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(For additional information see "Intravenous immune globulin: Drug information" and see "Intravenous immune globulin: Patient

drug information") ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or Special Alerts Voluntary Market Withdrawal of Octagam Due to Thromboembolic Events - Updated September 2010 Octapharma USA, Inc, manufacturer of the Octagam brand of intravenous immune globulin 5%, is initiating a voluntary market withdrawal of all currently remaining lots in the U.S. market. This precautionary action is being taken until the cause of previously reported thromboembolic events potentially associated with Octagam has been determined. In August 2010, nine thromboembolic events potentially associated with the product lead to the withdrawal of 31 lots of Octagam from the U.S. market. The company is currently advising customers to immediately quarantine the use of all lots, and to contact Octapharmas customer service department to arrange for immediate product return. Additional information, including affected lot numbers, can be found at: Gammagard Liquid: Market Withdrawal of Certain Lots Due to Adverse Events Reported - June 2010 Baxter BioScience and the Food and Drug Administration (FDA) are notifying healthcare professionals of a voluntary market withdrawal of 2 lots of Gammagard Liquid due to an increased frequency of reports of allergic reactions associated with the affected lots. Customers should contact Baxter BioScience for Urgent Market Withdrawal instructions. For information regarding the withdrawal, including the lots affected, refer to U.S. Brand Names Carimune NF; Flebogamma DIF; Flebogamma [DSC]; Gammagard S/D; Gammagard Liquid; Gammaplex; Gamunex; Octagam; Privigen Medication Safety Issues Sound-alike/look-alike issues: Gamimune N may be confused with CytoGam Immune globulin (intravenous) may be confused with hepatitis B immune globulin

Canadian Brand Names Gamimune N; Gammagard Liquid; Gammagard S/D; Gamunex; IGIVnex; Privigen Therapeutic Category Immune Globulin Dosing (For additional information see "Intravenous immune globulin: Drug information") Children and Adults: I.V.: Primary immunodeficiency disorders: Adjust dose/frequency based on desired IgG concentration and clinical response: Manufacturers dosing recommendations vary based on individual product used. General dosing range: 200-800 mg/kg every 3-4 weeks; maintain a trough IgG concentration of 500 mg/dL Chronic lymphocytic leukemia (CLL): 400 mg/kg/dose every 3-4 weeks Immune (idiopathic) thrombocytopenic purpura: 400-1000 mg/kg/day for 2-5 consecutive days (total dose: 2 g/kg); maintenance dose: 400-1000 mg/kg/dose every 36 weeks based on clinical response and platelet count Pediatric HIV infection: 400 mg/kg/dose every 2-4 weeks in those patients with hypogammaglobulinemia (IgG <400 mg/dL). Consider IGIV for HIV-infected children who have recurrent, serious bacterial infections during a 1-year period. HIV-associated thrombocytopenia: 500-1000 mg/kg/day for 3-5 days Kawasaki disease (AHA guidelines): 2 g/kg as a single dose, given over 10-12 hours; if signs and symptoms persist, retreatment with a second 2 g/kg infusion should be considered. Must be used in combination with aspirin. Hematopoietic guidelines): stem cell transplantation with hypogammaglobulinemia (CDC

Children: 400 mg/kg/month; increase dose or frequency to maintain IgG concentration >400 mg/dL Adolescents and Adults: 500 mg/kg/week Guillain-Barr syndrome: 400 mg/kg/day for 5 days or 1 g/kg/day for 2 days or 2 g/kg as a single dose Refractory dermatomyositis: 2 g/kg per month administered over 2-5 days Refractory polymyositis: 2 g/kg per month administered over 2-5 days

Chronic inflammatory demyelinating polyneuropathy: 400 mg/kg/day for 5 days once each month or 1 g/kg/day for 2 days once each month Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product Injection, powder for reconstitution [preservative free]: Carimune NF: 3 g, 6 g, 12 g [contains sucrose] Gammagard S/D: 2.5 g, 5 g, 10 g [contains albumin (human), glucose, glycine, natural rubber/natural latex in packaging, polyethylene glycol, polysorbate 80] Injection, solution [preservative free]: Flebogamma: 5% [50 mg/mL] (10 mL [DSC], 50 mL [DSC], 100 mL [DSC], 200 mL [DSC]) [contains polyethylene glycol, sorbitol] Flebogamma DIF: 5% [50 mg/mL] (10 mL, 50 mL, 100 mL, 200 mL, 400 mL); 10% [100 mg/mL] (100 mL, 200 mL) [contains polyethylene glycol, sorbitol] Gammagard Liquid: 10% [100 mg/mL] (10 mL, 25 mL, 50 mL, 100 mL, 200 mL) [sucrose free; contains glycine] Gammaplex: 5% [50 mg/mL] (50 mL, 100 mL, 200 mL) [sucrose free; contains glycine, natural rubber/natural latex in packaging, polysorbate 80, sorbitol] Gamunex: 10% [100 mg/mL] (10 mL, 25 mL, 50 mL, 100 mL, 200 mL) [contains glycine] Octagam: 5% [50 mg/mL] (20 mL, 50 mL, 100 mL, 200 mL) [sucrose free; contains maltose, sodium 30 mmol/L] Privigen: 10% [100 mg/mL] (50 mL, 100 mL, 200 mL) [sucrose free; contains L-proline] Generic Equivalent Available: U.S. No Administration Do not administer I.M. or SubQ I.V. infusion over 2-12 hours; for initial treatment, a lower concentration and/or a slower rate of infusion should be used. Administer in separate infusion line from other medications; if using primary line, flush with saline prior to administration. Refrigerated product should be warmed to room temperature prior to infusion. Some products require filtration; refer to individual product labeling. Antecubital veins should be used, especially with concentrations 10% to prevent injection site discomfort. Decrease dose,

