VA Class:IM500

AHFS Class:

• Antitoxins and Immune Globulins 80:04

Generic Name(s):

• Immune Globulin, Human

• Immune Globulin Intramuscular, Human

• Immune Globulin Intravenous, Human

• Immune Globulin Subcutaneous, Human

Immune globulin IM (IGIM), immune globulin IV (IGIV), and immune globulin subcutaneous are sterile, nonpyrogenic preparations of globulins containing many antibodies normally present in adult human blood.125,154,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Immune Globulin IM (IGIM)

Hepatitis A Virus Infection

IGIM (GamaSTAN^®) is used to provide short-term passive immunity to hepatitis A virus (HAV) infection for preexposure or postexposure prophylaxis in certain susceptible individuals who are at risk of or have been exposed to the virus.105,115,154,186

HAV usually is transmitted via the fecal-oral route either by person-to-person contact or ingestion of contaminated food or water.105,115,186 Transmission is facilitated by poor personal hygiene, poor sanitation, and intimate contact (e.g., household or sexual exposure).105,115,186 Common-source infections from contaminated food and water also occur.105,186 Illicit drug use is another common source of HAV infection.105,186,199,200 The incubation period for HAV infection following exposure to the virus ranges from 15-50 days and averages 28 days.105,115 For further information on types of exposure, risk of exposure, and management of exposure, see Uses in Hepatitis A Virus Vaccine Inactivated 80:12.

Primary immunization with hepatitis A virus vaccine inactivated (hepatitis A vaccine) using an age-appropriate schedule is preferred for HAV preexposure and postexposure prophylaxis in most adults, adolescents, children, and infants 12 months of age or older, unless contraindicated, since active immunization provides long-term protection.105,115,186 IGIM can be used alone for short-term protection against HAV in susceptible individuals when hepatitis A vaccine is unavailable or cannot be used (e.g., infants younger than 12 months of age†, individuals hypersensitive to vaccine components).105,115,186 Combined passive immunization with IGIM and active immunization with hepatitis A virus vaccine should be used for HAV preexposure prophylaxis in certain individuals to ensure protection against HAV when exposure may occur before protection is provided by the vaccine (e.g., travelers whose departure is imminent).105,115,186 A combined regimen of active immunization with hepatitis A vaccine and passive immunization with IGIM also is recommended for HAV postexposure prophylaxis in susceptible individuals 12 months of age or older who are immunocompromised or have chronic liver disease and also may be considered in healthy adults older than 40 years of age since such individuals may have lower seroconversion rates after vaccination and are at increased risk of more severe manifestations of HAV.115,186 For information regarding recommendations for vaccination against HAV infection, see Uses in Hepatitis A Virus Vaccine Inactivated 80:12.

Although IGIM is 80-90% effective in preventing symptomatic HAV if administered within 2 weeks of exposure,105,186 monovalent hepatitis A vaccine appears to be as effective as IGIM for HAV postexposure prophylaxis in healthy individuals 1 through 40 years of age if administered within 2 weeks of exposure.105,287 The vaccine offers certain advantages over IGIM (e.g., induces active immunity and longer protection, more readily available, easier to administer, greater patient acceptance).186 However, if only IGIM or only hepatitis A vaccine is available at the time HAV postexposure prophylaxis is needed, either product can be administered, unless contraindicated.186

When HAV postexposure prophylaxis is indicated, hepatitis A vaccine and/or IGIM as appropriate should be administered as soon as possible (within 2 weeks of exposure).105,115,186 Data are not available regarding efficacy of hepatitis A vaccine or IGIM administered for HAV postexposure prophylaxis more than 2 weeks after exposure.105,115 Routine screening of contacts for serologic markers of HAV infection prior to administration of HAV postexposure prophylaxis is not recommended because such screening would delay prophylaxis.105,186

IGIM is recommended for HAV postexposure prophylaxis in infants younger than 12 months of age†.105,186 For HAV postexposure prophylaxis in susceptible, healthy individuals 12 months through 40 years of age, the US Public Health Service (USPHS) Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) prefer use of monovalent hepatitis A vaccine.105,186 For HAV postexposure prophylaxis in susceptible, healthy adults older than 40 years of age, ACIP recommends use of monovalent hepatitis A vaccine and states that concomitant use of IGIM (administered at a separate site) can be considered based on risk assessment.186

ACIP states that individuals 12 months of age or older who are immunocompromised or have chronic liver disease should receive a combined regimen of monovalent hepatitis A vaccine and IGIM (at separate sites) for HAV postexposure prophylaxis.186

Travelers

HAV is one of the most common vaccine-preventable diseases acquired during travel.115,186 Travelers to areas with intermediate or high levels of endemic HAV are at substantial risk of acquiring the disease.115,186 The risk increases with the duration of travel and is highest for those living in or visiting rural areas, trekking in back country, or eating or drinking frequently in settings with poor sanitation.115,186 However, cases of travel-related HAV can occur in travelers who have standard tourist itineraries and accommodations and food and beverage consumption behaviors considered low risk.115,186 The CDC website ([Web]) should be consulted for information regarding which countries have intermediate or high levels of HAV endemicity.115

ACIP and CDC recommend HAV preexposure prophylaxis in all susceptible individuals (i.e., unvaccinated, partially vaccinated, or never infected) traveling for any purpose, frequency, or duration to areas where HAV endemicity is intermediate or high.115,186 In addition, because of the complexity of determining HAV endemicity globally, some experts advise individuals traveling outside the US to consider HAV preexposure prophylaxis regardless of their travel destination.115,186

Primary immunization with a complete age-appropriate schedule of hepatitis A vaccine before travel is preferred for HAV preexposure prophylaxis in adults, adolescents, children, and infants 12 months of age or older, unless contraindicated, since active immunization provides long-term protection.186 A single dose of hepatitis A vaccine administered before departure can provide adequate protection for most healthy travelers.115 IGIM should be used for HAV preexposure prophylaxis when the vaccine is unavailable or cannot be used (e.g., in infants younger than 12 months of age†, individuals hypersensitive to vaccine components) or when the traveler chooses not to receive the vaccine, provided that only short-term protection is required.105,115,186,231 For optimal protection in travelers at greatest risk for HAV (adults older than 40 years of age or individuals with altered immunocompetence, chronic liver disease, or other chronic medical condition) who plan to depart within 2 weeks, ACIP and CDC recommend that a single dose of IGIM be given for preexposure prophylaxis concurrently with the first dose of hepatitis A vaccine (at a separate site).115,186

Recommendations for HAV postexposure prophylaxis in travelers who are not adequately immunized with hepatitis A vaccine are the same as those for other individuals.115

Household or Sexual Contacts

HAV postexposure prophylaxis is recommended for all susceptible individuals who had household or sexual (heterosexual or homosexual) contact (within the past 2 weeks) with an individual with serologically confirmed HAV infection.105,186

