TY - JOUR
AU - Vaughan,, Leslie
AB - Abstract Purpose Considerations for selecting an immune globulin treatment, transitioning patients with primary immune deficiency disease who are receiving long-term treatment between settings of care, and the role of the pharmacist in these endeavors are described. Summary Numerous immune globulin formulations are commercially available, and these formulations differ in immune globulin concentration, stabilizing additives, trace non–immune globulin proteins, and the manufacturing process, all of which may elicit different adverse reactions in patients. Patients may also exhibit differences in tolerability to the route of administration. The complex process of formulating, establishing, and maintaining an immune globulin treatment regimen requires the participation of the patient and healthcare providers. For patients transitioning between settings of care, particular attention must be paid to any changes to a treatment that has been individualized for a patient. Factors affecting the decision process include medical history, immune globulin formulation characteristics, formulary stock, payer formulary, and patient preference. For patients switching between immune globulin formulations or routes of administration, dosage adjustments of and tolerance to immune globulin may be important considerations. A clinical pharmacist with knowledge of the pharmaceutical suitability of immune globulin formulations can safely facilitate these transitions. Conclusion Selecting a route of administration for and formulation of immune globulin involves the consideration of many factors, including the patient’s medical history, formulation characteristics, formulary stock, payer formulary, and patient preference. A pharmacist is essential in helping the patient navigate the decision-making process and in coordinating care and communication among patients, caregivers, and healthcare providers to monitor patient progress and adherence and ensure safe and efficient transitions of care. Patients with immunodeficiencies, immune-mediated demyelinating motor neuropathies, or dysregulation of immunologic homeostasis may suffer from a range of symptoms, including chronic infections, motor weakness, and excessive bruising and bleeding.1 Some of these symptoms may be managed with immune globulin therapy.1 Indications included in the prescribing information for various immune globulin formulations (Table 1) include primary immune deficiency disease (PIDD), neurologic conditions (e.g., multifocal motor neuropathy, chronic inflammatory demyelinating disease), hematologic conditions (i.e., immune thrombocytopenia purpura [ITP]), and febrile illnesses of unknown origin (e.g., Kawasaki disease).1,–15 Immune globulin is used for immunomodulation to treat some conditions (e.g., ITP, chronic inflammatory demyelinating neuropathy) and may grant patients periods of remission that span weeks to years.16 Patients with PIDD, specifically those with antibody deficiencies, require lifelong immunoglobulin G (IgG) replacement therapy to prevent serious, recurrent infections that may lead to increased morbidity and mortality (e.g., pulmonary complications leading to terminal lung disease) when not appropriately managed.1,10,17,–19 The selection of a treatment plan to which these patients can adhere is important to their health and quality of life.1,10,20 Table 1 Indications for Immune Globulin Products Disorder and Goal of Treatment Immune Globulin Product(s) Indicated for Treatmenta Chronic inflammatory demyelinating polyneuropathy  Improve neuromuscular disability and impairment Gammaked,2 Gamunex-C3  Maintenance therapy to prevent relapse Gammaked,2 Gamunex-C3 Chronic lymphocytic leukemia  Prevention of bacterial infections Gammagard S/D4 Idiopathic thrombocytopenic purpura (ITP)  Raise or maintain platelet counts in acute ITP and maintain platelet counts in chronic ITP Carimune NF5  Raise platelet counts Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 10%,7 Privigen8  Allow patients to undergo surgery Gammaked,2 Gamunex-C3  Prevention or control of bleeding Gammagard S/D,4 Gammaked,2 Gamunex-C,3 Privigen8 Kawasaki syndrome  Prevention of coronary artery aneurysms Gammagard S/D4 Multifocal motor neuropathy  Maintenance therapy Gammagard Liquid9 Primary immune deficiency disease  Replacement or maintenance therapy Carimune NF,5 Bivigam,27 Flebogamma 5%,11 Flebogamma 10%,11,12 Gammagard Liquid,9 Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 5%,15 Privigen8 Subcutaneous administration: Gammagard Liquid,9 Gammaked,2 Gamunex-C,3 Hizentra,13 HyQvia14 Disorder and Goal of Treatment Immune Globulin Product(s) Indicated for Treatmenta Chronic inflammatory demyelinating polyneuropathy  Improve neuromuscular disability and impairment Gammaked,2 Gamunex-C3  Maintenance therapy to prevent relapse Gammaked,2 Gamunex-C3 Chronic lymphocytic leukemia  Prevention of bacterial infections Gammagard S/D4 Idiopathic thrombocytopenic purpura (ITP)  Raise or maintain platelet counts in acute ITP and maintain platelet counts in chronic ITP Carimune NF5  Raise platelet counts Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 10%,7 Privigen8  Allow patients to undergo surgery Gammaked,2 Gamunex-C3  Prevention or control of bleeding Gammagard S/D,4 Gammaked,2 Gamunex-C,3 Privigen8 Kawasaki syndrome  Prevention of coronary artery aneurysms Gammagard S/D4 Multifocal motor neuropathy  Maintenance therapy Gammagard Liquid9 Primary immune deficiency disease  Replacement or maintenance therapy Carimune NF,5 Bivigam,27 Flebogamma 5%,11 Flebogamma 10%,11,12 Gammagard Liquid,9 Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 5%,15 Privigen8 Subcutaneous administration: Gammagard Liquid,9 Gammaked,2 Gamunex-C,3 Hizentra,13 HyQvia14 a All products to be administered intravenously unless noted otherwise. Table 1 Indications for Immune Globulin Products Disorder and Goal of Treatment Immune Globulin Product(s) Indicated for Treatmenta Chronic inflammatory demyelinating polyneuropathy  Improve neuromuscular disability and impairment Gammaked,2 Gamunex-C3  Maintenance therapy to prevent relapse Gammaked,2 Gamunex-C3 Chronic lymphocytic leukemia  Prevention of bacterial infections Gammagard S/D4 Idiopathic thrombocytopenic purpura (ITP)  Raise or maintain platelet counts in acute ITP and maintain platelet counts in chronic ITP Carimune NF5  Raise platelet counts Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 10%,7 Privigen8  Allow patients to undergo surgery Gammaked,2 Gamunex-C3  Prevention or control of bleeding Gammagard S/D,4 Gammaked,2 Gamunex-C,3 Privigen8 Kawasaki syndrome  Prevention of coronary artery aneurysms Gammagard S/D4 Multifocal motor neuropathy  Maintenance therapy Gammagard Liquid9 Primary immune deficiency disease  Replacement or maintenance therapy Carimune NF,5 Bivigam,27 Flebogamma 5%,11 Flebogamma 10%,11,12 Gammagard Liquid,9 Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 5%,15 Privigen8 Subcutaneous administration: Gammagard Liquid,9 Gammaked,2 Gamunex-C,3 Hizentra,13 HyQvia14 Disorder and Goal of Treatment Immune Globulin Product(s) Indicated for Treatmenta Chronic inflammatory demyelinating polyneuropathy  Improve neuromuscular disability and impairment Gammaked,2 Gamunex-C3  Maintenance therapy to prevent relapse Gammaked,2 Gamunex-C3 Chronic lymphocytic leukemia  Prevention of