rate, and/or concentration of infusion in patients who may be at risk of renal impairment or thrombosis. Decreasing the rate or stopping the infusion may help relieve some adverse effects (flushing, changes in pulse rate, changes in blood pressure). Epinephrine should be available during administration. See Intravenous Immune Globulin Product Comparison for more information. Use Treatment of immunodeficiency syndrome, idiopathic thrombocytopenic purpura (ITP) and B-cell chronic lymphocytic leukemia (CLL); used in conjunction with appropriate anti-infective therapy to prevent or modify acute bacterial or viral infections in patients with iatrogenically-induced or disease-associated immunodepression; autoimmune neutropenia, hematopoietic stem cell transplant patients, Kawasaki disease, pediatric HIV infection, HIV-associated thrombocytopenia, Guillain-Barr syndrome, dermatomyositis, polymyositis, demyelinating polyneuropathies FDA (see FDA website for approval age groups) and NIH Recommendations for the use of IGIV: Primary immunodeficiencies Kawasaki disease Pediatric HIV infection Chronic B-cell lymphocytic leukemia Recent stem cell transplantation Immune-mediated thrombocytopenia Chronic inflammatory demyelinating polyneuropathy Adverse Reactions Cardiovascular: Chest pain, flushing of the face, hypotension, pallor, pulmonary embolism, tachycardia, thromboembolism (see Warnings) Central nervous system: Anxiety, aseptic meningitis syndrome, chills, dizziness, fever, headache, irritability, lightheadedness, malaise, seizures Dermatologic: Contact dermatitis, eczema, erythema, pruritus, urticaria Gastrointestinal: Abdominal pain, gastroenteritis, nausea, toothache, vomiting Hematologic: Hemolytic anemia, transient neutropenia Neuromuscular & skeletal: Arthralgia, back pain, myalgia, rigors Ocular: Conjunctivitis

Renal: Acute renal failure Respiratory: Acute respiratory distress syndrome, difficulty breathing, pulmonary edema (see Warnings), tightness in the chest, transfusion-related acute lung injury (see Warnings) Miscellaneous: Aseptic meningitis, diaphoresis, hypersensitivity reactions, rigors <1%, postmarketing, and/or case reports: Apnea, ARDS, autoimmune pure red cell aplasia (PRCA) exacerbation, bronchopneumonia, bronchospasm, bullous dermatitis, cardiac arrest, chest pain, coma, Coombs' test positive, cyanosis, epidermolysis, erythema multiforme, hepatic dysfunction, hypoxemia, leukopenia, loss of consciousness, pancytopenia, papular rash, pulmonary embolism, seizure, StevensJohnson syndrome, tremor, vascular collapse Contraindications Hypersensitivity to immune globulin, blood products, or any component; IgA deficiency (except with the use of Gammagard S/D or Polygam S/D; these agents are contraindicated in selective IgA deficiency where IgA deficiency is the only abnormality of concern); Privigen contains the stabilizer L-proline and is contraindicated in patients with hyperprolinemia.Patients may experience severe hypersensitivity reactions or anaphylaxis in the setting of detectable IgA levels following infusion of Polygam S/D. The occurrence of severe hypersensitivity reactions or anaphylaxis under such conditions should prompt consideration of an alternative therapy. Polygam S/D is contraindicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern. Precautions Use with caution in patients with a history of cardiovascular disease or thrombotic episodes. Rapid IVIG infusion may be a possible risk factor for vascular occlusive events associated with IVIG. Do not exceed manufacturer's recommended initial infusion rate, use a lower IVIG concentration, and advance slowly in patients at risk. Monitor for adverse events during and after the infusion. Discontinue administration with signs of infusion reaction (fever, chills, nausea, vomiting, and rarely shock). Risk of adverse events may be increased with initial treatment, when switching brands of immune globulin, and with treatment interruptions of >8 weeks. Assure that patients are not volume depleted prior to the initiation of an IVIG infusion. Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer. Response to live vaccines may be reduced following immune globulin treatment, refer to package insert or current practice guidelines for recommendations on separation intervals. Products may contain maltose, sorbitol, sucrose, and some packaging may contain latex. Warnings