Staff and Attendees of Child-care Facilities and Schools

If HAV infection occurs in one or more attendees of a child-care facility that cares for children in diapers or in household contacts of 2 or more of the attendees (within the past 2 weeks), ACIP and AAP recommend HAV postexposure prophylaxis for all staff and attendees who are not adequately vaccinated against HAV.105,186 If HAV infection occurs in one or more employees of a child-care facility, HAV postexposure prophylaxis for other staff and for attendees should be considered based on the duties, hygienic practices, and presence of symptoms in the index case while at work.186 If HAV infection is identified in an employee or attendee in a child-care facility in which all children are toilet trained, HAV postexposure prophylaxis should be considered only for susceptible contacts of the index case.105,186

Schoolroom exposure to HAV in primary or secondary schools generally does not pose an appreciable risk of infection and HAV postexposure prophylaxis is not indicated for pupils and teachers if only a single case occurs and the source of infection is outside the school.105,186 However, HAV postexposure prophylaxis is recommended for susceptible close personal contacts of the index case if an epidemiologic investigation indicates that HAV transmission has occurred (e.g., among students in a school).105,186

Food Handlers

If HAV infection is diagnosed in an individual who handles food and common-source transmission of the disease is likely, HAV postexposure prophylaxis is recommended (within 2 weeks) for coworkers of the food handler.186 Because common-source transmission is unlikely, administration of HAV postexposure prophylaxis to patrons usually is not indicated but may be considered if, during the time the food handler was likely to be infectious, the food handler handled (without gloves) uncooked or cooked foods and the food handler had diarrhea or poor hygienic practices and patrons can be identified and given prophylaxis within 2 weeks of exposure.186 In settings in which repeated exposures to HAV may have occurred (e.g., institutional cafeterias), stronger consideration of HAV postexposure prophylaxis is warranted.186 In the event of a common-source outbreak, HAV postexposure prophylaxis should not be administered to exposed individuals after cases have begun to occur because the 2-week period during which such prophylaxis is effective will have been exceeded.186

Healthcare Personnel

Healthcare personnel are not at substantially increased risk for HAV infection as the result of occupational exposures and healthcare-associated HAV transmission is rare.186,235 HAV postexposure prophylaxis within the healthcare setting should be considered on a case-by-case basis if the risk for HAV exposure is considered high.186

Neonates

Neonates of HAV-infected mothers do not usually need HAV postexposure prophylaxis since perinatal transmission of HAV is rare.105 Although efficacy has not been established, some experts suggest that the infant† should receive IGIM for HAV postexposure prophylaxis if the mother's symptoms began between 2 weeks before and 1 week after delivery.105

Measles

IGIM (GamaSTAN^®) and IGIV† are used for postexposure prophylaxis to prevent or modify symptoms of measles (rubeola) in susceptible individuals exposed to the disease less than 6 days previously.105,133,154 Immune globulin should not be used in an attempt to control measles outbreaks.133

Individuals born before 1957 and individuals with documentation of adequate vaccination against measles at 12 months of age or older, laboratory evidence of measles immunity, or laboratory confirmation of prior measles infection usually can be considered to have presumptive evidence of measles immunity.105,133 Other individuals should be considered susceptible to measles.133

Because administration of vaccine containing measles virus vaccine live (e.g., measles, mumps, and rubella virus vaccine live; MMR) within 72 hours of initial measles exposure may provide some protection against infection or modify the clinical course of measles and also provides future protection in individuals who do not contract the disease, ACIP and AAP recommend that susceptible individuals receive postexposure vaccination with a vaccine containing measles virus vaccine live within 72 hours after exposure, unless the vaccine is contraindicated.105,133 Postexposure vaccination is preferred to postexposure prophylaxis with immune globulin for most susceptible individuals 12 months of age or older who are exposed to measles in most settings (e.g., day-care facilities, schools, colleges, health-care facilities), provided the vaccine can be administered within 72 hours of the exposure and is not contraindicated.105,133

Postexposure prophylaxis with immune globulin administered within 6 days of measles exposure is recommended in certain individuals at risk for severe disease and complications from measles, including infants younger than 12 months of age, pregnant women without evidence of measles immunity, and severely immunocompromised patients.105,133,154 ACIP and AAP recommend that IGIM be used for such prophylaxis in infants younger than 12 months of age† and that IGIV† be used for such prophylaxis in susceptible pregnant women and severely immunocompromised individuals.105,133

Although infants usually are immune to measles at birth because of passively acquired maternal antibodies, the duration of immunity depends on the amount of maternal antibody transferred to the infant.133 Most women of childbearing age in the US have vaccine-derived immunity to measles, which results in lower antibody titers compared with women who have had measles, and epidemiologic data indicate that 7% of infants born in the US do not have anti-measles antibodies and up to 90% may be seronegative for such antibodies by 6 months of age.133 Because infants are at higher risk for severe measles and complications and are susceptible to measles if mothers are nonimmune or have low antibody titers, ACIP and AAP state that infants younger than 12 months of age† should receive IGIM following exposure to measles.105,133 Alternatively, infants 6 through 11 months of age can receive postexposure vaccination with MMR, provided the vaccine can be administered within 72 hours of exposure.133

Pregnant women are at increased risk for severe measles and complications, and ACIP and AAP state that those without evidence of measles immunity should receive postexposure prophylaxis with immune globulin (preferably IGIV) within 6 days following exposure to measles.105,133 (See Measles under Uses: Immune Globulin IV [IGIV].)

Severely immunocompromised patients are at increased risk for severe measles and complications, and ACIP and AAP state that such individuals should receive postexposure prophylaxis with immune globulin (preferably IGIV) within 6 days following exposure to measles, regardless of immunologic or vaccination status.105,133 (See Measles under Uses: Immune Globulin IV [IGIV].)

Because passive immunity to measles following administration of immune globulin is temporary (unless modified or typical measles occurs), individuals who receive immune globulin for postexposure prophylaxis should receive immunization with a vaccine containing measles virus vaccine live (e.g., MMR) initiated 6 months after IGIM or 8 months after IGIV, providing the individual is at least 12 months of age and there are no contraindications to the vaccine.105,133 Immune globulin should not be given concurrently with MMR.105,133,134,154 (See Measles, Mumps, Rubella, and Varicella Vaccines under Drug Interactions: Live Vaccines.)

Mumps

IGIM is not effective for prevention of mumps105,133 and should not be used for prophylaxis or treatment of mumps.133,154

Poliomyelitis

IGIM is not indicated for and should not be used for prophylaxis or treatment of poliomyelitis.154

Rubella

IGIM has not been shown to prevent rubella and should not be used for that purpose.105,133

IGIM (GamaSTAN^®) is labeled by FDA for use to modify symptoms of rubella in pregnant women who will not consider therapeutic abortion,154 but should not be used for routine prophylaxis of rubella in early pregnancy in women who have not been exposed.154

The manufacturer states that some studies suggest that use of IGIM in susceptible pregnant women exposed to rubella may lessen the likelihood of rubella infection and associated adverse fetal effects.154 However, ACIP and AAP state that IGIM should not be used routinely for postexposure prophylaxis of rubella in early pregnancy or any other circumstance.105,131 These experts state that use of IGIM after exposure to rubella will not prevent infection or viremia, but may modify or suppress symptoms and can create an unwarranted sense of security.105,131 Infants with congenital rubella syndrome have been born to women who received IGIM shortly after exposure to the disease.105,131

Varicella

IGIM (GamaSTAN^®) is labeled by FDA for use to modify symptoms of varicella (chickenpox) in susceptible individuals.154 IGIM is not indicated for and should not be used for routine prophylaxis or treatment of varicella.154

Although the manufacturer states that IGIM may be considered for postexposure prophylaxis of varicella in susceptible individuals who are immunocompromised if varicella-zoster immune globulin (VZIG) is unavailable,154 IGIV (not IGIM) is recommended when VZIG is unavailable.105,156,269 (See Varicella under Uses: Immune Globulin IV [IGIV].)