bacterial infections Gammagard S/D4 Idiopathic thrombocytopenic purpura (ITP)  Raise or maintain platelet counts in acute ITP and maintain platelet counts in chronic ITP Carimune NF5  Raise platelet counts Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 10%,7 Privigen8  Allow patients to undergo surgery Gammaked,2 Gamunex-C3  Prevention or control of bleeding Gammagard S/D,4 Gammaked,2 Gamunex-C,3 Privigen8 Kawasaki syndrome  Prevention of coronary artery aneurysms Gammagard S/D4 Multifocal motor neuropathy  Maintenance therapy Gammagard Liquid9 Primary immune deficiency disease  Replacement or maintenance therapy Carimune NF,5 Bivigam,27 Flebogamma 5%,11 Flebogamma 10%,11,12 Gammagard Liquid,9 Gammagard S/D,4 Gammaked,2 Gammaplex,6 Gamunex-C,3 Octagam 5%,15 Privigen8 Subcutaneous administration: Gammagard Liquid,9 Gammaked,2 Gamunex-C,3 Hizentra,13 HyQvia14 a All products to be administered intravenously unless noted otherwise. A treatment plan can be individualized to maximize clinical benefit and minimize adverse events while considering patient preferences.21,–23 Factors to consider include the immune globulin formulation and route of administration (i.e., intravenous [IVIG], conventional subcutaneous [SCIG], or recombinant human hyaluronidase [rHuPH20]-facilitated subcutaneous [IGHy]).14,21 Although both IGHy and conventional SCIG are delivered subcutaneously, IGHy requires the administration of a separate enzyme (rHuPH20) before immune globulin (10%) administration. rHuPH20 increases the bioavailability of immune globulin by transiently depolymerizing a component of the extracellular matrix (i.e., hyaluronan) that normally restricts the absorption and dispersion of immune globulin during conventional subcutaneous infusions, allowing for infusion volumes and rates approximately 10- to 15-fold higher than with conventional SCIG administration.3,14,24,–26 Numerous immune globulin formulations are commercially available (Table 2).28 These formulations differ in immune globulin concentration, stabilizing additives, trace non– immune globulin proteins, and the manufacturing process, all of which may elicit different adverse reactions in patients (Table 3).21,29,–61 Patients may also exhibit differences in tolerability to the route of administration (Table 4).21,25,61,–70 Table 4 Comparative Characteristics of Route of Administration of Immune Globulin in Patients With Primary Immune Deficiency Diseasea Characteristic IVIG Subcutaneous Conventional SCIG IGHy Efficacy Same as SCIG62,–64 Same as IVIG62,–64 Same as IVIG25 Pharmacokinetics Higher peak serum immune globulin levels and larger peak-to-trough variation compared with SCIG62,63,65,66 Low peak-to-trough variation and higher trough immune globulin levels compared with IVIG62,63,65,66 Lower peak serum immune globulin levels than IVIG25; similar trough serum immune globulin levels compared with IVIG25 Bioavailability 100% of dose administered67 ~60–70% of dose administered67 93.3% relative to IVIG dose Typical no. infusion sites 124 ≥16 per month13,24 ~114,25 Frequency of infusions and infusion duration Generally once every 3–4 wk; ~2–4 hr65,68,69 Generally once or twice weekly; ~1–2 hr21,70 Generally once every 3–4 wk/2.08 hr/infusion (median duration)14,25 Risk of systemic adverse reactions Higher compared with SCIG and IGHy25,61,65 to IGHy65,67Lower than IVIG61 and similar Similar to SCIG65,67 and lower than IVIG Risk of local adverse reactions Lower than SCIG and IGHy24,25,61 Higher than IVIG and similar to IGHy24,25,61 Similar to SCIG65,67 Administration considerations Requires venous access and medical supervision65,67 Almost always self-administered at home (except in rare cases)65,67 May be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic67 Characteristic IVIG Subcutaneous Conventional SCIG IGHy Efficacy Same as SCIG62,–64 Same as IVIG62,–64 Same as IVIG25 Pharmacokinetics Higher peak serum immune globulin levels and larger peak-to-trough variation compared with SCIG62,63,65,66 Low peak-to-trough variation and higher trough immune globulin levels compared with IVIG62,63,65,66 Lower peak serum immune globulin levels than IVIG25; similar trough serum immune globulin levels compared with IVIG25 Bioavailability 100% of dose administered67 ~60–70% of dose administered67 93.3% relative to IVIG dose Typical no. infusion sites 124 ≥16 per month13,24 ~114,25 Frequency of infusions and infusion duration Generally once every 3–4 wk; ~2–4 hr65,68,69 Generally once or twice weekly; ~1–2 hr21,70 Generally once every 3–4 wk/2.08 hr/infusion (median duration)14,25 Risk of systemic adverse reactions Higher compared with SCIG and IGHy25,61,65 to IGHy65,67Lower than IVIG61 and similar Similar to SCIG65,67 and lower than IVIG Risk of local adverse reactions Lower than SCIG and IGHy24,25,61 Higher than IVIG and similar to IGHy24,25,61 Similar to SCIG65,67 Administration considerations Requires venous access and medical supervision65,67 Almost always self-administered at home (except in rare cases)65,67 May be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic67 a IVIG = i.v. immune globulin, SCIG = subcutaneous immune globulin, IGHy = recombinant human hyaluronidase-facilitated immune globulin. Table 4 Comparative Characteristics of Route of Administration of Immune Globulin in Patients With Primary Immune Deficiency Diseasea Characteristic IVIG Subcutaneous Conventional SCIG IGHy Efficacy Same as SCIG62,–64 Same as IVIG62,–64 Same as IVIG25 Pharmacokinetics Higher peak serum immune globulin levels and larger peak-to-trough variation compared with SCIG62,63,65,66 Low peak-to-trough variation and higher trough immune globulin levels compared with IVIG62,63,65,66 Lower peak serum immune globulin levels than IVIG25; similar trough serum immune globulin levels compared with IVIG25 Bioavailability 100% of dose administered67 ~60–70% of dose administered67 93.3% relative to IVIG dose Typical no. infusion sites 124 ≥16 per month13,24 ~114,25 Frequency of infusions and infusion duration Generally once every 3–4 wk; ~2–4 hr65,68,69 Generally once or twice weekly; ~1–2 hr21,70 Generally once every 3–4 wk/2.08 hr/infusion (median duration)14,25 Risk of systemic adverse reactions Higher compared with SCIG and IGHy25,61,65 to IGHy65,67Lower than IVIG61 and similar Similar to SCIG65,67 and lower than IVIG Risk of local adverse reactions Lower than SCIG and IGHy24,25,61 Higher than IVIG and similar to IGHy24,25,61 Similar to SCIG65,67 Administration considerations Requires venous access and medical supervision65,67 Almost always self-administered at home (except in rare cases)65,67 May be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic67 Characteristic IVIG Subcutaneous Conventional SCIG IGHy Efficacy Same as SCIG62,–64 Same as IVIG62,–64 Same as IVIG25 Pharmacokinetics Higher peak serum immune globulin levels and larger peak-to-trough variation compared with SCIG62,63,65,66 Low peak-to-trough variation and higher trough immune globulin levels compared with IVIG62,63,65,66 Lower peak serum immune globulin levels than IVIG25; similar trough serum immune globulin levels compared with IVIG25 Bioavailability 100% of dose administered67 ~60–70% of dose administered67 93.3% relative to IVIG dose Typical no. infusion sites 124 ≥16 per month13,24 ~114,25 Frequency of infusions and infusion duration Generally once every 3–4 wk; ~2–4 hr65,68,69 Generally