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INTRODUCTION

Primary immunodeficiencies (PIDs) were first identified and characterized in the middle of the 20^th century. The development of immunoglobulin (Ig) administration as a therapeutic option for PIDs has extended and improved the quality of life for many patients who lack life-sustaining antibody function. Initially, Ig was only available in a preparation that could be administered via subcutaneous (SC) or intramuscular (IM) routes. This limited the use of Ig products for PIDs because many indications, primarily immunomodulatory disorders, required higher doses than could feasibly be administered SC or IM due to volume restrictions. Intravenous (IV) administration of Ig (IVIG) was introduced to the market in the 1970s, and its introduction expanded the use of Ig to other medical conditions while increasing the availability of treatment options for patient with PIDs.

Marketed Ig products evolved substantially over the next several decades and they now give patients and clinicians additional therapeutic options with significantly improved safety and quality profiles. For example, the most frequently used Ig products in the United States (U.S.) today have reduced overall reliance on sugars for antibody stabilization; the products are available in premixed, ready-to-use packages that contain Ig at physiologic osmolarity and osmolality. These enhancements compared to early Ig products have relegated the IM route to rare use and given patients and providers options for IV and SC administration that can be completed in ambulatory clinics or home-care settings, the latter of which facilitates patient self-administration of medications.^1-3

PIDs are characterized by defects in either the innate immune system, such as complement deficiencies, or the adaptive immune system, such as T-cell defects. Patients who are untreated for PIDs experience increased susceptibility to infection: the spectrum of infections varies according to specific PID subtype and extent of the immunocompromised state.⁴ Approximately 1 in 1200 persons in the U.S. have a clinically significant PID.⁵

More than 120 specific PIDs are characterized in the medical literature, but this review for pharmacy clinicians focuses on those in which Ig treatment is a mainstay of disease management, including:

• Common variable immune deficiency (CVID), which is a heterogeneous group of disorders that is primarily characterized by a reduction in the serum levels of IgG, IgA, or IgM. CVID is the most frequent and most symptomatic type of PID, with a prevalence estimated to be between 1 in 25,000 and 1 in 50,000.⁶ The hallmark of CVID is primary hypogammaglobulinemia, which necessitates life-long Ig maintenance therapy.
• Severe combined immunodeficiency (SCID), which is another group of heterogeneous disorders. SCID is characterized by the inability of T-cells to differentiate. In contrast to CVID, patients with SCID present with severe infections early in life, usually younger than 1 year of age. Without treatment, the majority of patients with SCID will experience mortality in the first year of life.⁷ SCID is present in between 1 in 50,000 and 1 in 500,000 live births. Treatment with hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for SCID, and Ig is used as a temporizing measure prior to HSCT. ⁸
• Wiskott–Aldrich syndrome (WAS), which is linked to 1 of several defects in a single gene on the X chromosome that encodes the Wiskott–Aldrich syndrome protein (WASp). WASp is a protein in the cytoplasm of hematopoietic cells; mutations in WASp lead to deficiencies in both B-cell and T-cell signaling and antigenic response.⁹ The majority of patients with WAS have near-normal levels of IgG. However, despite these near-normal IgG levels, the antibodies do not function properly, which leads to an increased risk of infection, even in the setting of immunization. Many patients with WAS will ultimately require HSCT. Supportive measures for these patients include splenectomy, antibiotic prophylaxis, and Ig supplementation.⁹

Life-long Ig replacement, either intravenously (IVIG) or subcutaneously (SCIG), is a cornerstone of PID management for most patients.¹⁰ For each Ig product, the clinician and patient must carefully consider product selection, dosage, route of administration, and monitoring characteristics. Appropriate replacement therapy will prevent serious, recurrent infections, which will improve overall morbidity and mortality (e.g., pulmonary complications leading to terminal lung disease) for these patients.¹⁰ Importantly, developing a treatment plan that optimizes adherence can further enhance the health and quality of life for patients with PIDs.¹¹