Immune Globulin IV (IGIV)

Primary Immunodeficiency Diseases

IGIV (i.e., Asceniv^® 10%, Bivigam^® 10%, Carimune^® NF, Flebogamma^® 5% DIF, Flebogamma^® 10% DIF, Gammagard^® S/D [IgA less than 1 mcg/mL], Gammagard^® 10%, Gammaked^® 10%, Gammaplex^® 5%, Gammaplex^® 10%, Gamunex^®-C 10%, Octagam^® 5%, Panzyga^® 10%, Privigen^® 10%) is used for replacement therapy in patients with primary humoral immunodeficiency who are unable to produce sufficient amounts of IgG antibodies.125,263,265,266,280,282,292,308,324,325,332,337,338,339 This includes, but is not limited to, patients with common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (SCID).125,263,265,266,280,282,292,308,324,325,332,337,338,339

IGIV is contraindicated in IgA-deficient individuals with antibodies against IgA and a history of hypersensitivity.125,263,265,266,282,292,294,308,324,325,327,331,332,337,338,339 (See Cautions: Precautions and Contraindications and see IgA Deficiency under Precautions and Contraindications: Sensitivity Reactions, in Cautions.)

Safety and efficacy of IGIV for replacement therapy in patients with primary immunodeficiency diseases have been established in various clinical trials in adults and children who received IGIV once every 3 or 4 weeks for 12 months.263,265,266,282,292,308,324,325,332,338,339 The primary efficacy end point in these studies generally was the rate of serious acute bacterial infections (e.g., pneumonia, bacteremia/sepsis, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess) per patient per year.263,266,282,292,308,324,325,332,338,339 Results indicated that the annual rate of serious acute bacterial infections in patients receiving IGIV was substantially less than 1 infection per patient year (0-0.2 infections per patient year).263,266,282,292,308,324,325,332,338,339

Idiopathic Thrombocytopenic Purpura

IGIV (i.e., Carimune^® NF, Flebogamma^® 10% DIF, Gammagard^® S/D [IgA less than 1 mcg/mL], Gammaked^® 10%, Gammaplex^® 5%, Gammaplex^® 10%, Gamunex^®-C 10%, Octagam^® 10%, Panzyga^® 10%, Privigen^® 10%) is used in the management of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura or immune thrombocytopenia).125,138,139,265,280,292,308,325,326,332,335,337,339 IGIV is designated an orphan drug by FDA for the treatment of ITP.148

IGIV is used to increase platelet counts125,265,280,292,308,325,326,332,337,339 to prevent and/or control bleeding in patients with ITP265,280,326,332,339 or to allow a patient with ITP to undergo surgery.125,265,332

Safety and efficacy of IGIV in adults125,265,280,308,325,326,332,339 and pediatric patients125,265,308,325,332,337 with chronic ITP (ITP of more than 6 months' duration) have been evaluated in various clinical trials and results indicate that a temporary increase in platelet counts can be obtained in patients who respond to the immune globulin.125,265,280,308,325,332,339 In many of these studies, the primary efficacy end point was the percentage of patients with an increase in platelet count to 50,000/mm³ or greater within 7-9 days after the first IGIV infusion (responders)265,292,308,325,326,332,339 and results indicated that 81-90% of patients with chronic ITP responded to IGIV.265,292,308,325,326,332,339 The median duration of response in patients who responded to IGIV with an increase in platelet count to 50,000/mm³ or greater was 10-15 days (range: 1-82 days or longer).292,308,325,326,339

Results of a clinical study evaluating Carimune^® in children with acute ITP (ITP of less than 6 months' duration) indicate that sequential platelet counts of 30,000, 100,000, and 150,000/mm³ are attained faster with the immune globulin than with corticosteroid therapy.125 However, many cases of acute ITP in children resolve spontaneously within weeks to months.125 Carimune^® also has been used with good results in the treatment of acute ITP in adults.125 In a study in 10 adults with ITP of less than 16 weeks' duration, platelet counts increased to within the normal range after a 5-day course of Carimune^® and this effect lasted a mean of greater than 173 days (range: 30-372 days).125

Individuals with B-cell Chronic Lymphocytic Leukemia

IGIV (i.e., Gammagard^® S/D [IgA less than 1 mcg/mL]) is used for the prevention of bacterial infections in adults with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia (CLL).144,145,153,157,280

Efficacy and safety of Gammagard^® S/D in reducing bacterial infections in patients with B-cell CLL were evaluated in a double-blind, placebo-controlled trial.153,280 Patients received Gammagard^® S/D (400 mg/kg) or placebo (saline solution) once every 3 weeks for a year (total of 17 infusions).153,280 The frequency of bacterial infections was 56% in patients receiving IGIV and 105% in those receiving placebo; the mean time to first bacterial infection was more than 365 days in patients receiving IGIV compared with 192 days in those receiving placebo.280 Patients receiving IGIV had fewer infections caused by Streptococcus pneumoniae and Haemophilus influenzae than those receiving placebo, but the incidence of other gram-negative infections was similar in both groups.280

Kawasaki Disease

IGIV (i.e., Gammagard^® S/D [IgA less than 1 mcg/mL]) is used in conjunction with aspirin therapy for initial treatment of the acute phase of Kawasaki disease.103,104,105,128,144,145,157,163,240,241,280,299,300

AAP, American Heart Association (AHA), and American College of Chest Physicians (ACCP) state that combined therapy with IGIV and aspirin should be administered as soon as possible after Kawasaki disease is diagnosed or strongly suspected (optimally within 7-10 days of disease onset).105,299,300 In those with a delayed diagnosis (i.e., more than 10 days after disease onset), AAP and AHA suggest that combined therapy with IGIV and aspirin should be initiated if the patient has unexplained persistent fever or aneurysms and manifestations of ongoing systemic inflammation (e.g., elevated erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP greater than 3 mg/dL]) or evolving coronary artery disease.105,299

Although fever usually resolves within 36 hours after initiation of IGIV and aspirin therapy,299 approximately 10-20% of patients fail to respond to the initial treatment regimen and have persistent fever or recurrence of fever after an initial afebrile period.105,299 In such situations, AHA and AAP state that IGIV retreatment and continued aspirin therapy is a reasonable option.105,299 Use of additional or alternative anti-inflammatory or immunosuppressive agents may be necessary in IGIV-resistant patients.105,299