once or twice weekly; ~1–2 hr21,70 Generally once every 3–4 wk/2.08 hr/infusion (median duration)14,25 Risk of systemic adverse reactions Higher compared with SCIG and IGHy25,61,65 to IGHy65,67Lower than IVIG61 and similar Similar to SCIG65,67 and lower than IVIG Risk of local adverse reactions Lower than SCIG and IGHy24,25,61 Higher than IVIG and similar to IGHy24,25,61 Similar to SCIG65,67 Administration considerations Requires venous access and medical supervision65,67 Almost always self-administered at home (except in rare cases)65,67 May be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic67 a IVIG = i.v. immune globulin, SCIG = subcutaneous immune globulin, IGHy = recombinant human hyaluronidase-facilitated immune globulin. Table 3 Risk Factors and Formulation Components Contributing to Adverse Reactions Associated With IVIGa Patient Risk Factor Adverse Reaction(s) Relevant Formulation Component(s) History of renal disease, diabetes, advanced age, cardiovascular disease Renal complications (acute renal failure, renal insufficiency, osmotic nephrosis)29,–33 Sucrose, glucose, maltose, sodium, osmolarity Predisposition to thrombotic events, cardiovascular disease, hypertension, diabetes, advanced age, prolonged periods of immobilization Thromboembolic events34,–37 or thrombosis38,–40 Sucrose, glucose, maltose, sodium, osmolarity IgA deficiency or IgA antibodies Anaphylaxis or anaphylactoid reactions41,–43 IgA content Predisposition to migraine headaches Aseptic meningitis44,–47 Antineutrophil antibodies Coadministration of products such as platelets or plasma containing additional isoagglutinins, nonsecretor status (with absence of circulating A and B substance) Hemolysis48,–54 Anti-A or anti-B isoagglutinins, anti-D or anti-K antibodies Unknown Neutropenia55,56 Antineutrophil antibodies, anti-Siglec-9 autoantibodies Unknown Hyponatremia57,58 Osmolarity, sugars Unknown Phlebitis59 pH Hyperprolinemia60 Unknown l-proline Fructose intolerance60 Unknown Sorbitol Corn allergy60 Unknown Maltose Latex allergy Unknown Latex packaging Patient Risk Factor Adverse Reaction(s) Relevant Formulation Component(s) History of renal disease, diabetes, advanced age, cardiovascular disease Renal complications (acute renal failure, renal insufficiency, osmotic nephrosis)29,–33 Sucrose, glucose, maltose, sodium, osmolarity Predisposition to thrombotic events, cardiovascular disease, hypertension, diabetes, advanced age, prolonged periods of immobilization Thromboembolic events34,–37 or thrombosis38,–40 Sucrose, glucose, maltose, sodium, osmolarity IgA deficiency or IgA antibodies Anaphylaxis or anaphylactoid reactions41,–43 IgA content Predisposition to migraine headaches Aseptic meningitis44,–47 Antineutrophil antibodies Coadministration of products such as platelets or plasma containing additional isoagglutinins, nonsecretor status (with absence of circulating A and B substance) Hemolysis48,–54 Anti-A or anti-B isoagglutinins, anti-D or anti-K antibodies Unknown Neutropenia55,56 Antineutrophil antibodies, anti-Siglec-9 autoantibodies Unknown Hyponatremia57,58 Osmolarity, sugars Unknown Phlebitis59 pH Hyperprolinemia60 Unknown l-proline Fructose intolerance60 Unknown Sorbitol Corn allergy60 Unknown Maltose Latex allergy Unknown Latex packaging a IVIG = i.v. immune globulin, IgA = immunoglobulin A. Table 3 Risk Factors and Formulation Components Contributing to Adverse Reactions Associated With IVIGa Patient Risk Factor Adverse Reaction(s) Relevant Formulation Component(s) History of renal disease, diabetes, advanced age, cardiovascular disease Renal complications (acute renal failure, renal insufficiency, osmotic nephrosis)29,–33 Sucrose, glucose, maltose, sodium, osmolarity Predisposition to thrombotic events, cardiovascular disease, hypertension, diabetes, advanced age, prolonged periods of immobilization Thromboembolic events34,–37 or thrombosis38,–40 Sucrose, glucose, maltose, sodium, osmolarity IgA deficiency or IgA antibodies Anaphylaxis or anaphylactoid reactions41,–43 IgA content Predisposition to migraine headaches Aseptic meningitis44,–47 Antineutrophil antibodies Coadministration of products such as platelets or plasma containing additional isoagglutinins, nonsecretor status (with absence of circulating A and B substance) Hemolysis48,–54 Anti-A or anti-B isoagglutinins, anti-D or anti-K antibodies Unknown Neutropenia55,56 Antineutrophil antibodies, anti-Siglec-9 autoantibodies Unknown Hyponatremia57,58 Osmolarity, sugars Unknown Phlebitis59 pH Hyperprolinemia60 Unknown l-proline Fructose intolerance60 Unknown Sorbitol Corn allergy60 Unknown Maltose Latex allergy Unknown Latex packaging Patient Risk Factor Adverse Reaction(s) Relevant Formulation Component(s) History of renal disease, diabetes, advanced age, cardiovascular disease Renal complications (acute renal failure, renal insufficiency, osmotic nephrosis)29,–33 Sucrose, glucose, maltose, sodium, osmolarity Predisposition to thrombotic events, cardiovascular disease, hypertension, diabetes, advanced age, prolonged periods of immobilization Thromboembolic events34,–37 or thrombosis38,–40 Sucrose, glucose, maltose, sodium, osmolarity IgA deficiency or IgA antibodies Anaphylaxis or anaphylactoid reactions41,–43 IgA content Predisposition to migraine headaches Aseptic meningitis44,–47 Antineutrophil antibodies Coadministration of products such as platelets or plasma containing additional isoagglutinins, nonsecretor status (with absence of circulating A and B substance) Hemolysis48,–54 Anti-A or anti-B isoagglutinins, anti-D or anti-K antibodies Unknown Neutropenia55,56 Antineutrophil antibodies, anti-Siglec-9 autoantibodies Unknown Hyponatremia57,58 Osmolarity, sugars Unknown Phlebitis59 pH Hyperprolinemia60 Unknown l-proline Fructose intolerance60 Unknown Sorbitol Corn allergy60 Unknown Maltose Latex allergy Unknown Latex packaging a IVIG = i.v. immune globulin, IgA = immunoglobulin A. Table 2 Immune Globulin Product Characteristicsa Brand Name Conc. Stabilizer Sodium Content IgA Content, μg/mL Sugar Content pH Osmolarity/Osmolality (mOsm/kg) Latex-Free Packaging Route(s) of Administration Bivigam27 Liquid 10% Glycine 0.100–0.140 M ≤200 None 4.0–4.6 ≤510 Yes Intravenous Carimune NF5 Lyophilized 3–12% Sucrose <20 mg/g protein 720 1.67 g sucrose/g protein 6.4–6.8 192–1074 No Intravenous Flebogamma 5%11 or 10%12 Liquid 5% or 10% d-sorbitol Trace <3 5% d-sorbitol 5.0–6.0 240–370 No Intravenous Gammagard Liquid9 Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Intravenous and subcutaneous Gammagard S/D4 Lyophilized 5% or 10% Glycine 8.5 mg/mL (5%) or 17 mg/mL (10%) ≤2.2 20 mg/mL (5%) or 40 mg/mL (10%) 6.8 ± 0.4 636 mOsm/L (5%) or 250 mOsm/L (10%) No Intravenous Gammaked2 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Gammaplex6 Liquid 5% Glycine 30–50 mM/L <4 5% d-sorbitol (polyol) 4.6–5.1 460–500 Yes Intravenous Gamunex-C3 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Hizentra13 Liquid 20% Proline Trace ≤50 None 4.6–5.2 380 Yes Subcutaneous HyQvia14,b Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Subcutaneous Octagam 5%15 or 10%7 Liquid 5% or 10% Maltose ≤30 mmol/L <100 100 mg/mL maltose 5.1–6.0 310–380 Yes Intravenous Privigen8 Liquid 10% Proline Trace ≤25 None 4.8 Isotonic 320 Yes Intravenous Brand Name Conc. Stabilizer Sodium Content IgA Content, μg/mL Sugar Content pH Osmolarity/Osmolality (mOsm/kg) Latex-Free Packaging