OPTIMIZING IMMUNOGLOBULIN THERAPY

A multitude of IgG formulations are currently commercially available in the U.S. market (Table 1).^12-26 The formulations differ in several aspects: Ig concentration, stabilizing additives, trace non-IgG proteins, and manufacturing process. These differences may lead to variations in adverse reactions experienced by patients.^27,28 In addition, patients may have medical considerations such as heart failure, diabetes, or renal dysfunction that influence their abilities to tolerate the different potential routes of administration (Table 2).^27,28 Formulating, establishing, and maintaining an Ig treatment regimen is a complex process that is most effectively determined with the collaboration of the patient and health care providers (i.e., physicians, nurses, and pharmacists). The route of administration, which should be chosen on the basis of a patient's overall clinical picture, is typically the first factor considered when selecting an Ig regimen. IgG formulation is chosen next on the basis of pharmaceutical suitability.

Table 1. Characteristics of Select Immunoglobulin Products12-26
Brand name	Formulation, concentration	Stabilizer	Sodium content	IgA content (mcg/mL)	Sugar content	pH	Osmolarity/ osmolality (mOsm/kg)	Latex-free packaging	Route of administration
Bivigam	Liquid, 10%	Glycine	0.100–0.140 M	≤200	None	4.0–4.6	≤510	Yes	IV
Carimune NF	Lyophilized, 3%–12%	Sucrose	<20 mg/g protein	720	1.67 g sucrose/g protein	6.4–6.8	192–1074	No	IV
Cuvitru	Liquid, 20%	Glycine	None	80	None	4.6–5.1	280-292	Yes	SC
Flebogamma 5%/10%	Liquid 5% and 10%	D-sorbitol	Trace	<3	5% D-sorbitol	5.0–6.0	240–370	No	IV
Gammagard Liquid	Liquid, 10%	Glycine	None	37	None	4.6–5.1	240–300	Yes	IV and SC
Gammagard S/D	Lyophilized, 5% and 10%	Glycine	8.5 mg/mL; 17 mg/mL	≤2.2	20 mg/mL; 40 mg/mL	6.8±0.4	636; 250 (mOsm/L)	No	IV
Gammaked	Liquid, 10%	Glycine	Trace	46	None	4.0–4.5	258	Yes	IV and SC
Gammaplex	Liquid, 5%	Glycine	30–50 mM/L	<4	5% D-sorbitol (polyol)	4.6–5.1	460–500	Yes	IV
Gamunex-C	Liquid, 10%	Glycine	Trace	46	None	4.0–4.5	258	Yes	IV and SC
Hizentra	Liquid, 20%	Proline	Trace	≤50	None	4.6–5.2	380	Yes	SC
HyQvia	Liquid, 10%	Glycine	None	37	None	4.6–5.1	240–300	Yes	SC
Octagam 5%/10%	Liquid, 5% and 10%	Maltose	≤30 mmol/L	<100	100 mg/mL maltose	5.1–6.0	310–380	Yes	IV
Privigen	Liquid, 10%	Proline	Trace	≤25	None	4.8	320 (isotonic)	Yes	IV
Abbreviations: Ig, immunoglobulin; IV, intravenous; SC, subcutaneous.

Table 2. Reported Adverse Reactions According to Patient Risk Factors and Immunoglobulin Component Cause27,28
Adverse reactions	Patient risk factors	Relevant component
Renal complications (acute renal failure, renal insufficiency, osmotic nephrosis)	History of renal disease; diabetes; age; cardiovascular disease	Sucrose, glucose, maltose, sodium, osmolarity
Thromboembolic events/thrombosis	Predisposition to thrombotic events; cardiovascular disease; hypertension; diabetes; age; prolonged periods of immobilization	Sucrose, glucose, maltose, sodium, osmolarity
Anaphylaxis/anaphylactoid reactions	IgA deficiency/IgA antibodies	IgA content
Aseptic meningitis	Predisposition to migraine headaches	Antineutrophil antibodies
Hemolysis	Co-administration of products such as platelets or plasma containing additional isoagglutinins; nonsecretor status (with absence of circulating A and B substance)	Anti-A or anti-B isoagglutinins; anti-D or anti-K antibodies
Neutropenia	NA	Antineutrophil antibodies; anti-Siglec-9 autoantibodies
Hyponatremia	NA	Osmolarity, sugars
Phlebitis	NA	pH
NA	Hyperprolinemia	L-proline
NA	Fructose intolerance	Sorbitol
NA	Corn allergy	Maltose
NA	Latex allergy	Latex packaging
Abbreviations: Ig, immunoglobulin; NA, not applicable.