Concomitant use of IGIV and high-dose aspirin therapy initiated within 10 days of onset of fever is more effective than aspirin alone in preventing or reducing the occurrence of coronary artery abnormalities associated with Kawasaki disease and may result in more rapid resolution of fever and other clinical and laboratory indicators of acute inflammation.104,105,128,280,299 Use of aspirin therapy alone in patients with Kawasaki disease does not decrease the risk of coronary artery abnormalities.105,299

In a controlled, multicenter, clinical study in patients with Kawasaki disease randomized to receive a single dose of IGIV (2 g/kg by IV infusion over 8-12 hours) given in conjunction with aspirin (80-100 mg/kg daily) or a 4-day IGIV regimen (400 mg/kg by IV infusion over 2 hours daily for 4 days) given in conjunction with aspirin (80-100 mg/kg daily), the single infusion of IGIV was as effective or more effective in preventing coronary artery abnormalities compared with the 4-day IGIV regimen.240 Coronary artery abnormalities were detected 2 weeks after treatment was initiated in 5 or 9% of patients receiving a single infusion of IGIV or a 4-day IGIV regimen, respectively, and at 7 weeks such abnormalities were detected in 4 and 7% of patients, respectively.240 In addition, patients receiving a single infusion of IGIV experienced more rapid defervescence, shorter duration of fever, and a more rapid return to normal clinical measures of inflammation than those receiving the 4-day IGIV regimen.240

Coronary artery abnormalities develop in 15-25% of children with Kawasaki disease if they are not treated within 10 days of fever onset;105,299 approximately 2-4% of patients develop coronary artery abnormalities despite prompt treatment with IGIV and aspirin.105 Long-term management of those who develop coronary abnormalities depends on the severity of coronary involvement and may include low-dose aspirin, anticoagulants, antithrombotic agents, and/or antiplatelet agents.105,299,300

For additional information on management of Kawasaki disease, including long-term management in individuals with coronary abnormalities, specialized references should be consulted.299,300

Neurologic and Neuromuscular Disorders

Chronic Inflammatory Demyelinating Polyneuropathy

IGIV (i.e., Gammaked^® 10%, Gamunex^®-C 10%, Privigen^® 10%) is used in adults for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse.265,292,298,332 Some clinicians consider IGIV the preferred treatment for CIDP, especially in children†, patients with poor venous access that precludes the use of plasma exchange, and in those susceptible to complications of long-term corticosteroid therapy.305,306

Safety and efficacy of Gamunex^®-C 10% IGIV for treatment of CIDP were evaluated in a multicenter, randomized, double-blind, placebo-controlled study in adults with CIDP who had progressive or relapsing motor and sensory dysfunction over the 2 months before study entry and substantial disability (defined as INCAT score of 2-9) (study 100538; ICE study).265,298 The study included IGIV-naive and IGIV-experienced patients.265,298 Patients were randomized to receive Gamunex^®-C 10% (loading dose of 2 g/kg given by IV infusion in divided doses over 2-4 consecutive days, then maintenance dosage of 1 g/kg given by IV infusion over 1-2 days once every 3 weeks) or placebo (0.1% albumin given in an equivalent volume).265,298 The study design included a 24-week efficacy period with response-conditional crossover (rescue) where patients who did not improve and maintain improvement over the 24-week efficacy period were switched to the alternative treatment; patients were withdrawn from the study if they failed to improve by week 3 after crossover or improved but then returned to baseline or lower.265,298 The response rate was measured by an adjusted INCAT disability score on day 16 and every 3 weeks for up to 24 weeks; responders were defined as those who had at least 1-point improvement from baseline in the adjusted INCAT score.265,298 In the intention-to-treat (ITT) population, the response rate in the 24-week efficacy period was 47.5% in those who received Gamunex^®-C 10% (43.6% in IGIV-naive and 55% in IGIV-experienced patients) compared with 22.4% in those who received placebo (28.3% in IGIV-naive and 0% in IGIV-experienced patients).265 After the 24-week efficacy period, patients who responded to Gamunex^®-C 10% were entered into a randomized, double-blind, 24-week extension phase and either continued to receive Gamunex^®-C 10% (1 g/kg over 1-2 days once every 3 weeks) or were reassigned to placebo.265,298 The time to relapse (relapse defined as 1 point or more decrease in adjusted INCAT score compared with baseline score at start of extension phase) was longer in those who continued to receive Gamunex^®-C 10%; the probability of relapse was 13% in those who continued to receive the drug compared with 45% in those who received placebo during the extension phase.265,298

Safety and efficacy of Privigen^® 10% IGIV for the treatment of CIDP were evaluated in a prospective, open-label, single-arm, phase 3 study (Privigen^® Impact on Mobility and Autonomy [PRIMA]).292,342 In this study, 28 adults with CIDP (15 considered not previously treated with IGIV [IGIV-naive] and 13 previously treated with IGIV) received an induction (loading) dose of 2 g/kg of Privigen^® 10% divided into equal doses and given over 2-5 days, followed by up to 7 maintenance doses of 1 g/kg given once every 3 weeks for up to 21 weeks.292,342 The primary efficacy end point was responder rate based on the adjusted 10-point INCAT score in those treated with Privigen^® 10% compared with an historical control.292,342 The responder rate was defined as the proportion of patients who demonstrated clinically meaningful improvement (at least a 1-point decrease in adjusted INCAT score) between baseline and week 25, with a prespecified threshold of 35% in the lower limit of the 2-sided 95% Wilson-Score confidence interval.292,342 The overall percentage of responders to Privigen^® 10% in the PRIMA study was 61% (47% in IGIV-naive and 77% in previously treated patients) and the overall median time to first adjusted INCAT response was 7.5 weeks (18 weeks in IGIV-naive and 3 weeks in previously treated patients).292,342 There was a clinically meaningful improvement in mean INCAT score of 1.4 points in those treated with Privigen^® 10%.292 In a post-hoc analysis, the overall percentage of patients in PRIMA who responded by week 10 and maintained the response through week 25 and lacked confounding changes in glucocorticoid/immunosuppressant dosage was 53.6%.292 Data regarding efficacy of Privigen^® 10% for the treatment of CIDP also are available from a randomized, double-blind, placebo-controlled study (Polyneuropathy and Treatment with Hizentra^® [PATH]) that included 207 adults with CIDP who had received previous treatment with IGIV and relapsed after the immune globulin was discontinued.292,343 In the PATH study, Privigen^® 10% (induction dose of 2 g/kg followed by up to 4 maintenance doses of 1 g/kg given once every 3 weeks for up to 13 weeks) was administered for restabilization and restabilized patients were then randomized to receive treatment with immune globulin subcutaneous (Hizentra^® 20%) or placebo;343 patients who had CIDP relapse after randomization received rescue treatment with the same Privigen^® dosage regimen used for restabilization.292,343 The overall response rate to the Privigen^® 10% dosage regimen used for restabilization was 73%.292,342 Among the subset of 151 patients who had deteriorated by 1 or more points in adjusted INCAT score following previous withdrawal of IGIV, 137 (90.7%) responded during the Privigen^® 10% restabilization period with an increase of at least 1 point in adjusted INCAT score.292