Route(s) of Administration Bivigam27 Liquid 10% Glycine 0.100–0.140 M ≤200 None 4.0–4.6 ≤510 Yes Intravenous Carimune NF5 Lyophilized 3–12% Sucrose <20 mg/g protein 720 1.67 g sucrose/g protein 6.4–6.8 192–1074 No Intravenous Flebogamma 5%11 or 10%12 Liquid 5% or 10% d-sorbitol Trace <3 5% d-sorbitol 5.0–6.0 240–370 No Intravenous Gammagard Liquid9 Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Intravenous and subcutaneous Gammagard S/D4 Lyophilized 5% or 10% Glycine 8.5 mg/mL (5%) or 17 mg/mL (10%) ≤2.2 20 mg/mL (5%) or 40 mg/mL (10%) 6.8 ± 0.4 636 mOsm/L (5%) or 250 mOsm/L (10%) No Intravenous Gammaked2 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Gammaplex6 Liquid 5% Glycine 30–50 mM/L <4 5% d-sorbitol (polyol) 4.6–5.1 460–500 Yes Intravenous Gamunex-C3 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Hizentra13 Liquid 20% Proline Trace ≤50 None 4.6–5.2 380 Yes Subcutaneous HyQvia14,b Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Subcutaneous Octagam 5%15 or 10%7 Liquid 5% or 10% Maltose ≤30 mmol/L <100 100 mg/mL maltose 5.1–6.0 310–380 Yes Intravenous Privigen8 Liquid 10% Proline Trace ≤25 None 4.8 Isotonic 320 Yes Intravenous a IgA = immunoglobulin A. b Immune globulin 10% component of HyQvia. Table 2 Immune Globulin Product Characteristicsa Brand Name Conc. Stabilizer Sodium Content IgA Content, μg/mL Sugar Content pH Osmolarity/Osmolality (mOsm/kg) Latex-Free Packaging Route(s) of Administration Bivigam27 Liquid 10% Glycine 0.100–0.140 M ≤200 None 4.0–4.6 ≤510 Yes Intravenous Carimune NF5 Lyophilized 3–12% Sucrose <20 mg/g protein 720 1.67 g sucrose/g protein 6.4–6.8 192–1074 No Intravenous Flebogamma 5%11 or 10%12 Liquid 5% or 10% d-sorbitol Trace <3 5% d-sorbitol 5.0–6.0 240–370 No Intravenous Gammagard Liquid9 Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Intravenous and subcutaneous Gammagard S/D4 Lyophilized 5% or 10% Glycine 8.5 mg/mL (5%) or 17 mg/mL (10%) ≤2.2 20 mg/mL (5%) or 40 mg/mL (10%) 6.8 ± 0.4 636 mOsm/L (5%) or 250 mOsm/L (10%) No Intravenous Gammaked2 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Gammaplex6 Liquid 5% Glycine 30–50 mM/L <4 5% d-sorbitol (polyol) 4.6–5.1 460–500 Yes Intravenous Gamunex-C3 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Hizentra13 Liquid 20% Proline Trace ≤50 None 4.6–5.2 380 Yes Subcutaneous HyQvia14,b Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Subcutaneous Octagam 5%15 or 10%7 Liquid 5% or 10% Maltose ≤30 mmol/L <100 100 mg/mL maltose 5.1–6.0 310–380 Yes Intravenous Privigen8 Liquid 10% Proline Trace ≤25 None 4.8 Isotonic 320 Yes Intravenous Brand Name Conc. Stabilizer Sodium Content IgA Content, μg/mL Sugar Content pH Osmolarity/Osmolality (mOsm/kg) Latex-Free Packaging Route(s) of Administration Bivigam27 Liquid 10% Glycine 0.100–0.140 M ≤200 None 4.0–4.6 ≤510 Yes Intravenous Carimune NF5 Lyophilized 3–12% Sucrose <20 mg/g protein 720 1.67 g sucrose/g protein 6.4–6.8 192–1074 No Intravenous Flebogamma 5%11 or 10%12 Liquid 5% or 10% d-sorbitol Trace <3 5% d-sorbitol 5.0–6.0 240–370 No Intravenous Gammagard Liquid9 Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Intravenous and subcutaneous Gammagard S/D4 Lyophilized 5% or 10% Glycine 8.5 mg/mL (5%) or 17 mg/mL (10%) ≤2.2 20 mg/mL (5%) or 40 mg/mL (10%) 6.8 ± 0.4 636 mOsm/L (5%) or 250 mOsm/L (10%) No Intravenous Gammaked2 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Gammaplex6 Liquid 5% Glycine 30–50 mM/L <4 5% d-sorbitol (polyol) 4.6–5.1 460–500 Yes Intravenous Gamunex-C3 Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes Intravenous and subcutaneous Hizentra13 Liquid 20% Proline Trace ≤50 None 4.6–5.2 380 Yes Subcutaneous HyQvia14,b Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes Subcutaneous Octagam 5%15 or 10%7 Liquid 5% or 10% Maltose ≤30 mmol/L <100 100 mg/mL maltose 5.1–6.0 310–380 Yes Intravenous Privigen8 Liquid 10% Proline Trace ≤25 None 4.8 Isotonic 320 Yes Intravenous a IgA = immunoglobulin A. b Immune globulin 10% component of HyQvia. The complex process of formulating, establishing, and maintaining an immune globulin treatment regimen requires the participation of the patient and healthcare providers (e.g., physicians, nurses, pharmacists). The healthcare providers collaborate to determine the most clinically and pharmaceutically appropriate formulation and route of administration. For patients transitioning between settings of care, particular attention must be paid to any changes to a treatment that has been individualized for a patient. The design of a treatment plan (e.g., selection of an immune globulin formulation, dose, frequency, and route of administration) for patients with PIDD should consider challenges posed to patients, such as the time commitment and effect on quality of life. Herein, we discuss primary differences between the different routes of immune globulin administration, key issues to consider when choosing a formulation and route of administration, and the role of the clinical pharmacist in establishing patients on a treatment regimen and ensuring safe transitions between settings of care. Key Points Patients with primary immunodeficiency diseases may require lifelong immune globulin treatment. Several factors must be considered when recommending an immune globulin treatment, such as formulation, rout of administration, hospital formulary, and patient preference. Treatment plans may be individualized to maximize clinical benefit and minimize adverse events. Clinical pharmacists with knowledge of immune globulin formulations and attributes are well suited to help establish ans optimal treatment regimen and safely facilitate patient transitions between settings of care. Selection of immune globulin formulation An immune globulin formulation is composed primarily of immune globulin purified from the plasma of a diverse population of donors, stabilizing additives, and trace amounts of other proteins, all of which may affect patient tolerability (Table 2).28 Immune globulin formulations are therefore inherently heterogeneous. Based on the results of a head-to-head trial in patients with PIDD that showed differing levels of efficacy between two IVIG products with equivalent dosing,71 it has been suggested that different IVIG products may not be bioequivalent.72 These differences may affect tolerability.28,61 Therefore, different immune globulin products and different lots of the same product should not be pooled or mixed, and switching between products should be done with full consideration of the products’ pharmaceutical differences.22,73 Prior immune globulin use and switching between products When selecting an immune globulin formulation, the healthcare provider must consider the patient’s history with immune globulin treatment.61 Patients with an established immune globulin formulation and route of administration with favorable tolerability should not routinely switch to another treatment method.61,73 Studies indicate that patients who consistently receive the same dose of a well-tolerated IVIG formulation at the same time interval have a low risk of systemic adverse reactions,74,75 but the risk may increase in patients switching between formulations.61,73 Switching formulations may be unavoidable when situations such as changes in product availability, patient insurance, or the formulary arise.73,76 In these cases, we recommend taking extra precautionary steps, including