Product formulation

Ig formulations are, by nature, heterogeneous. An Ig formulation or polyclonal antibody is composed primarily of IgG purified from the pooling of plasma from a diverse group of donors. Stabilizing additives and trace amounts of other proteins are also contained in the formulation, all of which may influence patient tolerance of the end product (Table 1).^12-26 For example, a head-to-head trial in patients with PIDs showed significantly different clinical efficacy between 2 IVIG products with equivalent dosing.²⁹ In addition to efficacy variability, the formulation differences affect tolerability and product side effect profiles.²⁷ Because of the formulation differences, different Ig products should not be pooled or mixed, as incompatibilities can influence product stability.³⁰

A patient's medical history is another important factor that must be considered when selecting the optimal Ig formulation, as there are specific comorbid medical conditions that can be exacerbated by components of some products (Table 2).²⁷ The route of administration may also influence the risk of adverse reactions and increase the probability of exacerbating comorbid conditions. Relevant product characteristics include product additives, osmolality, and the presence of trace proteins other than Ig. Therefore, selecting a product suited to a patient's health history is a prudent step in optimizing the care plan of individual patients.^11,27

Contraindications and warnings in the prescribing information for all Ig products highlight the potential for issues with Ig use in patients with comorbid conditions that may increase the risk of less common, but more serious, adverse reactions. For example, the use of Ig formulations with stabilizing agents proline or fructose are contraindicated in patients with hyperprolinemia and congenital fructose intolerance.^{16, 18,22}

Prescribing information also includes warnings about the increased risk for renal complications and thromboembolic events that have been reported in patients treated with Ig products.^12-26 The warnings indicate that the product formulation is a contributing factor for these risks.^12-26 These complications also share a number of patient characteristics, such as age, cardiovascular disease, and diabetes, that further influence the risk of eliciting negative reactions.²⁷ Clinicians can reduce the risk of a patient with those comorbidities experiencing renal complications or thromboembolic events by avoiding products with high sugar and sodium contents or with hyperosmolarity.^11,27 When the use of a product that contains elements that may exacerbate a comorbid condition is unavoidable, precautions such as prehydration, using slower infusion rates, and administering the dose over several days should be implemented to mitigate against those events.²⁷

In patients predisposed to thrombotic events, the risk of these events has been more frequently reported with IVIG than with SCIG administration.²⁷ Patients at risk for thrombotic events need to be evaluated on a case-by-case basis to develop a risk mitigation plan, which may include using an anticoagulant, encouraging patients to remain active during the infusion period, or not administering Ig. Importantly, a study of 47 patients older than 65 years of age with PID demonstrated there was no increase in the risk of local or systemic adverse events in the 45% of patients who were taking anticoagulants and/or platelet inhibitors (acetylsalicylic acid [36%], warfarin [15%], and clopidogrel [9%]) concomitant with conventional SCIG over a 13-month period.³¹ However, a black box warning to use caution in patients due to the risk of thrombosis is included in the prescribing information of all Ig formulations, including those intended for SC or IV administration.