Multifocal Motor Neuropathy

IGIV (i.e., Gammagard^® Liquid 10%) is used for maintenance therapy to improve muscle strength and disability in adults with multifocal motor neuropathy (MMN),266 and is designated an orphan drug by FDA for this use.148 Some clinicians recommend IGIV as a treatment of choice for MMN301,305,306,310,311 when disability is severe enough to warrant treatment.311

Safety and efficacy of Gammagard^® Liquid 10% for maintenance therapy of MMN were evaluated in a randomized, double-blind, placebo-controlled, cross-over, withdrawal study in 44 adults with MMN already receiving IGIV at the time of study enrollment.266,330 The study protocol included 5 study periods consisting of three 12-week clinical stabilization phases, a 12-week double-blind withdrawal phase, and a 12-week double-blind cross-over period.266 Patients were evaluated for grip strength in the more affected hand (measured with dynamometer) and Guy's Neurological Disability Scale (GNDS) for upper limbs.266 Results of this study indicate that a relative decline of 30% or more in grip strength in the more affected hand occurred in approximately 43% of patients during the placebo period but not during treatment with Gammagard^® Liquid 10%, whereas approximately 5% of patients experienced a 30% or greater decline during treatment with Gammagard^® Liquid 10%, but not during treatment with placebo.266 As determined by GNDS scores for upper limbs, approximately 36% of patients deteriorated while receiving placebo but not during treatment with the immune globulin, whereas approximately 12% of patients deteriorated during treatment with the immune globulin but not during the placebo period.266 The Overall Disability Sum Score (ODSS) changed by -7.14% during treatment with placebo (indicating worsening of disability) and by -1.11% during treatment with Gammagard^® Liquid 10% (indicating minimal change in disability).266

Other Neurologic and Neuromuscular Disorders

IGIV is used in the treatment of Guillain-Barré syndrome† (GBS),165,219,301,304,305,306,310,312,317,318 and is designated an orphan drug by FDA for this use.148 Although safety and efficacy have not been definitely established, IGIV initiated within 2 weeks of symptom onset appears to be as effective as plasma exchange218,301,305,306,310,312,317 and is recommended by some clinicians as a treatment of choice for GBS in adults and children,218,301,305,306,310,312,318 especially if disease is severe.301,312 Additional study is needed to determine whether IGIV is beneficial in patients with mild GBS or Miller Fischer syndrome.310,312,317

IGIV has been used in the management of multiple sclerosis† (MS) and has provided benefits (e.g., reduced exacerbations, reduced disability scores) in some patients with relapsing-remitting MS.301,305,306,310,318 However, subsequent studies did not confirm these findings.333,334 Although some clinicians suggest that IGIV can be considered as second- or third-line treatment in patients with relapsing-remitting MS,306,310 others state that IGIV is not recommended for the treatment of relapsing-remitting333 or secondary progressive MS310,333 or the treatment of chronic symptoms of MS.310

Although further study is needed,305,306,318,320 IGIV has been used with some success in the treatment of myasthenia gravis†108,110,217,301,304,305,306,310,312,318,319,320 and Lambert-Eaton myasthenic syndrome† (LEMS).301,304,306,318,320,322 IGIV is designated an orphan drug by FDA for the treatment of myasthenia gravis.148 It has been suggested that IGIV may be beneficial for second-line or adjunctive treatment of severe or worsening myasthenia gravis when other treatments have been unsuccessful or are not tolerated218,305,306,318,320 and also can be considered for second-line treatment of LEMS.306,320,322 Although there is some evidence that IGIV may be beneficial in patients with severe myasthenia gravis exacerbation,310,312,319,320 data are insufficient regarding use of the drug (either alone or in conjunction with other agents) in those with stable or chronic myasthenia gravis.310,312,319,320

There is evidence that IGIV may provide some benefits in the management of stiff person syndrome† (Moersch-Woltmann syndrome);301,304,305,306,310,312,321 IGIV is designated an orphan drug by FDA for this use.148 Although safety and efficacy have not been established, some clinicians recommend use of IGIV as a second-line treatment when other treatments have been unsuccessful or cannot be used.301,310

IGIV has been used in a limited number of children with intractable epilepsy†.218,306,310 Although there is some evidence that IGIV may be beneficial in some patients with Lennox-Gastaut syndrome† or Rasmussen syndrome†,306,310 further study is needed to evaluate efficacy of IGIV in the treatment of these conditions.145,157,165,218 Some clinicians suggest that IGIV can be considered in children with intractable epilepsy if they have not responded to antiepileptic agents and corticosteroids,306,310 especially if they are otherwise candidates for surgical resection.306

Infections in Immunocompromised Individuals

HIV-infected Individuals

IGIV has been used in an attempt to control or prevent infections and improve immunologic parameters in children with symptomatic human immunodeficiency virus (HIV) infection† who are immunosuppressed in association with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC).144,145,130,139,156,157,175,176,177,178,179,180,181,184,216 IGIV also has been used in an attempt to control or prevent infections in HIV-infected adults†.130,144,145,157 Results of studies in adults and children with symptomatic HIV infection indicate that IGIV, used in dosages similar to those used for replacement therapy in patients with primary immunodeficiencies, reduces the incidence of recurrent bacterial infections and sepsis, including upper respiratory tract infections in such patients.144,145,157,175,176,177,178,216

AAP, CDC, National Institutes of Health (NIH), and other experts state that HIV-infected children who have hypogammaglobulinemia (IgG less than 400 mg/dL) should receive primary prophylaxis with IGIV (400 mg/kg once every 2-4 weeks) to prevent serious bacterial infections (e.g., those caused by Streptococcus pneumoniae or other invasive bacteria);156 such prophylaxis should be discontinued if hypogammaglobulinemia resolves.156 IGIV also is recommended as an alternative to co-trimoxazole for secondary prophylaxis of serious bacterial infections in certain HIV-infected children.156

Bone Marrow Transplant Recipients

IGIV has been used in adults and children undergoing bone marrow transplantation† (BMT) to decrease the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic etiologies, and acute graft-versus-host disease (GVHD).221,223,224,225,304,306 However, the effect of IGIV on the incidence of cytomegalovirus (CMV) infection, other infections, or GVHD in patients undergoing allogeneic BMT is unclear.221,222,223,224,225,304,306 IGIV prophylaxis in BMT patients does not appear to affect survival or risk of cancer relapse, and the long-term effects of such therapy remain to be determined.221

In a controlled study in adults who underwent BMT with or without IGIV prophylaxis, there was a clinically important decrease in the incidence of acute GVHD and associated interstitial pneumonia and septicemia during the first 100 days following the procedure in patients who received IGIV; a beneficial effect was not evident in patients younger than 20 years of age.221 Other studies failed to demonstrate decreased rates of GVHD or infection when IGIV was used in patients undergoing unrelated allogeneic BMT.306 In a study in patients at risk for developing CMV (i.e., patients who were CMV-seropositive prior to transplantation or CMV-negative patients who received a transplant from a CMV-positive donor), administration of IGIV resulted in a substantial decrease in the incidence of CMV pneumonitis, but this effect did not occur in other studies.221,223,225