supplying patients with anaphylaxis kits and premedication. Further, the provision of “sit-through” visits (i.e., remaining with the patient through the duration of the infusion) is considered to be the safest clinical practice, according to consensus of expert opinion.77 Differences in the efficacy and pharmacokinetics of various immune globulin products should also be considered.59,78 Patients switching from IVIG to SCIG may also require dosage adjustments to achieve bioequivalence to IVIG.63 Contraindications and precautions A patient’s medical history is another important factor in the selection of immune globulin formulation, as the risk for a number of adverse reactions associated with treatment may be increased in patients with certain comorbid conditions.28 The immune globulin formulation and route of administration may also increase the risk of adverse reactions and affect tolerability.28,61 Contributing factors include additives, osmolality, and trace proteins other than immune globulin in the formulation. Therefore, selecting a product suited to a patient’s health history may reduce the risk of adverse reactions (Table 3). The prescribing information for all immune globulin products, regardless of the indicated route of administration, highlights these issues, with contraindications and warnings against use in patients with certain predispositions that may increase the risk of less common but more dangerous adverse reactions (Table 3). For example, the use of immune globulin formulations with proline or fructose is contraindicated in patients with hyperprolinemia or congenital fructose intolerance, respectively.6,8,13 Warnings outlined in the prescribing information for immune globulin products include an increased risk for renal complications and thrombosis or thromboembolic events2,–6,8,9,11,–15,27; product formulation has been shown to be a contributing factor to these adverse reactions.29,34,35 Other patient factors, including older age, history of cardiovascular disease, and history of diabetes, contribute to the risk of complications.61 Patients with these comorbid factors may reduce their risk by avoiding products with a high sugar and sodium content and products that exhibit hyperosmolarity.28,61,79 Additional precautions may include screening for comorbidities before treatment, prehydrating, using slower infusion rates, and administering the dose over a greater number of days.61 In patients predisposed to thrombotic events, this risk may be increased with the use of IVIG versus SCIG due to the higher volume of immune globulin infused into a single site.61 Patients at risk for thrombotic events must be evaluated on a case-by-case basis by the treating provider and pharmacist to develop a risk mitigation plan, which may include using an anticoagulant, encouraging patients to remain active during the infusion period, or not administering immune globulin. However, in a study of 47 patients age 65–89 years with PIDD, the risk of local or systemic adverse events did not increase in the 45% of patients who were taking an anticoagulant, platelet inhibitors, or both (aspirin [36%], warfarin [15%], and clopidogrel [9%]) concomitantly with conventional SCIG over a 13-month period.80 Nonetheless, a black-box warning recommending caution when using immune globulin in patients with thrombosis is included in the prescribing information of all immune globulin formulations, including those intended for subcutaneous or i.v. administration, which also includes IGHy. Trace amounts of non–immune globulin proteins may also have a significant effect on tolerability.28,61 For example, current Food and Drug (FDA) regulations require the removal of a procoagulant contaminant that has been associated with an increased risk of thromboembolic events.21 Furthermore, trace amounts of immunoglobulin A (IgA) in immune globulin formulations or the presence of anti-IgA antibodies in patients with selective IgA deficiency may elicit anaphylactic or anaphylactoid reactions during IVIG administration.41,42 However, a recent literature review suggests that the role of IgA antibodies within this context remains controversial.43 Patients with IgA deficiency or anaphylactic reactions to IVIG may reduce their risk with SCIG.81,82 In addition, the presence of antineutrophil antibodies has been implicated in aseptic meningitis,44 for which patients with a history of migraine headaches may have increased susceptibility.45 As with anaphylactic or anaphylactoid reactions, the risk of aseptic meningitis is higher with IVIG than SCIG.46,83,84 While the risk of some IVIG-related systemic adverse reactions may be lower with conventional SCIG and IGHy, subcutaneous administration may not always be the better choice. For example, some preexisting conditions, such as severe thrombocytopenia, bleeding disorders, and widespread eczema, may contraindicate the use of SCIG and likely IGHy (though no such data currently exist for IGHy).66 For patients treated with conventional SCIG or IGHy and at risk for thrombosis, as with IVIG, treatments should be administered with caution (at the minimum possible dose and infusion rate).2,3,9,13,14 Furthermore, patients being treated for both PIDD and ITP may not receive immune globulin by the subcutaneous route due to the risk of hematoma formation.2,3 Patients with these conditions may consider IVIG. However, it should be noted that to date, the FDA-approved labeling for SCIG formulations, including IGHy, includes the treatment of PIDD as the only indication. Considerations in designing a treatment plan Route of administration IgG replacement regimens demand a substantial time commitment that may disrupt the normal daily activities of patients and caregivers.85,86 For patients with PIDD, immune globulin administration typically requires 2–4 hours (or longer for patients with low tolerability to IVIG infusions) once every three to four weeks in a clinical or home setting with IVIG,61,87,88 1–2 hours once or twice weekly at home with SCIG 10% formulations (approximately 2 hours daily to biweekly for more highly concentrated immune globulin formulations [e.g., 20% protein]),13,21,22,24,70 and 0.83–4.68 hours (median, 2.08 hours) once every three to four weeks in the clinical or home setting with IGHy.14,25 The number of monthly infusion sites required are lowest with IVIG (1) and IGHy (typically 1)14 compared with conventional SCIG (16 sites [range, 12–20 sites]).9,13,25 While the mean number of infusion sites was 1.09 in a Phase III study in patients receiving IGHy,25 in one of our current practice settings, patients prefer using 2 infusion sites once a maintenance dosasge is reached (of 37 patients treated, all switched from 1 to 2 sites). Several immune globulin formulations that are currently available are indicated for i.v. or subcutaneous administration (Table 2).14,28 The route of administration (based on a patient’s overall clinical picture) is typically considered first, and the formulation is then chosen based on pharmaceutical suitability. While both i.v. and subcutaneous routes of administration are effective in preventing infections, there are inherent differences, including pharmacokinetics, risk of adverse events, requirement for medical supervision, site of infusion, volume of dose, cost, and quality of life. Dosing considerations and pharmacokinetics The dose of immune globulin