Trace amounts of non-IgG proteins are also known to impact patient tolerance.²⁷ For example, trace amounts of IgA, or the presence of anti-IgA antibodies in patients with selective IgA deficiency, may elicit anaphylactic or anaphylactoid reactions during IVIG administration.³² Patients with anti-IgA antibodies or anaphylactic reactions to IVIG may have a lower risk of these events with SCIG.¹¹ In addition, the presence of antineutrophil antibodies has been implicated in aseptic meningitis for which patients with a history of migraine headaches may have increased susceptibility.²⁷ As with anaphylactic or anaphylactoid reactions, the risk for aseptic meningitis is higher with IVIG than with SCIG.¹¹

While the risk for some IVIG-related systemic adverse reactions may be lower with SCIG treatment, SCIG may not always be the best option. For example, some preexisting conditions, such as severe thrombocytopenia, bleeding disorders, and widespread eczema, may contraindicate the use of SCIG. For example, patients being treated for both PID and idiopathic thrombocytopenic purpura should not receive Ig by the SC route due to the risk of hematoma development.^13,22,23,26 Patients with these conditions should alternatively pursue treatment with IVIG.

Route of administration

In addition to the Ig product formulation, the route of administration is also an important consideration when individualizing a treatment plan for PID. Ig may be administered by IV or SC routes. SC administration can be subdivided into SCIG, which is often characterized as conventional subcutaneous administration, or recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous administration (IGHy).¹¹

IGHy and SCIG employ the same route of administration, but IGHy is distinguished by the utilization of a separate enzyme (rHuPH20) that is administered prior to Ig infusion. The rHuPH20 increases the bioavailability of Ig by transiently depolymerizing the hyaluronan contained in the extracellular matrix of the SC space that normally constrains the absorption and dispersion of Ig during conventional SC infusions. This action facilitates Ig infusion volumes and rates that are in the order of 10- to 15-times greater than with conventional SC administration of Ig.^33-35 IGHy infusions use a 10% concentration product and require the use of a battery-powered infusion pump; the infusions take approximately 1 hour to complete.

Conventional SCIG is traditionally administered with a 20% concentration product using a spring-loaded pump; the infusion lasts 1 to 2 hours and it is administered once weekly. Some Ig products with a 10% concentration are labeled for administration via the SC route, but they are rarely used in this manner. Rapid-push administration of conventional SCIG is an emerging method of Ig administration that is gaining traction in clinical practice. This method employs a syringe and butterfly needle to infuse up to 15 mL of the 20% concentration Ig product to a single site in 3 to 20 minutes. The advantages of this rapid-push technique include decreased infusion time and increased cost savings owing to the lack of need of an infusion pump.³⁶ One disadvantage of rapid-push administration is the fact that it requires dexterity to manually compress the syringe. Therefore, this method may not be appropriate for patients with limitations to joint function or dexterity.

Ig replacement regimens demand a substantial time commitment that is disruptive to normal daily activities of patients and caregivers.¹¹ For most patients with PIDs who tolerate the infusions well, IVIG administration generally requires 2 to 4 hours once every 3 to 4 weeks in a clinical or home setting.²⁷ Alternatively, SCIG requires 1 to 2 hours once or twice weekly at home.^13,22,23,26 IGHy requires 0.83 to 4.68 (median 2.08) hours once every 3 to 4 weeks in a clinical or home setting.²³ IVIG requires the fewest monthly infusion sites (1) and IGHy requires a similarly low number of sites (typically 1–2); conventional SCIG requires substantially more injection sites (16 [range 12–20]).¹¹ Several Ig formulations that are currently available are indicated for IV and/or SC administration (Table 1).^12-26

Another key consideration for clinician and patient choice of Ig method or route of administration is the quality of a patient's IV access. Conventional SCIG and IGHy offer a clear benefit and should be the leading option for patients with compromised or difficult IV access. The abdomen is the most common site for IGHy infusions and the thighs are a viable alternative infusion site. The infusion volumes required for SCIG are typically much lower than for IGHy, so, in addition to the abdomen and thighs, the upper arms and lower back/hip can be used for SCIG infusion.¹¹ While both IV and SC routes of administration are effective for prevention of infections, the inherent differences, including pharmacokinetics, risk of adverse events, requirement for medical supervision, site of infusion, volume of dose, cost, and quality of life, must be considered when choosing a method of administration.