Acute renal dysfunction (increased serum creatinine, oliguria, acute renal failure, osmotic nephrosis) can rarely occur [U.S. Boxed Warning]; most cases usually occur within 7 days of use (more likely with products stabilized with sucrose). Due to risk of renal dysfunction, use caution in patients with renal disease, diabetes mellitus, volume depletion, sepsis, paraproteinemia, the elderly, and concomitant use of nephrotoxic medications; discontinue if renal function deteriorates. Reports of noncardiogenic pulmonary edema with severe respiratory distress, hypoxemia, and fever occurring within 1-6 hours after a dose have occurred. Thrombotic events have been reported; patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, impaired cardiac output, hyperviscosity/hypercoagulable disorders, and prolonged periods of immobilization. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur; distinguishing true hyponatremia from a pseudohyponatremia as treatment aimed at decreasing free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a higher risk of thrombotic events. Hypersensitivity and anaphylactic reactions can occur; a severe fall in blood pressure may rarely occur with anaphylactic reaction; immediate treatment (including epinephrine 1:1000) should be available. Aseptic meningitis syndrome has been reported which usually starts within several hours to 2 days following IVIG. Symptoms include severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Aseptic meningitis syndrome may occur more frequently with high dose (2 g/kg) therapy. Intravenous immune globulin has been associated with antiglobulin hemolysis; monitor for signs of hemolytic anemia. High-dose regimens (1 g/kg for 1-2 days) are not recommended for individuals with fluid overload or where fluid volume may be of concern. Drug Interactions Vaccines (Live): Immune Globulins may diminish the therapeutic effect of Vaccines (Live). Management: Live organism vaccination should be withheld for up to six months following immune globulin administration. Live vaccine given immediately prior to immune globulin administration may require repeat vaccination. Exceptions: Yellow Fever Vaccine. Risk D: Consider therapy modification Pregnancy Risk Factor C (show table) Pregnancy Implications Reproduction studies have not been conducted. Immune globulins cross the placenta in increased amounts after 30 weeks gestation. Intravenous immune globulin has been recommended for use in fetal-neonatal alloimmune thrombocytopenia and pregnancyassociated ITP. Monitoring Parameters Platelet count, blood pressure, vital signs, Quantitative Immunoglobulins (QUIGS), trough IgG concentration; periodic monitoring of renal function tests, including BUN,

serum creatinine, and urine output in patients with an increased risk for developing acute renal failure; signs and symptoms of hemolysis; hemoglobin and hematocrit; signs of infusion reaction or anaphylaxis Stability Do not mix with other drugs or I.V. infusion fluids. Stability is dependent upon the manufacturer and brand. Do not freeze. Dilution is dependent upon the manufacturer and brand. Gently swirl; do not shake; avoid foaming. Do not mix products from different manufacturers together. Discard unused portion of vials. Carimune NF: Prior to reconstitution, store 30C (86F). Reconstitute with NS, D5W, or SWI. Following reconstitution, store under refrigeration. Begin infusion within 24 hours. Flebogamma: Store at 2C to 25C (36F to 77F). Dilution is not recommended. Gammagard Liquid: May dilute in D5W only. Prior to use, store at 2C to 8C (36F to 46F) for up to 36 months; do not freeze. May store at room temperature of 25C (77F) within the first 24 months of manufacturing. Storage time at room temperature varies with length of time previously refrigerated; refer to product labeling for details. Gammagard S/D: Store at 25C (77F). Reconstitute with SWI; may store diluted solution under refrigeration for up to 24 hours. Gamunex: May be stored for up to 36 months at 2C to 8C (36F to 46F); may be stored at 25C (77F) for up to 6 months. Dilute in D5W only. Octagam: Store at 2C to 25C (36F to 77F). Privigen: Store at 25C (77F); do not freeze (do not use if previously frozen). Protect from light. If necessary to further dilute, D5W may be used. Mechanism of Action Replacement therapy for primary and secondary immunodeficiencies; interference with Fc receptors on the cells of the reticuloendothelial system for autoimmune cytopenias and ITP Pharmacokinetics (Adult data unless noted) Half-life: 21-29 days Patient Information (For additional information see "Intravenous immune globulin: Patient drug information") Notify physician of any sudden weight gain, fluid retention/edema, decreased urine output, and/or shortness of breath

Nursing Implications Appropriate agents for treatment of a hypersensitivity reaction (eg, epinephrine, diphenhydramine) should be readily available; patients may need to be pretreated with an antipyretic, antihistamine, and/or corticosteroid to prevent chills and fever; adverse reactions may also be alleviated by decreasing the rate or the concentration of infusion or utilizing a different IGIV preparation

INTRODUCTION Immune globulin is used in the treatment of an array of disorders, including primary and secondary immune deficiency states and a variety of autoimmune and inflammatory disorders (table 1) [1,2]. Routes of administration Immune globulin may be administered by different routes: Intravenously (Immune globulin, intravenous (human) will be referred to as "IVIG" in this review, because this term is commonly used by clinicians, although the abbreviation used by industry and various regulatory agencies is "IGIV")Subcutaneously (SCIG will be used here, although IGSC is the term preferred by regulatory agencies), orIntramuscularly (IM ISG) Multiple products are available, which vary in concentration of IgG, additives and stabilizers, and IgA content (see 'Production and composition' below). Most products are labeled for a specific route of administration. Only one product marketed in the US is labeled for both intravenous and subcutaneous administration, Gamunex-C. However, anecdotal reports suggest that most intravenous products are well tolerated by the subcutaneous route. Subcutaneous and intramuscular products are generally more concentrated than intravenous preparations and should not be given intravenously. (See "Subcutaneous and intramuscular immune globulin therapy".) This topic will review the indications, proposed mechanisms of action, production, composition, administration, and pharmacokinetics of immune globulin. The use of immune globulin in the treatment of specific disease states and the adverse effects of intravenous immune globulin are discussed separately. (See "Intravenous immune globulin in hematologic disorders" and "Immune globulin therapy in primary immunodeficiency" and "Overview of polyneuropathy" and "Treatment and prognosis of Guillain-Barr syndrome in adults" and "Initial treatment and prognosis of Kawasaki disease" and "Intravenous immune globulin: Adverse effects".) BACKGROUND The first use of immunoglobulin therapy was probably in the late 19th century when animal sera came into use for the treatment of tetanus, diphtheria and other infectious diseases. Immune horse sera were utilized as treatment for a number of infectious disorders, although the utility of sera was limited by their propensity to cause anaphylaxis, serum sickness, and other immunologic reactions. (See "Serum sickness and serum sickness-like reactions".) Immune serum globulin preparations made from pooled human plasma became available during World War II, and their efficacy in preventing hepatitis and measles was