should be customized individually for each patient to achieve optimal clinical benefit,21,68 as the same dose of the same formulation could result in different outcomes in patients of similar weights.89 Therefore, dosing guidelines should be considered a starting point for working toward decreasing the frequency of infections in patients with PIDD. Patients with PIDD may be initiating i.v. or subcutaneous (either conventional SCIG or IGHy) immune globulin treatment or transitioning between routes of administration. Newly diagnosed patients prescribed IVIG are typically given initial doses between 400 and 600 mg/kg every three to four weeks.68 Those initiating conventional SCIG treatment may begin with a single infusion of IVIG at 1 g/kg followed by weekly doses of SCIG at 100 mg/kg/week.90 Alternatively, patients may be given a 100 mg/kg dose of SCIG daily for 5 days before continuing with weekly doses. Patients transitioning from IVIG to conventional SCIG may receive their first SCIG dose 7–10 days after a loading dose of their current IVIG dose.90 Patients initiating or switching to IGHy undergo a dose ramp-up (i.e., escalation of infusion rates and volume) period before proceeding to a three- or four-week dosing interval.14 This dose-escalation period allows time for training sessions for patients while they are also psychologically acclimating to larger infusion volumes into a single needle site. During the dose-escalation period (generally spanning the first four doses), initial IGHy infusions are administered more frequently and at lower infusion rates and volumes and then are increased in a step-up fashion until the patient achieves the maximum infusion rate and volume. At this point, IGHy may be administered every three or four weeks, similar to the schedule with IVIG. For example, during the first dose-escalation infusion, patients may be administered one-fourth of the four-week dose (one-week dose), followed one week later by one-half of the four-week dose (two-week dose), and so on until the full three- or four-week IGHy dosage is achieved. For patients switching from IVIG to SCIG or IGHy, FDA-approved labeling recommends achieving serum immune globulin concentrations relative to their IVIG dose, as measured by area under the IgG concentration-versus-time curve (AUC).14,90 Patients’ serum immune globulin levels and clinical correlation (i.e., infection rate) should be monitored to assess the need for dosage adjustments. The efficacy and safety results of clinical trials conducted in the United States substantiate the rationale for immune globulin doses with conventional SCIG to be larger and more frequent than with IVIG (i.e., once or twice weekly or optional frequent dosing two to seven times per week with Hizentra (immune globulin subcutaneous [human], 20% liquid, CSL Behring AG, Bern, Switzerland) at 137% of a 10% or 20% immune globulin formulation, per the package insert).2,3,9,13,90 European physicians do not typically implement a dosage adjustment, preferring to dose according to the previous IVIG dose (i.e., 1:1) while monitoring the patient to ensure an appropriate clinical response. Therefore, clinical trials in Europe have been conducted to be in line with clinical practice, demonstrating that a dose-equivalent switch may be made from IVIG to conventional SCIG.21,90,–92 As the current perspective on PIDD by physicians in both the United States and Europe focuses on individualization of treatment, approaches for dose conversion from IVIG to conventional SCIG may vary according to physician experience and patient response.21,68 In contrast to switching from IVIG to SCIG, a dosage adjustment is not necessary, per the FDA-approved labeling, to match the AUC of the previous IVIG dose for switching from IVIG to IGHy, as the hyaluronidase-mediated absorption and dispersion of immune globulin lead to improved bioavailability compared with conventional SCIG.14,25 The differences among IVIG, SCIG, and IGHy treatments affect the pharmacokinetics of immune globulin. Because of the higher dose per infusion for IVIG compared with conventional SCIG and the direct delivery of immune globulin into the intravascular compartment, IVIG may achieve higher peak serum levels of immune globulin—often more than twice the preinfusion trough level—than those achieved with conventional SCIG.62,63,93 A rapid decline in immune globulin levels occurs in the days after infusion when immune globulin is redistributed into the extravascular compartment, resulting in a large peak-to-trough variation.62,93 In contrast, the lower doses used in conventional SCIG and the need for subcutaneously administered immune globulin to be taken up from the site of infusion into the lymphatic system before entering the intravascular compartment lessen the peak concentration of immune globulin and delay the time to achieve peak concentration.62,63,93 IGHy administered at a similar dose and frequency as IVIG provides similar trough levels and AUC to IVIG while achieving a lower peak concentration of immune globulin compared with that of IVIG and a peak-to-trough variation more similar to that of conventional SCIG.14,25,62,67 In general, the rapid attainment of high peak levels of immune globulin concentration from IVIG, compared with SCIG and IGHy, is associated with an increased frequency of systemic adverse reactions.25,64,67,93 Overall, the importance of pharmacokinetics in immune globulin dosing is to keep the serum peak level low enough to reduce the risk of a systemic adverse reaction and the trough level high enough to prevent an infection. Adverse reactions The treatment regimen for immunoglobulin replacement may elicit adverse reactions.85,86 Conventional SCIG and IGHy have similar safety and tolerability profiles. When compared with SCIG and IGHy, IVIG is associated with a decreased frequency of local adverse reactions and an increased frequency of systemic adverse reactions,25,61 which may affect patients’ overall quality of life.86,–88,94 Therefore, patient tolerability is an important factor in choosing a route of administration. Common reactions for patients receiving IVIG are chills, fever, headache, and muscular pain, which may be managed with premedication, such as nonsteroidal antiinflammatory drugs, acetaminophen, antihistamines, and corticosteroids61; however, there are currently no data from well-controlled clinical trials to indicate that these treatments reduce the rate of systemic adverse events. A reduction in the infusion rate may alleviate some adverse reactions.22,61 In contrast, systemic adverse reactions with SCIG and IGHy are less frequent,22,24,25,64,95 reducing the need for premedication and close monitoring once tolerability is established.61 Conversely, the risk of local adverse reactions is higher with SCIG than with IVIG. Patients receiving SCIG commonly experience swelling and redness at the site of infusion. As some patients develop site-specific tolerance, some investigators in other countries have advocated that site rotation may not be necessary64,95; however, the FDA-approved labeling for SCIG recommends alternating infusion sites, which is what is done in clinical studies conducted in the United States. Furthermore, the rate of local adverse reactions may be reduced by using proper technique and a needle of an appropriate length (i.e., 4, 6, 9, 12, or 14 mm) to prevent intradermal