Dosing considerations and pharmacokinetics

Newly diagnosed patients initiated on IVIG treatment are typically started with doses in the range of 300 to 600 mg/kg every 3 to 4 weeks.³⁷ The Ig dose and frequency are then adjusted for each patient according to Ig levels and clinical response to ensure that the treatment's clinical benefits are realized.^11,37 Importantly, the same dose of the same Ig formulation could result in different outcomes in patients of similar weights due to pharmacokinetic and pharmacodynamic differences. Thus, dosing guidelines function as a starting place for developing a regimen that will decrease the incidence of infections in patients with PIDs.³⁸

Pharmacists may encounter patients with PIDs that are initiating IV or SC, either conventional SCIG or IGHy, treatment with Ig, or pharmacists may become involved with patients converting between different routes of administration. For conventional SCIG, therapy often starts with a single loading dose infusion of IVIG at 1 g/kg followed by weekly doses of SCIG at 100 mg/kg.¹¹ An alternate strategy is to start with doses of 100 mg/kg of SCIG daily for 5 days and then convert to once-weekly dosing.¹¹ To transition a patient from IVIG to conventional SCIG, the first SCIG dose should be administered 7 to 10 days after the last IVIG treatment.^13,22,26 To start therapy with IGHy, regardless of whether a patient is new to Ig or switching from another product, a dose ramp-up should be used to gradually escalate the infusion rates and volume. The ramp-up time usually occurs over 1 to 2 months until the patient reaches comfort with the maximum flow rate and infusion volume. Once the ramp-up is completed, it is expected that the IGHy will be infused every 3 to 4 weeks, which is similar to an IVIG treatment regimen.²³ Ramping up provides an opportunity to train patients to perform self-infusions and helps them adjust to increasing volumes of infusions. This is also a good time for patients to determine if a single infusion site or dual infusion sites work best for them.

For patients switching from IVIG to SCIG or IGHy, the U.S. Food and Drug Administration (FDA) requires product recommendations to suggest patients reach IgG serum concentrations that are similar to those achieved with IVIG treatment; the FDA requires manufacturers to conduct comparisons through measurement of areas under the IgG concentration-time curve (AUC).^13,22,23,26 Clinically, in addition to serum IgG levels, patients must be monitored for outcomes, such as incidence of infection, and the dose will be adjusted and optimized accordingly.

Data supporting the recommendation for using higher Ig doses when administering conventional SCIG are derived from several studies comparing SCIG to IVIG. For example, the product labeling for Hizentra (Immune Globulin Subcutaneous [Human], 20% Liquid, CSL Behring AG, Bern, Switzerland) recommends increasing the Ig dose by 137% when converting from IVIG to conventional SCIG.²² However, in clinical practice, not all providers follow the practice of increasing the dose, and, outside the U.S., physicians commonly forgo the dose adjustment and use a 1-to-1 IVIG-to-SCIG dose conversion. Since the Ig dose needs to be adjusted to clinical response regardless of the dose, and Ig treatment has a wide therapeutic window, this practice is clinically reasonable. Importantly, when interpreting the medical literature, clinicians find that clinical trials conducted in Europe utilized dose-equivalence when converting patients from IVIG to conventional SCIG.¹¹ Still, pharmacy clinicians should be aware that this may translate into variability in clinical practice among providers in the U.S. Ultimately, in all practice settings, the providers will modify the dose over time according to Ig levels and patient response.^11,37 In contrast to switching from IVIG to SCIG, there is consensus that dose adjustment is not required when converting from IVIG to IGHy, since the AUC of IVIG and IGHy meet the criteria of equivalent bioavailability. The reason for the improved bioavailability of IGHy compared to conventional SCIG is that hyaluronidase-mediated absorption improves dispersion of Ig because there is less compression of lymphatics; this, in turn, allows more of the Ig to enter the circulation before catabolism occurs.^23,37