Although efficacy and safety in BMT patients have not been established, some clinicians suggest that IGIV be used for prophylaxis in all allogeneic BMT patients, especially those who are CMV-positive or have received a transplant from a CMV-positive donor.222

Some clinicians suggest that, although there is a perceived benefit of IGIV prophylaxis in infants with severe combined immunodeficiency or other primary immunodeficiency diseases undergoing BMT, the effect of IGIV in these children is difficult to study since they generally are receiving IGIV for replacement therapy.306 These clinicians also state that use of IGIV appears to offer little benefit in patients with malignancies undergoing human leukocyte antigen (HLA)-identical sibling BMT and that additional study is needed to determine whether the drug is beneficial in those undergoing HLA-matched unrelated BMT or cord blood transplants.306

Hematopoietic Stem Cell Transplant Recipients

Individuals who undergo hematopoietic stem cell transplant (HSCT) are at risk for a variety of opportunistic infections during the period prior to engraftment and subsequent immune system recovery.262 CDC, Infectious Diseases Society of America (IDSA), and American Society of Blood and Marrow Transplantation (ASBMT) have established guidelines for preventing opportunistic infections in HSCT recipients that include recommendations regarding certain vaccinations and prophylactic regimens.262 These guidelines state that, although routine administration of IGIV for prophylaxis is not recommended for autologous HSCT recipients, some clinicians recommend use of IGIV to prevent bacterial infections (e.g., S. pneumoniae sinopulmonary infections) in adult, adolescent, or pediatric allogeneic HSCT recipients† who experience severe hypogammaglobulinemia (IgG less than 400 mg/dL) within the first 100 days after transplant.262 If IGIV is used in hypogammaglobulinemic allogeneic HSCT recipients, the fact that the pharmacokinetics of IGIV in these individuals may differ from that in healthy adults should be considered.262 It is recommended that trough serum IgG concentrations should be monitored regularly (e.g., approximately every 2 weeks) in HSCT recipients and IGIV dosage adjusted to maintain trough serum IgG concentrations exceeding 400-500 mg/dL.262 Routine administration of IGIV in HSCT recipients more than 90 days after HSCT is not recommended in the absence of severe hypogammaglobulinemia.262

The guidelines for preventing opportunistic infections among HSCT recipients published by CDC, IDSA, and ASBMT should be consulted for additional information on preventing opportunistic infections in these patients (including vaccinations) and for information on hospital infection control, strategies for safe living after transplantation, and hematopoietic stem cell safety.262

Other Individuals

IGIV has been used alone or in conjunction with appropriate anti-infective therapy to prevent or modify acute bacterial or viral infections (e.g., CMV infections) in patients with iatrogenically induced or disease-associated immunosuppression†, such as patients undergoing major surgery (e.g., cardiac transplant) or patients with hematologic malignancies, extensive burns, or collagen-vascular diseases.130,136,141,144,145,157

Infections in Low-birthweight Neonates

IGIV has been used for prophylaxis and treatment of infections in certain high-risk, preterm, low-birthweight neonates†.130,137,144,145,157,162,167,168,169,170,171,172,214 Preterm neonates generally have low serum IgG concentrations at birth since the bulk of transplacental transfer of IgG to the fetus occurs at 32 weeks of gestation or later.144,145,157,162,167,168,170,172 Although the role of low neonatal IgG concentrations in the pathogenesis of nosocomial bacterial infections in preterm, low-birthweight infants has not been elucidated, some clinicians have suggested that IGIV therapy may be used to prevent or modify systemic bacterial infections in these infants by maintaining therapeutic concentrations of IgG.144,145,157,167,170 However, use of IGIV for prophylaxis of infections in high-risk neonates is controversial.144,145,157,167,170,183,214 AAP does not recommend routine use of IGIV for prophylaxis of infections in preterm neonates.105 Results of several controlled and uncontrolled studies indicate that administration of IGIV to preterm, low-birthweight neonates beginning shortly after birth reduces the incidence of nosocomial sepsis (including infections caused by S. agalactiae [group B streptococci]) in these infants; however, administration of IGIV appeared to have a negligible influence on mortality in some studies.144,157,167,168,214 Results of other studies have failed to show that IGIV therapy resulted in any clinically important reductions in the incidence of sepsis and/or mortality due to sepsis in the neonatal period.144,145,167,168,213,214 In one prospective, controlled study sponsored by the NICHD Neonatal Research Network, use of prophylactic IGIV in low-birthweight neonates had no clinically important effect on nosocomial infections;213 septicemia, meningitis, or urinary tract infections occurred in 17% of neonates receiving IGIV and 19% of neonates receiving placebo.213 Until results of other studies are available and until further studies are done to evaluate safety of IGIV therapy in neonates, IGIV should not be used routinely for prophylaxis or treatment of nosocomial infections in preterm, low-birthweight infants.105,144,167,170,171,172,214

Autoimmune Neutropenia and Autoimmune Hemolytic Anemia

IGIV has been used with some success in a limited number of adults and children for the treatment of autoimmune neutropenia†.130,138,140,145,157,164 Although there is some evidence that IGIV may be beneficial in patients with autoimmune neutropenia,304,306 it is unclear whether IGIV offers any advantages over corticosteroid therapy.306

IGIV has been used with variable results in patients with autoimmune hemolytic anemia†.130,140,142,143,157 A few patients with autoimmune hemolytic anemia appeared to respond to IGIV, but the drug either had no effect or potentiated hemolysis in other patients.138,140,142,143,157 Some clinicians state that IGIV should be used in the management of autoimmune hemolytic anemia only in patients who fail to respond to other treatment options.306

Coronavirus Disease 2019 (COVID-19)

IGIV is being investigated for and has been used in the treatment of coronavirus disease 2019† (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).346,347,348,349,350,352,354,355

There is some evidence that commercially available preparations of IGIV may contain antibodies against some previously circulating coronaviruses,344,351 including antibodies that cross-react with SARS-CoV-2 antigens.351 In addition, it has been suggested that the various immunomodulatory and anti-inflammatory effects of IGIV potentially could help combat the hyperinflammatory state and symptoms of cytokine release syndrome in patients with severe COVID-19.346,351,353,354 However, it is unclear whether IGIV contains clinically important titers of SARS-CoV-2 antibodies and additional study is needed to determine whether the general immunomodulatory effects of IGIV provide benefits in patients with COVID-19.354,356

Specific SARS-CoV-2 immune globulin prepared using plasma obtained from individuals who have recovered from COVID-19 (not commercially available in the US) also is being investigated for the treatment of COVID-19.355,356 Such concentrated immune globulin (hyperimmune globulin) preparations containing antibodies specific to SARS-CoV-2 could potentially suppress the virus and modify the inflammatory response to COVID-19 infection.356