rapidly appreciated [3]. In the 1950s, passive intramuscular immunization with the immunoglobulin fraction of pooled normal human sera was found to have a dramatic impact on the frequency of sepsis and severe invasive bacterial infections in subjects lacking immunoglobulins [4]. Intravenous preparations of immune globulin first became available in the 1960s, although these contained impurities and protein aggregates that caused severe anaphylactoid reactions, presumably by activation of the complement cascade, and were not widely used [5]. Subsequent refinements allowed for safe administration of higher doses intravenously that more closely approximated physiologic levels. INDICATIONS, USAGE PATTERNS, AND COST ISSUES Indications Immune globulin is approved by the United States Food and Drug Administration (US FDA) for use in the following conditions [1,6,7]: Idiopathic thrombocytopenic purpuraPrimary immunodeficiency statesSecondary immunodeficiency in chronic lymphocytic leukemiaPediatric HIV infectionKawasaki syndromePrevention of graft versus host disease and infection in adult hematopoietic cell transplantationChronic inflammatory demyelinating polyneuropathy (CIDP) In addition to the above approved uses, there are many other disorders for which immune globulin has been administered (table 1) [1]. One medical center reviewed the use of IVIG during a single calendar year. A total of 194 patients received 48,230 grams of IVIG, at an estimated cost of four million US dollars [6]. The six most common conditions for which IVIG was used included: Chronic neuropathy 29 percentSecondary hypogammaglobulinemia 18 percentIdiopathic thrombocytopenic purpura 10 percentPrimary hypogammaglobulinemia 9 percentRenal transplantation 6 percentMyasthenia gravis 5 percent A 2010 analysis performed in Canada concluded that the estimated cost of treating one patient with chronic neuropathy (eg, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy) was approximately 70,000 dollars per year [8]. Based on this, the cost of the same treatment in the US could be estimated at 100,000 to 150,000 dollars annually. Hyperimmune globulin preparations Several immune globulin products are prepared from plasma of individuals with high titers of specific antibodies to certain pathogens and/or from plasma of hyper-immunized donors. These "hyperimmune" globulins impart temporary, passive immunization to the target pathogen, or can be used to neutralize certain antigens, most importantly, the Rh(D) antigen on fetal erythrocytes of Rh- mothers. Preparations have been made available for use against hepatitis B (HBIG), cytomegalovirus (CMVIG), varicella zoster (VariZIG), rabies, vaccinia, tetanus, and botulinum toxin. Certain animal antisera are also used, such as pertussis and botulism antitoxins, and in some countries, tetanus and rabies antisera. It is theoretically possible to produce a hyperimmune globulin from convalescent plasma to any organism, which

can safely be used as passive immunization. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Hyperimmune globulins'.) MECHANISMS OF ACTION Immune globulin is believed to have multiple mechanisms of action, most of which are incompletely understood. It has two primary clinical applications: Protection of the recipient against infection, andSuppression of inflammatory and immune-mediated processes Congenital or acquired hypogammaglobulinemia IVIG is given in congenital (primary) hypogammaglobulinemia and other primary immune deficiencies to protect the patient against infection by providing adequate concentrations of antibodies against a broad range of pathogens. (See "Immune globulin therapy in primary immunodeficiency".) IVIG is also used in patients with secondary immunodeficiencies, although less uniformly (table 1). Examples include the following: Progressive hypogammaglobulinemia is common in chronic lymphocytic leukemia (CLL) and is associated with an increased risk of bacterial infections, especially of the respiratory tract. (See "Overview of the complications of chronic lymphocytic leukemia".)Patients undergoing hematopoietic cell transplantation for malignancy are sometimes treated with IVIG to prevent specific viral infections. (See "Prophylaxis of infections in hematopoietic cell transplant recipients", section on 'Antiviral prophylaxis'.)Certain complications of chronic parvovirus B19 infection and HIV infection are treated with IVIG. (See "Treatment and prevention of parvovirus B19 infection", section on 'Chronic infection' and "Diagnosis, treatment and prognosis of HIV-associated neuropathies".)Patients can be treated with IVIG to prevent antibody-mediated transplant rejection. (See "Acute renal allograft rejection: Treatment", section on 'Intravenous immune globulin'.) Autoimmune disorders The mechanisms by which IVIG acts as an antiinflammatory and immunomodulatory agent are believed to include the following [1,9]: IVIG may reduce immune activity by interacting with Fc receptors on effector cells [10,11] or by the presence of anti-idiotypic antibodies directed against idiotypes on circulating autoantibodies. Thus, the efficacy of IVIG in immune (idiopathic) thrombocytopenic purpura may be mediated by prevention of reticuloendothelial uptake of autoantibody-coated platelets through the blockade of Fc-receptors [12,13] and/or down-regulation of their function [14]. (See "Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults", section on 'Intravenous immunoglobulin'.) On the other hand, anti-idiotypic antibodies directed against antineutrophil cytoplasmic antibodies (ANCA) and HLA-specific antibodies may be responsible for the possible benefit in Wegener's granulomatosis and highly sensitized patients awaiting transplantation, respectively [15-20]. These anti-idiotypic antibodies provide a negative feedback signal capable of downregulating the pathogenic immune response; this effect is mediated by direct binding either to circulating autoantibodies (leading to increased clearance) or to B cell immunoglobulin receptors bearing the specificity of the