There are other important pharmacokinetic differences among IVIG, conventional SCIG, and IGHy treatments strategies. The direct delivery of a high dose of Ig into the vascular circulation with IVIG leads to a significantly higher peak blood concentration of Ig than is observed with either conventional SCIG or IGHy.^33-35 In addition, patients will experience a quick drop in Ig levels over the first few days after the IVIG infusion as Ig molecules distribute into the extravascular spaces, which creates significant variations in the peak-to-trough Ig ratios.³⁷ For comparison, the lower, more frequent doses used in conventional SCIG lead to a delayed peak concentration time, since the Ig must be taken up from the site of infusion into the lymphatic system before entering circulation.³⁷ As noted earlier, IGHy administered with the same dose and frequency as IVIG generates similar trough levels and AUCs compared to IVIG. IGHy also reaches lower peak Ig concentrations than IVIG, which results in peak-to-trough ratios that more closely match those observed with conventional SCIG.^33-35 In general, the rapid attainment of high peak levels of Ig concentration from IVIG, compared with SCIG and IGHy, is the main cause for the higher rate of systemic adverse reactions observed with IVIG.³⁷ Overall, with respect to the pharmacokinetics of Ig, the goal is to match the kinetics of a normally functioning human immune system by achieving Ig peak levels low enough to reduce the risk of a systemic adverse reaction and maintaining the Ig trough level high enough to prevent the occurrence of infections.

Adverse effects

There are several important adverse effects that patients may experience when receiving Ig replacement therapy.^11,27 In addition to having similar pharmacokinetic profiles, conventional SCIG and IGHy treatments also exhibit similar safety and tolerability. IVIG treatments are characterized by higher rates of systemic adverse reactions but fewer local adverse effects compared to treatment with SCIG and IGHy.^11,34 These differences in adverse effect profiles and tolerability can impact patient quality of life, but these differences also provide opportunities for pharmacy clinicians to offer alternate therapeutic products or routes of administration to improve the patient experience for patients with PIDs.^11,27,40

The most prevalent adverse reactions patients receiving IVIG will experience are chills, fever, headache, and muscular pain. These adverse effects can often be managed effectively by premedicating with nonsteroidal anti-inflammatory drugs, acetaminophen, antihistamines, or corticosteroids.²⁷ Another effective strategy for mitigating adverse reactions is to slow the infusion rate to the point where the patient no longer experiences the negative effects.^11,27 Systemic adverse effects are rare with SCIG and IGHy, and, therefore, premedication is not commonly used with these methods; likewise, close monitoring is not necessary once patient tolerability is established.^30-36

Compared with IVIG, the incidence of local adverse effects is more frequent with the 2 methods of SC administration of Ig. Patients receiving SCIG often experience swelling and redness at the infusion site. Over time, patients will typically develop tolerance to the site-specific effects of the SCIG infusions and some clinicians recommend rotating the SC sites of infusion to mitigate against the local site irritation.²⁷ Importantly, the prevalence of local adverse effects can be reduced by implementing optimal infusion technique and by using an infusion needle length most suitable to individual characteristics to ensure the infusion is not given in the intradermal space. Infusions into the intradermal space will lead to tissue necrosis and can cause significant pain.²² Local adverse reactions, such as pain, bleeding, and bruising at the infusion site, are rare for patients receiving IVIG but common with SCIG; only patients with difficult venous access experience significant pain and swelling at the infusion site with SCIG.²⁷

IGHy is relatively new to the market, so most of the safety data are derived from the phase 3 trial and long-term extension study that led to the product's approval. As such, patients and clinicians may have concerns about long-term safety when committing to life-long therapy with this relatively new formulation. However, data from the clinical trials reveal that, with up to 3.5 years of exposure to IGHy, patients did not experience clinically observable changes to the SC tissue or to the skin, nor did any patients develop neutralizing anti-rHuPH20 antibodies that could impact the long-term efficacy of the hyaluronidase. Some patients in the study did develop non-neutralizing anti-rHuPH20 antibodies, but there was no association with any local or systemic adverse events.³⁷ This is reassuring because other forms of hyaluronidase used in clinical practice have shown formation of neutralizing antibodies that limit the chronic use of those products. Overall, Ig infusions with IGHy demonstrate local and systemic adverse effect profiles similar to those observed with conventional SCIG.³⁷