There are a few case reports suggesting that IGIV (0.3-0.5 g/kg daily for 5 days) provided some benefit when used in patients with COVID-19 who were at the early stage of clinical deterioration346 and results of a small, retrospective study that included patients with severe or critical COVID-19 who received IGIV in addition to various other treatments indicated that IGIV treatment initiated within 48 hours of hospital admission was associated with reduced duration of hospitalization, reduced length of stay in an intensive care unit (ICU), and reduced need for mechanical ventilation.350 However, data from another retrospective study that included patients with severe or critical COVID-19 indicated that there was no statistically significant difference in 28- or 60-day mortality or survival time in patients who received IGIV in addition to other treatments (e.g., antivirals, anti-inflammatory agents) compared with those who received such treatments without IGIV.352

Clinical trials have been initiated to evaluate use of commercially available IGIV (e.g., 400-500 mg/kg IV daily for 3-5 days; 0.8-1 g/kg IV daily for 2 days) in patients with COVID-19.355 Clinical trials also are being initiated to evaluate use of investigational SARS-CoV-2 immune globulin prepared using plasma obtained from individuals who have recovered from COVID-19.355

The NIH COVID-19 Treatment Guidelines Panel recommends against the use of commercially available IGIV (i.e., immune globulin not specific for SARS-CoV-2) for the treatment of COVID-19, except in the context of a clinical trial; however, this does not preclude the use of IGIV when it is otherwise indicated for the treatment of complications arising during the course of COVID-19 disease.356 The NIH panel states that it is not known whether products derived from the plasma of donors without confirmation of prior SARS-CoV-2 infection contain high titers of SARS-CoV-2 neutralizing antibodies and, although other blood components in IGIV may have general immunomodulatory effects, it is unclear whether these theoretical effects benefit patients with COVID-19.356

The Surviving Sepsis Campaign COVID-19 subcommittee (a joint initiative of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine) suggests against the routine use of IGIV in critically ill adults with COVID-19 because efficacy data are not available, commercially available IGIV preparations are unlikely to contain adequate titers of neutralizing antibodies against SARS-CoV-2, and IGIV can be associated with increased risk of severe adverse effects (e.g., anaphylaxis, aseptic meningitis, renal failure, thromboembolism, hemolytic reactions, transfusion-related lung injury).357

The NIH COVID-19 panel states that there are insufficient data to date to recommend either for or against the use of investigational SARS-CoV-2 immune globulin for the treatment of COVID-19.356

Dermatomyositis and Polymyositis

IGIV has been used in the treatment of dermatomyositis† and polymyositis†.220,301,304,305,306,310,312,318 IGIV and immune globulin subcutaneous are designated as orphan drugs for the treatment of dermatomyositis.148

In a limited number of patients with biopsy-proven, treatment-resistant dermatomyositis, IGIV therapy resulted in improvements in muscle strength and neuromuscular symptoms within about 2 weeks after the first dose; some patients had marked clearance of rash and scaling.220 Although efficacy and safety have not been established, it has been suggested that IGIV (usually in conjunction with corticosteroids) may be beneficial as second-line therapy in patients with dermatomyositis when other therapies are unsuccessful or cannot be used.218,301,305,306,310,312,318

Graves' Ophthalmopathy

Although further study is needed,305 there is some evidence that IGIV may be beneficial in the management of Graves' ophthalmopathy†.301,302,303,304,305,306 Some patients treated with IGIV had improvements in diplopia, proptosis, visual acuity, and intraocular pressure;302,303 the response rate appeared to be similar to that obtained with corticosteroid treatment.301,302,303,305

Measles

IGIV is used for postexposure prophylaxis to prevent or modify symptoms of measles† (rubeola) in susceptible individuals exposed to the disease less than 6 days previously.105,133 Immune globulin should not be used in an attempt to control measles outbreaks.133

Individuals born before 1957 and individuals with documentation of adequate vaccination against measles at 12 months of age or older, laboratory evidence of measles immunity, or laboratory confirmation of prior measles infection usually can be considered to have presumptive evidence of measles immunity.105,133 Other individuals should be considered susceptible to measles.133

Because administration of vaccine containing measles virus vaccine live (e.g., MMR) within 72 hours of initial measles exposure may provide some protection against infection or modify the clinical course of measles and also provides future protection in individuals who do not contract the disease, ACIP and AAP recommend that susceptible individuals receive postexposure vaccination with a vaccine containing measles virus vaccine live within 72 hours after exposure, unless the vaccine is contraindicated.105,133 Postexposure vaccination is preferred to postexposure prophylaxis with immune globulin for most susceptible individuals 12 months of age or older who are exposed to measles in most settings (e.g., day-care facilities, schools, colleges, health-care facilities), provided the vaccine can be administered within 72 hours of the exposure and is not contraindicated.105,133

Postexposure prophylaxis with immune globulin administered within 6 days of measles exposure is recommended in certain individuals at risk for severe disease and complications from measles, including infants younger than 12 months of age, pregnant women without evidence of measles immunity, and severely immunocompromised patients.105,133 ACIP and AAP recommend that IGIM be used for such prophylaxis in infants younger than 12 months of age† and that IGIV be used for such prophylaxis in susceptible pregnant women and severely immunocompromised individuals.105,133

Because infants are at higher risk for severe measles and complications and are susceptible to measles if mothers are nonimmune or have low antibody titers, ACIP states that infants younger than 12 months of age should receive immune globulin (preferably IGIM) following exposure to measles.133 Alternatively, infants 6 through 11 months of age can receive postexposure vaccination with MMR, provided the vaccine can be administered within 72 hours of exposure.133 (See Measles under Uses: Immune Globulin IM [IGIM].)

Pregnant women are at increased risk for severe measles and complications, and ACIP and AAP state that those without evidence of measles immunity should receive postexposure prophylaxis with immune globulin (preferably IGIV) within 6 days following exposure to measles.105,133 IGIV is recommended instead of IGIM in pregnant women to ensure protective levels of measles antibody titers.133

Severely immunocompromised patients are at increased risk for severe measles and complications, and ACIP and AAP state that such individuals should receive postexposure prophylaxis with immune globulin (preferably IGIV) within 6 days following exposure to measles, regardless of immunologic or vaccination status.105,133 Severely immunocompromised individuals who should receive postexposure prophylaxis with immune globulin include those with severe primary immunodeficiency; bone marrow transplant recipients (until at least 12 months after completion of immunosuppressive treatment or even longer in those with graft-versus-host disease); patients being treated for acute lymphocytic leukemia (until at least 6 months after completion of immunosuppressive chemotherapy); and HIV-infected patients with AIDS or other HIV-infected individuals with severe immunosuppression (defined as CD4⁺ T-cell percentage less than 15% [all ages] or CD4⁺ T-cell count less than 200/mm³ [older than 5 years of age]).105,133 Postexposure prophylaxis with immune globulin also is recommended for HIV-infected individuals who have not received a dose of MMR since effective antiretroviral therapy was initiated105,133 and for those without laboratory evidence of measles immunity.133

Because passive immunity to measles following administration of immune globulin is temporary (unless modified or typical measles occurs), individuals who receive immune globulin for postexposure prophylaxis should receive immunization with a vaccine containing measles virus vaccine live (e.g., MMR) initiated 8 months after IGIV was given or 6 months after IGIM was given, providing the individual is at least 12 months of age and there are no contraindications to the vaccine.105,133 Immune globulin should not be given concurrently with MMR.105,133,134 (See Measles, Mumps, Rubella, and Varicella Vaccines under Drug Interactions: Live Vaccines.)