infusions that can cause tissue necrosis and pain.21 Local adverse reactions, such as pain, bleeding, and bruising at the infusion site, are rare for patients receiving IVIG, but patients with poor venous access have reported prolonged pain and swelling.61 The safety profile of IGHy was evaluated in a Phase III trial and a long-term extension trial.14,67 After up to approximately 3.5 years of exposure to IGHy, patients had no clinically observable changes to the subcutaneous tissue or skin, and no patient developed neutralizing anti-rHuPH20 antibodies. Of those patients developing nonneutralizing anti-rHuPH20 antibodies in the Phase III trial, there was no association with any local or systemic adverse events.14,67 With regard to local and systemic adverse events associated with immune globulin infusion, IGHy has been shown to have a profile similar to SCIG.67 Considerations for site of infusion Patients with poor venous access may opt for conventional SCIG or IGHy with a choice of infusion sites. The abdomen (accounting for 90% of infusions in the Phase III trial) and thighs are recommended for IGHy infusions.14 For SCIG, recommended infusion sites include the abdomen and thighs (primarily), upper arms, lower back, and hips.3,9 Quality-of-life issues Patients who previously received IVIG treatment reported an increase in quality of life after switching to conventional SCIG self-administration at home due to improved tolerability (i.e., reduction in the rate of systemic adverse reactions), reduced absence from school or work, and freedom from the need to travel to infusion appointments.86,–88,94 A study by Nicolay et al.88 found that the majority of assessable patients who previously received IVIG at a hospital or physician’s office (group A) or at home (group B) and then switched to home-based conventional SCIG administration preferred conventional SCIG self-infusion (group A, 81% [17 of 21 patients]; group B, 69% [9 of 13 patients]) and home-based administration (group A, 90% [19 of 21 patients]; group B, 92% [12 of 13 patients]), respectively, regardless of the previous site of care. Life Quality Index (LQI) and Global Treatment Satisfaction scale scores were significantly higher (i.e., better) from baseline to 12 months for patients previously receiving hospital- or physician office-based, but not home-based, IVIG. For patients receiving prior home-based IVIG, all LQI subscale scores, as well as the Global Treatment Satisfaction subscale score for place of immune globulin administration, were already high at baseline but were numerically lower and all subscale scores were nonsignificant after 12 months of conventional SCIG self-administration. A more recent study of 216 patients and 84 caregivers corroborated the stronger preferences for self-administration and home-based administration versus administration by a healthcare professional (p < 0.05) or at a physician’s office, hospital, or clinic (p < 0.05).96 This same study revealed a significantly greater preference for shorter infusion times (p < 0.05). Notably, although self-administration of conventional SCIG may be preferred by some patients, self-infusion (or infusion administered by the primary caregiver) at multiple sites does not appeal to others.96,–98 The study by Espanol and colleagues96 revealed a significantly greater preference for one needle stick among patients (p < 0.05) and caregivers (p < 0.05). Another study found stronger agreement among IVIG recipients (n = 28) with the statement “I think I would have problems to puncture myself” versus SCIG recipients (n = 32) with the statement “I have problems to puncture myself” (p < 0.001).97 The investigators also found a significantly greater preference for less frequent (monthly) infusions compared with more frequent (weekly or every other week) infusions (p < 0.05). IGHy offers the benefits of home administration, limited sites of infusion, and low frequency and short duration of infusions desired by patients with PIDD.14,25,96 Data from the IGHy Phase III trial in patients with PIDD revealed that among patients (or their parent, if younger than 14 years) completing a treatment preference questionnaire, 83% (57 of 69 respondents) would choose to continue with IGHy rather than return to the previous SCIG or IVIG therapy.25 The majority of patients and caregivers also stated a preference (“like very much” or “like”) for IGHy regarding the ability to fit into the treatment schedule (80%, 55 of 69 respondents), the frequency of administration (71%, 49 of 69 respondents), the ease of administration (70%, 48 of 69 respondents), and the number of monthly needle sticks (62%, 42 of 68 respondents). For patients requiring lifelong immune globulin treatment, quality-of-life issues should be carefully considered when designing a treatment plan. Each route of administration has inherent attributes different patient populations may prefer. Patient lifestyle and preference should therefore be weighed when selecting a route of administration. Cost Cost may be an important consideration when choosing between IVIG and SCIG, as patients may assume a portion of their healthcare expenses as out-of-pocket costs. Cost considerations include direct costs (i.e., formulation, services of a healthcare provider, and facility charge) and indirect costs (i.e., cost of travel to appointments outside of home and opportunity cost of time lost to traveling to appointments and recovering from adverse reactions). Although there are many considerations, the major differences in cost may arise from a few factors: who administers the immune globulin, the site of administration, the dosage adjustment when switching from IVIG to SCIG, the acquisition costs of individual products, and the payer. Cost calculations, however, may be confounded by the heterogeneity of insurance coverage and payer reimbursement to patients. Patients with private health insurance may have similar coverage for home-and hospital-based care if healthcare expenses exceed the out-of-pocket maximum, regardless of the site of care. However, some insurance companies allow coverage for SCIG only if other standard therapies have failed.76 On the other hand, patients covered under Medicare may face different challenges. For example, patients covered under Medicare Part B with supplemental insurance may be fully covered for the IVIG product when administered at home for a diagnosis of congenital hypogammaglobulinemia, immunodeficiency with increased immunoglobulin M, common variable immune deficiency, Wiskott-Aldrich syndrome, or combined immunity deficiency. Aside from a small group of patients participating in a Centers for Medicare and Medicaid Services demonstration project, there is no coverage for supplies or nursing services for this patient population. Coverage for traditional SCIG for the same limited set of diagnosis codes is available, with additional payment for a pump and supplies. Nursing services are not covered under the benefit; however, most patients are taught to be independent with self-administration. If, however, these patients were additionally diagnosed with another diagnosis outside of the five specified (e.g., other selective immunoglobulin deficiencies and multifocal motor neuropathy), home administration would have to be covered under Medicare Part D, which may leave them with significant out-of-pocket costs. For