autoantibody. Anti-idiotypic antibodies are believed to account for the ability of IVIG to neutralize antibodies to factor VIII ("inhibitors"), which have developed in hemophilia patients treated with exogenous Factor VIII concentrates [16]. It is not clear whether, in any given disease state, all the IgG molecules present in the polyclonal IgG preparation, or only a small sub-fraction are responsible for the clinically beneficial effect. For example, when IVIG is used to neutralize certain autoantibodies or anti-HLA antibodies, only that small fraction of IgG molecules with specific anti-idiotypic activity are likely to be needed. In addition, laboratory evidence suggests that some IgG molecules with heavily sialylated Fc regions may preferentially exert antiinflammatory effects. Nevertheless, at present, commercial products are not characterized for, nor differentiated by, their content of antibodies of different specificities or chemical compositions. Other possible mechanisms of action include the following: IVIG may promote solubilization and clearance of immune complex deposits [11]. This may be important in an immune complex disorder, such as membranous nephropathy [20]. (See "Treatment of idiopathic membranous nephropathy".)IVIG may contain neutralizing antibodies. In diarrhea-induced hemolytic-uremic syndrome, example, IVIG may provide antibodies against the verocytotoxins that appear to be responsible for the disease [21]. IVIG also contains antibodies to staphylococcal toxin and streptococcal "superantigens." Superantigens are proteins that can bind simultaneously to MHC class II antigens and to the non-antigen-binding region of whole families of T cell receptors, thereby stimulating large numbers (up to 20 percent) of T cells [22,23]. Antisuperantigen antibodies may explain the apparent efficacy of IVIG in staphylococcal toxic shock syndrome, severe group A streptococcal infections, and Kawasaki disease; their possible role in the treatment of the hemolytic-uremic syndrome is unproven. (See "Treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".)IVIG may accelerate the fractional rate of catabolism of IgG by increasing the total plasma concentration of IgG, thereby preferentially eliminating pathogenic IgG molecules by saturating the transport system which preserves IgG in the plasma with normal IgG molecules [24,25]. At normal plasma total IgG concentrations, IgG appears to be protected from catabolism by binding to the molecule FcRn on vascular endothelial cells [22]. When this receptor is saturated, as in hypergammaglobulinemia and/or with high dose therapy, IgG is no longer protected, and is degraded according to its relative serum level.IVIG may alter the number of T cells and T cell subsets [26-28]. One study of 46 patients treated with IVIG found an approximately 35 percent reduction in lymphocytes in 95 percent of patients, with a selective reduction of T, but not B or interleukin 2 receptor positive cells [28].IVIG may increase the effect of regulatory T cells, which are engaged in dominant control of self-reactive T-cells, contributing to the maintenance of immunologic self-tolerance [9].IVIG can serve as an alternate binding site or "sink" or C3b, diverting it from binding to targets of complement activation [29]. IVIG may also neutralize the inflammatory actions of the complement fragments, C3a and C5a, via a physical association between these anaphylatoxins and the constant region of F(ab)'2 [30]. PRODUCTION AND COMPOSITION Production of IVIG begins with pooled human plasma from several thousand screened volunteer donors. Cold alcohol fractionation (by the Cohn or Kistler-Nitschmann procedures) is used to isolate the immunoglobulin-

containing fraction. This is followed by further purification techniques, including additional precipitation steps to remove non-IgG proteins and ion exchange chromatography. Most IgG preparations also undergo several specific treatments to inactivate or removal potentially present blood-borne pathogens. These include low pH treatment, fatty acid treatment, solvent-detergent treatment, heat-treatment (pasteurization) and/or nanofiltration. The World Health Organization has published minimum standards for manufacturing IVIG preparations [31,32]: IVIG should be extracted from a pool of at least 1000 individual donors.It should contain as little IgA as possible.The IgG molecules should be modified biochemically as little as possible and possess opsonizing and complement-fixing activities.It should be free from preservatives or stabilizers that might accumulate in vivo. There are slight differences in the manufacturing procedures utilized by the different producers, and different stabilizers are used in the excipients (table 2 and table 3). However, the final preparations are highly purified (>90 percent) polyvalent IgG.

