and autoimmune disease states. Am J Manag Care. 2019;25(6 suppl):S92-S97.
3. Saeedian M, Randhawa I. Immunoglobulin replacement therapy: a twenty-year review and current update. Int Arch Allergy Immunol. 2014;164(2):151-166.
4. Williams SJ, Gupta S. Anaphylaxis to IVIG. Arch Immunol Ther Exp (Warsz). 2017;65(1):11-19.
5. Department of Health and Human Services. Evaluation of the Medicare Patient Intravenous Immunoglobulin Demonstration Project: Interim Report to Congress. March 2016. CMS website. Available from: https://innovation.cms.gov/files/reports/ivig-intrtc.pdf. Accessed September 1, 2021.
6. Tichy EM, Schumock GT, Hoffman JM, et al. National trends in prescription drug expenditures and projections for 2020. Am J Health Syst Pharm. 2020;77(15):1213-1230.
7. Markvardsen LH, Harbo T. Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs. J Neurol Sci. 2017;378:19-25.
8. Le Masson G, Solé G, Desnuelle C, et al. Home versus hospital immunoglobulin treatment for autoimmune neuropathies: A cost minimization analysis. Brain Behav. 2018;8(2):e00923.
9. Fu LW, Song C, Isaranuwatchai W, et al. Home-based subcutaneous immunoglobulin therapy vs hospital-based intravenous immunoglobulin therapy: A prospective economic analysis. Ann Allergy Asthma Immunol. 2018;120(2):195-199.
10. Vaughan LJ. Managing cost of care and healthcare utilization in patients using immunoglobulin agents. Am J Manag Care. 2019;25(6 suppl):S105-S111.
11. Windegger TM, Nghiem S, Nguyen KH, et al. Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency. Vox Sang. 2019;114(3):237-246.
12. Luthra R, Quimbo R, Iyer R, et al. An analysis of intravenous immunoglobin site of care: home versus outpatient hospital. Am J Pharm Benefits. 2014;6(2):e41-e49.
13. Runken MC, Noone JM, Blanchette CM, et al. Differences in patient demographics and healthcare costs of patients with PIDD receiving intravenous or subcutaneous immunoglobulin therapies in the United States. Am Health Drug Benefits. 2019;12(6):294-304.
14. van Wilder P, Odnoletkova I, Mouline M, et al. Immunoglobulin replacement therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from common variable immunodeficiency disorders (CVID): A health-economic assessment. PLoS One. 2021;16(3):e0247941.
15. Rajabally YA, Afzal S. Clinical and economic comparison of an individualised immunoglobulin protocol vs. standard dosing for chronic inflammatory demyelinating polyneuropathy. J Neurol. 2019;266(2):461-467.
16. Orange JS, Johnson M, Lennert B, et al. Multispecialty rating of evidence-based conditions for intravenous immunoglobulin therapy using a 3-axis prioritization algorithm. Am Health Drug Benefits. 2017;10(3):134-142.
17. 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;139(3S):S1-S46.
18. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-205.e2078.
19. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev. 2010;24(suppl 1):S7-S27.
20. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012;78:1009-1015.
21. Enk A, Hadaschik E, Eming R, et al. European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology. J Dtsch Dermatol Ges. 2017;15(2):228-241.
22. Jolles S, Michallet M, Agostini C, et al. Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. Eur J Haematol. 2021;106(4):439-449.
23. D'Mello RJ, Hsu CD, Chaiworapongsa P, et al. Update on the use of intravenous immunoglobulin in pregnancy. Neoreviews. 2021;22(1):e7-e24.
24. American Academy of Allergy, Asthma & Immunology. Eight guiding principles for effective use of IVIG for patients with primary immunodeficiency. Available from: https://www.aaaai.org/. Accessed September 1, 2021.
25. Williams D, Argaez C. Off-label use of intravenous immunoglobulin for hematological conditions: a review of clinical effectiveness. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Mar 23. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531790/. Accessed September 1, 2021.
26. Peprah K, Adcock L. Off-label use of intravenous immunoglobulin for autoimmune or inflammatory conditions: a review of clinical effectiveness. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Apr 6. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531791/. Accessed September 1, 2021.
27. Hill JA, Giralt S, Torgerson TR, et al. CAR-T - and a side order of IgG, to go? Immunoglobulin replacement in patients receiving CAR-T cell therapy. Blood Rev. 2019;38:100596.
28. Jarczak D, Kluge S, Nierhaus A. Use of intravenous immunoglobulins in sepsis therapy—a clinical view. Int JMol Sci. 2020;21(15):5543.
29. Chang MC, Park D. Effectiveness of intravenous immunoglobulin for management of neuropathic pain: a narrative review. J Pain Res. 2020;13:2879-2884.
30. Liu X, Cao W, Li T. High-dose intravenous immunoglobulins in the treatment of severe acute viral pneumonia: the known mechanisms and clinical effects. Front Immunol. 2020;11:1660.