patients treated with IGHy, the infusion ramp-up period may or may not be covered by Medicare Part B when the infusion is administered in a physician’s office or hospital outpatient setting (based on PIDD diagnosis), and ramp-up is not covered when IGHy is administered at home. After the ramp-up period, IGHy maintenance at home is covered under the same group of ICD-10 codes as conventional SCIG. For reimbursement, IGHy must be administered by a programmable pump, and the pump must be sent to the patient preprogrammed and locked. Nursing is not currently covered at home unless the patient is homebound, and then nursing would be covered by Medicare Part A. For PIDD diagnoses not covered by Medicare Part B, IGHy may be covered by Medicare Part D; however, this typically requires authorization. Nursing and supplies, which are not covered by Medicare Part D, may thus be the responsibility of the patient. However, as Medicare coverage may change based on numerous factors, readers are encouraged to periodically check coverage. Coordination of care by a clinical pharmacist The selection of and adherence to a treatment plan may be a challenging process for patients. They may benefit from a discussion with their healthcare team regarding their medical history and how the route of immune globulin administration may affect tolerability. The discussion may also encompass a consideration of practical issues, such as cost and quality of life, which are important to patients requiring lifelong treatment. A clinical pharmacist is an essential member of the healthcare team to help guide the patient through this process (Figure 1) and to coordinate treatment initiation and continued care. Any changes in the treatment regimen, transitions in the site of care, or changes in health status (i.e., pregnancy or development of comorbid conditions, such as hypertension, hypercholesterolemia, and atrial fibrillation) should also involve a clinical pharmacist. Figure 1 Open in new tabDownload slide Decision tree for selecting i.v. immune globulin (IVIG) versus subcutaneous immune globulin (SCIG) treatment. IGHy may be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic. SCIG is almost always self-administered at home (except in rare cases). IVIG requires venous access and medical supervision. IGHy = immune globulin infusion 10% (human) with recombinant human hyaluronidase (HyQvia). Figure 1 Open in new tabDownload slide Decision tree for selecting i.v. immune globulin (IVIG) versus subcutaneous immune globulin (SCIG) treatment. IGHy may be self-administered by the patient at home or by a healthcare practitioner in the home or at an infusion center, hospital, or clinic. SCIG is almost always self-administered at home (except in rare cases). IVIG requires venous access and medical supervision. IGHy = immune globulin infusion 10% (human) with recombinant human hyaluronidase (HyQvia). For cases in which patients opt for home-based treatment, a clinical pharmacist may collaborate with other healthcare providers (i.e., nurses and physicians) for the transition and monitoring of the patient.99 This transition process typically involves a preadmission assessment of the patient, development of an individualized care plan, and patient education. Because not all patients can self-administer treatment at home, a clinical pharmacist may initially assess a patient’s eligibility for home care, while a nurse may evaluate the home environment for safety and family support structure and the patient and caregiver for willingness to learn about and participate in the treatment. Since immunoglobulin replacement is unique for each patient, the pharmacist and nurse should also develop an individualized care plan that includes creating a proposal for patient education and monitoring. Because education is important for patient safety and adherence to treatment, both the pharmacist and the nurse share responsibility for counseling patients on their condition, treatment, and expected outcomes. They should also teach patients proper drug storage, handling, and administration. Importantly, patients should learn how to identify potential adverse reactions, understand how to intervene, and know when to get help. Once a patient is established in home-based treatment, the pharmacist is responsible for coordinating the ongoing monitoring of the patient between appointments with physicians.99 Pharmacists are responsible for bridging the communication between nurses and physicians on patient status or any other changes that may affect care. For example, the pharmacist may review reports on patient tolerability (i.e., adverse drug reactions) and response to treatment and may suggest modifying the regimen. The pharmacist may also assist in managing infusion-related supplies and overseeing insurance authorizations.100 Patient safety depends on continuing effective communication among members of the healthcare team.99,100 It is particularly important to have pharmacist-to-pharmacist communication when transitioning a patient receiving immune globulin replacement to a new site of care. For example, patients with PIDD may require hospitalization for infections or other unrelated medical conditions. In such cases, the patient’s exact formulation of immune globulin may not be included in the hospital formulary. As pharmacists have knowledge of a specific patient’s medical history and immune globulin products, they can facilitate patient care in such situations. Furthermore, it is important that inpatient pharmacists communicate the patient’s immune globulin treatment with the home infusion pharmacist at discharge; however, a recent survey found that inpatient pharmacists communicate orders for home infusions in only about 10.2% of hospitals.101 From our experience, shared knowledge and communication between pharmacy practitioners and other members of the healthcare team and among sites of care can lead to safer transitions and decreases in the duplication of efforts. Conclusion Selecting a route of administration for and formulation of immune globulin involves the consideration of many factors, including the patient’s medical history, formulation characteristics, formulary stock, payer formulary, and patient preference. A pharmacist is essential in helping the patient navigate the decision-making process and in coordinating care and communication among patients, caregivers, and healthcare providers to monitor patient progress and adherence and ensure safe and efficient transitions of care. Disclosures Dr. Tichy serves on advisory boards and as a consultant for Grifols and Baxalta and is a speaker for Grifols. Ms. Vaughan serves on an advisory board for Baxalta and as a speaker for Grifols. The editorial support provided by Ashfield Healthcare Communications was funded by Baxalta US Inc. Baxalta US Inc. was not involved in the writing of this manuscript. The authors have declared no other potential conflicts of interest. 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TI - Selecting a polyclonal immune globulin treatment for a patient with primary immune deficiency disease: Role of the clinical pharmacist
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp150320
DA - 2016-04-15
UR - https://www.deepdyve.com/lp/oxford-university-press/selecting-a-polyclonal-immune-globulin-treatment-for-a-patient-with-cx0kh0Y0w3
SP - 533
VL - 73
IS - 8
DP - DeepDyve
ER -