Constituents IVIG preparations contain highly purified (>90 percent) polyvalent IgG. Products differ in storage requirements and shelf life. Stabilizers may include sugars, such as sucrose, glucose, or maltose. Some IVIG products contain amino acids such as glycine or proline. The sodium content of different products also varies. The resulting products are generally believed to be equally effective for treatment of the autoimmune and immunodeficiency disorders. However, they differ from each other in ways that may be important in a particular patient. As an example, the variability in IgA levels may be important in rare patients who have selective IgA deficiency and anti-IgA antibodies. Certain stabilizers may be associated with adverse effects in some patients: sucrose can cause osmotic nephropathy, maltose can alter readings of certain glucose meters, and glucose may be problematic for diabetics. (See "Immune globulin therapy in primary immunodeficiency", section on 'Constituents and production methods'.) OVERVIEW OF DOSING Dosing varies depending upon whether IVIG is administered for the purpose of preventing infections in immune deficient patients or suppressing an inflammatory or autoimmune process. Lower intravenous doses are administered in immunodeficiency disorders involving immunoglobulin deficiency or dysfunction. Typical doses start at 300 to 400 mg/kg per month, although doses as high as 800 to 900 mg/kg are needed in order to keep some patients infection-free [33]. Subcutaneous preparations are widely used in immunodeficiency because the gradual and steady introduction of IgG into the patient's circulation appears to have advantages. In addition, SCIG is frequently self-administered at home, which is more convenient for many patients. (See "Immune globulin therapy in primary immunodeficiency" and "Subcutaneous and intramuscular immune globulin therapy".)Higher doses are given when IVIG is administered for its antiinflammatory or immunomodulatory properties. In many cases, the intent of therapy is to flood the circulation with IgG with the goal of interrupting the pathologic immune process. Intravenous administration is usually required to administer the desired quantities. As

examples, patients with Kawasaki disease are usually given 2 grams/kg as a single dose as part of initial therapy, and patients with immune thrombocytopenia are treated with 1 to 2 grams/kg. Dosing for specific diseases is discussed in the appropriate topic reviews. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis" and "Treatment of Guillain-Barr syndrome in children" and "Intravenous immune globulin in hematologic disorders".) Serum trough levels of IgG may be used as one criterion of the adequacy of treatment in patients with hypogammaglobulinemia receiving IVIG. In contrast, it is not clear that this measurement is relevant in patients with autoimmune disorders, where the endpoint is clinical improvement. (See "Immune globulin therapy in primary immunodeficiency", section on 'Target trough levels'.) Pharmacokinetics Bioavailability is, by definition, 100 percent with intravenous administration. The fate of an administered dose is entirely dependent upon its distribution, degradation and excretion. Studies in both humans and animals have shown that the degradation rate of IgG is dependent upon the absolute concentration of IgG, with higher concentrations (serum levels) resulting in more rapid catabolism once the recycling capacity of FcRn has been exceeded [34,35]. The clinical significance of this observation when choosing the dosage of IVIG is not clear. The rate of metabolism of IVIG may vary with the clinical state. One study, for example, evaluated 15 patients with chronic lymphocytic leukemia who were given 400 mg/kg of IVIG every three weeks; the mean half-life was 39.1 days (SD = 9.6 days) [34]. This is longer than the half-life of approximately three to four weeks observed in patients with primary immunodeficiencies or in normal volunteers given IVIG. The rate of metabolism does not appear to increase with chronic administration. However, detailed pharmacokinetic studies are not available in patients with autoimmune diseases given repeated high dosages of IVIG. SELECTING A PRODUCT The majority of patients tolerate most products with a minimum of adverse events, with simple premedications and at an acceptable infusion rate. Thus, for many patients, selection of a product to conform to local dispensing or formulary preferences is fine, particularly when a limited duration of therapy is anticipated. However, there are some circumstances in which one product may be more suitable than another for a given patient. A table of the properties of the IGIV products currently available in the United States is available (table 2 and table 3). Some products contain higher titers of antibodies to human blood group substances than other products, and may cause Coombs positivity, although clinically significant hemolysis is unlikely [36]. Primary immune deficiency patients, who generally require life-long therapy, often have fewer adverse effects with one preparation rather than with others. In such patients, administration of alternative products should only be done with the clinician's approval. If an alternative product must be given to a patient on chronic therapy, it is usually prudent to use slow infusion rates and monitor the patient closely. (See "Immune globulin therapy in primary immunodeficiency".) It should be noted that the use of subcutaneous immune globulin (SCIG) has not been extensively studied in autoimmune/inflammatory disorders. No SCIG products have been licensed for use in autoimmune/inflammatory diseases in the US, but several small studies in neuromuscular disease have shown promising results [37].

Examples of patients that may be better served by certain IVIG products include the following: Patients with severe IgA deficiency (ie, serum levels below the limit of detection of standard laboratories) can produce anti-IgA antibodies, which have been implicated in causing anaphylaxis to IgA-containing blood products, including IVIG. Such patients may require products low in IgA, although this is unpredictable, as most IgA deficient patients tolerate products that contain IgA. Nevertheless, most clinicians choose a product with very low IgA content when treating a patient with undetectable levels of IgA. (This may be less important in patients with Xlinked (Bruton's) agammaglobulinemia, since those patients cannot make the IgE and IgG antibodies that cause anaphylactic reactions). Alternatively, IgA deficient patients could receive immune globulin by the subcutaneous route, as serious systemic reactions are rare with this route of delivery, and induction of tolerance to IgA in treated individuals has been reported [38]. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'IgA deficient patients'.)Patients with renal impairment may need products with low sucrose due to an increased risk of osmotic renal injury with this particular sugar [39-41]. (See "Intravenous immune globulin: Adverse effects", section on 'Renal complications'.)Patients with diabetes should be careful with maltosecontaining products, as certain types of glucose meters cannot discriminate between maltose and glucose. Diabetics should also be careful with glucose-containing products. (See "Blood glucose self-monitoring in management of diabetes mellitus", section on 'Sources of error'.)Patients who have trouble tolerating increased intravascular volume may do better with preparations that are low in sodium and albumin. Some products may contain as much as 30 mg/mL (3 percent) albumin, in addition to the IgG itself.Patients with hyperviscosity syndromes (cryoglobulinemia, monoclonal gammopathies, or polyclonal hyperglobulinemia, including some children with HIV), extremely elevated lipoprotein concentrations, or who are bedridden may be at higher risk for thrombotic complications and should be given preparations with lower osmolality. (See "Intravenous immune globulin: Adverse effects", section on 'Thrombotic complications'.) Adverse effects due to amino acid stabilizers, such as glycine or proline, have not been reported. However, proline-containing products should not be given to patients with hyper-prolinemia. ADMINISTRATION In the US, IVIG is usually administered in an infusion center or health care facility. However, IVIG may be infused in the home setting, usually by an experienced infusion nurse. In some situations, this practice has been found to be more cost effective and result in improved quality of life measures [33,42]. The first few infusions should be administered with medical supervision, regardless of the longerterm plan. Consent Many institutions require signed consent before any blood product is administered, and we document in the records of all of our patients that potential risks have been explained and that the patient/parent has received this information, has been given the opportunity to ask questions, and has given consent to receiving IGIV