Quality of life

Several studies have reported that patients who converted from IVIG treatment to SCIG treatment experienced improvements in quality-of-life scores. The cause of these improvements are thought to be due to the increased flexibility that is enabled when patients can self-administer the Ig treatments at home. In this scenario, patients no longer need to schedule appointments, travel to an infusion center, or deal with delays or other hassles that can accompany frequent medical visits. In addition, the reduction in systemic adverse reactions in patients with poor tolerance to IVIG further contributes to the quality-of-life improvements observed with SC administration.¹¹

Nicolay and colleagues demonstrated that the majority of patients who previously received IVIG at a hospital/physician's office or at home and then switched to home-based conventional SCIG administration preferred conventional SCIG self-infusion or home-based administration, regardless of previous site of care. Life Quality Index and global treatment satisfaction scores were significantly improved from baseline after 1 year for patients previously receiving hospital/physician office-based, but not home-based, IVIG treatment. Of note, the authors commented that patients who received prior home-based IV treatment already had quality-of-life scores in the high range at baseline, which left little room to demonstrate further significant improvement.³⁹ These results were validated by another report that showed a preference for self- and home-administration over administration by a health care professional and doctor's office, hospital, or clinic site of care in a survey of patients and caregivers. The survey also documented a strong preference for shorter infusion times.⁴⁰

While self-administration of Ig via the SC route is preferred by many patients, the need for the use of multiple sites to provide the full dose is a limitation.^40-42 For example, studies have documented a significantly greater preference for fewer needle sticks among patients and caregivers.⁴⁰ Another study found stronger agreement among IVIG recipients with the statement "I think I would have problems to puncture myself" than among SCIG recipients with the statement "I have problems to puncture myself."⁴² Intuitively, data also show a significantly greater preference among patients for less frequent infusions.⁴¹ These patient insights highlight the room that remains to further optimize administration via the SC route.

IGHy attempts to meet some of these patient preferences by providing the opportunity for home administration, requiring fewer sites of infusion, and allowing less frequent and shorter duration of infusions compared to conventional SCIG.^11,40 Data from the IGHy pivotal study in patients with PID showed that, among patients or caregivers completing a treatment preference questionnaire, 83% opted to continue with IGHy rather than returning to the SCIG or IVIG that they had been receiving prior to conversion. The majority of patients or caregivers also stated a preference ("like very much" or "like") for IGHy with respect to several factors: the ability to fit into treatment schedule, the frequency of administration, the ease of administration, and the number of monthly needle sticks.³⁴ However, IGHy infusions are somewhat more complex than conventional SCIG infusions because of the 2-step process required for hyaluronidase administration followed by the Ig administration, which can confuse or intimidate some patients and caregivers.

When clinicians are collaborating with patients to determine a strategy for life-long Ig treatment, these quality-of-life issues must be carefully considered. Patient engagement is critical for ensuring that lifestyle and other preferences are considered when selecting a product and route of administration. In addition, when a patient struggles with the initial therapy strategy selected, clinicians should be familiar with the product attributes, since the therapy can be converted to an alternative strategy that the patient may prefer. Finally, these considerations may change over time: for example, as a child grows and requires more independence or other life circumstances evolve, the preference and tolerance for certain products or routes of administration may change.

CONCLUSION

Ig infusions are typically a life-long treatment for patients who carry a diagnosis of PID. Selecting the route of administration and Ig formulation involves the consideration of many factors, including medical history, Ig formulation characteristics, patient tolerance, and patient preference. These considerations provide opportunities for the pharmacist to collaborate with other members of the health care team, as well as patients, to identify and guide the treatment strategy in a direction that optimizes clinical outcomes and patient experiences.

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