31. Amreen S, Brar SK, Perveen S, et al. Clinical efficacy of intravenous immunoglobulins in management of toxic shock syndrome: an updated literature review. Cureus. 2021;13(1):e12836.
32. Allen JA, Gelinas DF, Freimer M, et al. Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG? J Neurol Sci. 2020;408:116497.
33. Ameratunga R, Sinclair J, Kolbe J. Increased risk of adverse events when changing intravenous immunoglobulin preparations. Clin Exp Immunol. 2004;136(1):111-113.
34. Sorensen R. Expert opinion regarding clinical and other outcome considerations in the formulary review of immune globulin. J Manag Care Pharm. 2007;13(3):278-283.
35. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520.
36. Ness S. Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin. Am J Manag Care. 2019;25(6 suppl):S98-S104.
37. Tichy EM, Prosser B, Doyle D. Expanding the role of the pharmacist: immunoglobulin therapy and disease management in neuromuscular disorders. J Pharm Pract. 2020:897190020938212.
38. IgNS Immunoglobulin Therapy Standards of Practice Committee. Immunoglobulin Therapy: Standards of Practice (2nd ed). Kirmse J, Schleis T, eds. Woodland Hills, CA: Immunoglobulin National Society; 2018.
39. Jolles S, Orange JS, Gardulf A, et al. Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease. Clin Exp Immunol. 2015;179:146-160.
40. Stump SE, Schepers AJ, Jones AR, et al. Comparison of weight-based dosing strategies for intravenous immunoglobulin in patients with hematologic malignancies. Pharmacotherapy. 2017;37(12):1530-1536.
41. Rocchio MA, Hussey AP, Southard RA, et al. Impact of ideal body weight dosing for all inpatient i.v. immune globulin indications. Am J Health Syst Pharm. 2013;70(9):751-752.
42. Berger M, Rojavin M, Kiessling P, et al. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin Immunol. 2011;139(2):133-141.
43. Tsapepas D, Der-Nigoghossian C, Patel K, et al. Medication stewardship using computerized clinical decision support: A case study on intravenous immunoglobulins. Pharmacol Res Perspect. 2019;7(5):e00508.
44. American Academy of Allergy, Asthma & Immunology. Guidelines for the site of care for administration of IGIV therapy. Available from: https://www.aaaai.org/. Accessed September 1, 2021.
45. Arumugham VB, Rayi A. Intravenous Immunoglobulin (IVIG). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; March 28, 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554446/. Accessed September 1, 2021.
46. Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. 2013;27(3):171-178.
47. eGuo Y, Tian X, Wang X, et al. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299.e
48. Immune Deficiency Foundation. Treatment experiences and preferences of patients with primary immune deficiency diseases: first national survey. Towson, MD, 2003. Available from: https://primaryimmune.org/. Accessed September 1, 2021.
49. Shapiro R. Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push. Clin Exp Immunol. 2013;173(2):365-371.
50. Cheng MJ, Christmas C. Special considerations with the use of intravenous immunoglobulin in older persons. Drugs Aging. 2011;28(9):729-736.
51. Levy JB, Pusey CD. Nephrotoxicity of intravenous immunoglobulin. QJM. 2000;93(11):751-755.
52. Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013;38(4):275-284.
53. Dilley M, Wangberg H, Noone J, et al. Primary immunodeficiency diseases treated with immunoglobulin and associated comorbidities. Allergy Asthma Proc. 2021;42(1):78-86.
54. Young MK, Cripps AW, Nimmo GR, et al. Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome. Cochrane Database Syst Rev. 2015;(9):CD010586.
55. Tunis MC, Salvadori MI, Dubey V, et al; National Advisory Committee on Immunization (NACI). Updated NACI recommendations for measles post-exposure prophylaxis. Can Commun Dis Rep. 2018;44(9):226-230.
56. Hobart-Porter N, Stein M, Toh N, et al. Safety and efficacy of rabies immunoglobulin in pediatric patients with suspected exposure. Hum Vaccin Immunother. 2021;17(7):2090-2096.
57. Wasserman RL. Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. Immunotherapy. 2017;9(12):1035-1050.
58. Immune Deficiency Foundation. 2013 IDF National Immunoglobulin Treatment Survey. Available from: www.primaryimmune.org. Accessed September 1, 2021.
59. Hadden RD, Marreno F. Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: improved tolerability and patient satisfaction. Ther Adv Neurol Disord. 2015;8(1):14-19.
60. Derman BA, Schlei Z, Parsad S, et al. Changes in intravenous immunoglobulin usage for hypogammaglobulinemia after implementation of a stewardship program. JCO Oncol Pract. 2021;17(3):e445-e453.
61. Tsapepas D, Der-Nigoghossian C, Patel K, Berger K, Vawdrey DK, Salmasian H. Medication stewardship using computerized clinical decision support: A case study on intravenous immunoglobulins. Pharmacol Res Perspect. 2019;7(5):e00508.

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