before initiating therapy. Potential complications and risks of IVIG therapy are reviewed in detail separately. (See "Intravenous immune globulin: Adverse effects".) Pre-treatment testing Before starting treatment with IVIG, patients should be tested for exposure to infection with known blood borne pathogens, although the risk of transmission of viruses and prions is felt to be extremely low. (See "Intravenous immune globulin: Adverse effects", section on 'Risk of transmission of blood borne pathogens'.) It should be noted that serologic tests for exposure to or infection with common pathogens such as Epstein-Barr virus, CMV and Hepatitis B will become positive in recipients of IgG therapy because of the passively transferred antibody. Therefore, if it is important to know if a patient has been infected with one of these organisms (for example, CMV in a potential transplant recipient), antibody tests should be done before IgG is administered, and/or PCR testing should be used. We perform testing for HIV and hepatitis A, B, and C, and measure transaminases and renal function before initiating immune globulin therapy by any route. This may establish that infection occurred before the IgG was administered and was not transmitted iatrogenically. In patients who are receiving therapy to treat defective antibody production, nucleic-acid based tests (PCR or RT-PCR) for pathogens are preferred to antibody-based tests. Some immunologists also include tests for exposure to parvovirus B19 and direct Coombs' tests in their baseline screening. Product handling and storage Liquid products and reconstituted solutions of lyophilized products that have been stored in refrigerators should be allowed to come to room temperature before administration, to minimize adverse events. However, IgG solutions should not be microwaved or otherwise heated because the immunoglobulin protein could become denatured. Reconstituted lyophilized products should be inspected before administration to assure that the product has been completely dissolved and that the solution is uniform, although vigorous mixing causing excessive foaming should be avoided. All products should be inspected for the presence of particulates and/or evidence of tampering before pooling or administration to the patient. Premedications Acetaminophen or NSAIDs (with the exception of aspirin, which is not recommended for children) may relieve and/or prevent phlogistic and anaphylactoid symptoms and are therefore frequently given 30 minutes prior to the infusion. The following are commonly used: Pediatric doses apply to infants through age 11 or weight up to 35 kg. Adult doses apply to children >age 11 and weight >35 kg. Acetaminophen, 10 to 15 mg/kg (max 500 mg) orally for children or 650 to 1000 mg orally for adults, orIbuprofen, 10 mg/kg (max 400 mg) orally for children or 400 to 800 mg orally for adults H1 antihistamines are also frequently given before or at the beginning of the infusion. Examples include:

Diphenhydramine, 1 mg/kg (max 50 mg) orally/IV/IM for children or 25 to 50 mg orally/IV/IM for adults, orCyproheptadine, 0.08 mg/kg (max 4 mg) orally for children or 4 mg orally for adults, which may be helpful in preventing headache Glucocorticoids are also frequently given, particularly before the initial infusion, or when changing products. Their mechanism of action suggests that they might be most effective if given one to two hours before the infusion is initiated. This may be done conveniently by dosing after the preceding meal or when the patient leaves home to come to the infusion site. Commonly used oral regimens include the following: Prednisone or prednisolone in children, 0.5 to 1 mg/kg (max 40 mg), orPrednisone or methylprednisolone in adults, 40 to 60 mg Some clinicians administer intravenous glucocorticoids (instead of oral) as soon as IV access is established and then wait 30 minutes before beginning the IGIV infusion. The following agents and doses can be used in this manner: Methylprednisolone, 0.5 to 1 mg/kg (max 40 mg) IV in children or 40 to 60 mg IV in adultsDexamethasone, 10 or 20 mg IV in adults Hydration with intravenous fluids Patients receiving IVIG should be well-hydrated prior to the infusion. This can be accomplished by ample oral fluid intake or by administration of normal saline before giving the drug. This is particularly important for patients with risk factors for hyperviscosity and/or renal complications of IVIG therapy, such as preexisting renal insufficiency, diabetes mellitus, age greater than 65, paraproteinemia, and concomitant use of nephrotoxic agents. Hydration should be given before IVIG preparations containing sucrose, as well. Most clinicians administer intravenous fluids before starting high dose IGIV, as therapy may be associated with adverse effects due to hyperviscosity, and preparations containing sucrose have been associated with osmotic renal damage. Normal saline, 10 to 20 mL/kg is suggested for this purpose. (See "Intravenous immune globulin: Adverse effects", section on 'Renal complications'.) Infusion rates Many infusion-related adverse effects seem related to the rate of administration. Therefore, it is customary to start each infusion at a slow rate, such as 0.01 mL/kg per min, which would provide 0.5 or 1 mg/kg per min of IgG depending upon whether a 5 or 10 percent solution is being infused, respectively. The infusion rate may then be increased at 15 or 30 min intervals, while monitoring the patient closely for alterations in vital signs or subjective symptoms. If the patient continues doing well, the rate of infusion may be stepped up to 0.02 mL/kg per min, then 0.04 mL/kg per min and in one of two additional increments until a maximum rate of 0.08 mL/kg per min (4 or 8 mg/kg per min if 5 percent or 10 percent solutions are used, respectively) is achieved. Higher rates may be tolerated in selected patients and with preparations that are low in sodium and/or free of high concentrations of sugar as stabilizers. After it has been established that a given patient tolerates a certain product at a specific rate, fewer steps

and/or shorter intervals may be used during the "ramp up", but patients should always be monitored closely because lot-to-lot variation in tolerability may occur. MONITORING Routine monitoring for development of complications of IVIG therapy and blood-borne infections is recommended every 6 to 12 months. (See 'Pre-treatment testing' above.) Serum creatinine (to evaluate for changes in renal function) and a complete blood count with differential (to evaluate for neutropenia and anemia) are also suggested. Since several IVIG products have been associated with positive Coombs' tests and/or frank hemolysis, the Coombs' (direct anti-globulin) test is frequently also used for monitoring. When high-dose IVIG is to be given over two or more days, it is prudent to check for Coombs' positivity before proceeding with the second or subsequent doses [43].

Record keeping Although all currently licensed products in the US are believed to be safe from transmission of blood-borne infections, the risk of disease transmission is always present. The lot number, expiration date, and manufacturer of any immune globulin product (and all other blood products) infused into any patient should be carefully recorded in the medical record. In addition, patients should be encouraged to keep their own logs of this information. VACCINATION OF PATIENTS RECEIVING IMMUNE GLOBULIN Patients receiving immune globulin therapy may fail to respond to vaccination for several reasons. Individuals with immune deficiency may not respond because of their underlying immunologic defect, and those being treated for other disorders may have disease states or concomitant medications that inhibit normal vaccine responses. If a patient has been given immunizations during or within weeks of receiving immune globulin, and subsequently stops therapy, then titers should be checked three to six months after stopping immune globulin to determine if the patient has protective immunity. If titers are not protective, then the immunization(s) should be repeated or, if necessary, immune globulin therapy should be resumed. This is particularly problematic in patients who receive live virus vaccines such as MMR or varicella vaccines while on or within months after receiving immune globulin, since the passively transferred IgG may prevent the viral replication which is necessary for inducing the desired immune response. The American Academy of Pediatrics has made specific recommendations for live vaccines for measles and varicella. (See "Standard immunizations for children and adolescents", section on 'Immune globulin recipients'.) SUMMARY AND RECOMMENDATIONS Immune globulin is used in the treatment of a wide variety of disorders, including primary and secondary immune deficiency states, autoimmune disorders, and inflammatory disorders (table 1). It can be given intravenously, subcutaneously, or intramuscularly. (See 'Introduction' above and 'Indications, usage patterns, and cost issues' above.)Immune globulin is applied clinically for two broad purposes: to protect the recipient from infection, and to suppress immune-mediated or inflammatory disease

processes. (See 'Mechanisms of action' above.)Multiple intravenous products are available, which differ in concentration of IgG, additives and stabilizers, and IgA content (table 2 and table 3). They are considered equivalent in efficacy, although certain products may be preferred for patients with particular disorders. (See 'Production and composition' above.)Lower doses (eg, beginning at 300 to 400 mg/kg per month) are given for replacement therapy in immune deficiency states, although doses should be individualized to keep patients free from infection. Higher doses (eg, 1 to 2 grams/kg per dose) are usually given when IVIG is administered for its antiinflammatory or immunomodulatory properties. Trough serum levels may be monitored to help assess the adequacy of replacement in patients with immunodeficiency, but this measurement is usually not relevant to treatment of autoimmune diseases. (See 'Overview of dosing' above and "Immune globulin therapy in primary immunodeficiency", section on 'Target trough levels'.)Most patients will tolerate most IVIG products, although there are certain concomitant conditions that should prompt consideration of specific IVIG preparations. These include severe IgA deficiency with undetectable levels of serum IgA, renal dysfunction, diabetes, disorders of hyperviscosity, and disorders that predispose patients to volume overload (eg, heart failure). The experience of patients on chronic therapy should be considered since these individuals may tolerate one product better than others. (See 'Selecting a product' above.)Informed consent and baseline testing for HIV and hepatitis viruses, as well as renal, hepatic, and hematologic disorders should be performed prior to administration. (See 'Consent' above and 'Pre-treatment testing' above.)Patients should be well-hydrated and premedications are often given, at least for the first few infusions. Since most adverse reactions to IVIG are rate-related, nave patients and those in whom brands are being switched should have their infusions initiated slowly under close observation. Rates may then be increased stepwise, as tolerated. (See 'Administration' above.)