Systemic Lupus Erythematosus

IGIV has been used with some success in the treatment of systemic lupus erythematosus† (SLE);218,301,304,305,306 however, efficacy and safety have not been established and additional study is needed to evaluate use of IGIV in patients with SLE.305,306 Some clinicians suggest that IGIV can be considered in patients with severe active SLE when other drugs have been ineffective or not tolerated;218 other clinicians recommend caution.306

Tetanus

Although tetanus immune globulin (TIG) is the immune globulin of choice, IGIV is recommended as an alternative for the treatment of tetanus† when TIG is unavailable.105

IGIV also has been recommended as an alternative for postexposure prophylaxis of tetanus† in individuals with tetanus-prone wounds when TIG is unavailable.105

Toxic Shock Syndrome

IGIV has been used as an adjunct to anti-infectives and surgical intervention in the treatment of staphylococcal or streptococcal toxic shock syndrome† or necrotizing fasciitis† in severely ill patients.105,201,306,323

Although data are limited and efficacy and safety have not been established, AAP and others suggest that use of IGIV may be considered as an adjunct in the management of severe staphylococcal or streptococcal toxic shock syndrome† or necrotizing fasciitis† (e.g., when the infection is refractory to several hours of aggressive therapy, an undrainable focus is present, the patient has persistent oliguria with pulmonary edema).105,323 The mechanism of action of IGIV in toxic shock syndrome is unclear, but may be related to neutralization of circulating bacterial toxins.105

Varicella

IGIV has been used and is recommended as an alternative to VZIG for postexposure prophylaxis of varicella† in susceptible individuals when VZIG is unavailable.105,156,268 Although VZIG or IGIV given shortly after exposure to varicella-zoster virus can prevent or modify the course of the disease, immune globulin preparations are not effective once disease is established.105

VZIG is the preferred immune globulin for postexposure prophylaxis of varicella in patients who do not have evidence of immunity (i.e., without a history of varicella or varicella vaccination) and are at high risk for severe disease and complications (e.g., HIV-infected or other immunocompromised patients, pregnant women).105,146,155,156,269 Clinical data demonstrating effectiveness of IGIV for postexposure prophylaxis of varicella are not available and, although commercially available IGIV preparations are known to contain anti-varicella antibody titers, the titer of any specific lot of IGIV is uncertain since IGIV is not routinely tested for anti-varicella antibodies.105,156

ACIP, AAP, CDC, NIH, and other experts state that HIV-infected adults, adolescents, or children or other individuals who are receiving IGIV therapy (400 mg/kg or greater given at regular intervals) and received a dose of IGIV within 3 weeks prior to exposure to wild-type varicella-zoster virus are likely to be protected and probably do not require postexposure prophylaxis with VZIG or IGIV.105,146,155,156,269

Immune Globulin Subcutaneous

Primary Immunodeficiency Diseases

Immune globulin subcutaneous (Cutaquig^® 16.5%, Cuvitru^® 20%, Gammagard^® Liquid 10%, Gammaked^® 10%, Gamunex^®-C 10%, Hizentra^® 20%, Xembify^® 20%)265,266,294,331,332,340,341 and immune globulin subcutaneous in conjunction with recombinant human hyaluronidase (Hyqvia^®; immune globulin subcutaneous 10% copackaged with recombinant human hyaluronidase)327 are used for replacement therapy in patients with primary humoral immunodeficiency.265,266,294,327,331,332,340,341 This includes, but is not limited to, patients with CVID, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.265,266,294,327,331,332,340,341

Immune globulin subcutaneous is contraindicated in IgA-deficient individuals with antibodies against IgA and a history of hypersensitivity.265,266,294,327,331,332,340,341 (See IgA Deficiency under Precautions and Contraindications: Sensitivity Reactions, in Cautions.)

Safety and efficacy of Cutaquig^® 16.5% administered subcutaneously for replacement therapy in patients with primary immunodeficiency were evaluated in an open-label, single-arm study that included 61 patients (38 adults and 23 pediatric patients younger than 16 years of age).340 All patients received Cutaquig^® 16.5% once weekly for 12 weeks (wash-in/wash-out period) followed by an additional 12 months of the immune globulin (efficacy period).340 During the efficacy period, the mean weekly dose of Cutaquig^® 16.5% was 175 mg/kg (individual doses ranged from 60-390 mg/kg) given over a median duration of 1.5 hours.340 At the time of data analysis, 47 patients (35 adults and 12 pediatric patients) had completed the study, 8 pediatric patients were continuing in the study, and 6 patients (3 adults and 3 pediatric patients) had discontinued the study prematurely.340 No serious bacterial infections were reported at any time during the efficacy period.340

Safety and efficacy of Cuvitru^® 20% administered subcutaneously for replacement therapy in patients with primary immunodeficiency were evaluated in an open-label, prospective study that included 77 adults and children 2 years of age and older.331 All patients received a regimen of IGIV initially (IGIV 10% given once every 3 or 4 weeks for 13 weeks) before being switched to subcutaneous Cuvitru^® 20% (once weekly for 12 weeks at an adjusted dose of 145% of the IGIV dose).331 The mean dose of subcutaneous Cuvitru^® 20% was 222 mg/kg once weekly and the median duration of treatment was 380.5 days (range: 30-629 days).331 The annual rate of acute serious bacterial infections during Cuvitru^® 20% treatment was lower than 1 infection per patient per year and the annual rate of any infection was 2.41 infections per patient per year.331

Safety and efficacy of Gammagard^® Liquid 10% administered subcutaneously for replacement therapy in adults and children with primary immunodeficiency were evaluated in an open-label, prospective, multicenter US study in 49 adult and pediatric patients, including those who had been receiving IGIV or another subcutaneous immune globulin preparation.266 All patients (regardless of their prior regimen) received an initial IV regimen of Gammagard^® Liquid 10% (IV once every 3 or 4 weeks for 12 weeks) before being switched to subcutaneous Gammagard^® Liquid 10%.266 The median duration of subcutaneous Gammagard^® Liquid 10% therapy was 379 days (range: 57-477 days).266 The annual rate of acute serious bacterial infections while patients were receiving subcutaneous Gammagard^® Liquid 10% was 0.067 infections per patient per year and the annual rate of any infection (including viral and fungal infections) was 4.1 infections per patient per year.266

Safety and efficacy of Hizentra^® 20% immune globulin subcutaneous for replacement therapy in patients with primary immune deficiency were evaluated in an open-label, prospective, multicenter US study that included 49 adult and pediatric patients who were previously receiving a once-monthly regimen of IGIV and were switched to a once-weekly regimen of subcutaneous Hizentra^® 20% given.294 After a 3-month wash-in/wash-out period, the dose of Hizentra^® 20% was adjusted individually to achieve an IgG area under the concentration-time curve (AUC) that was equivalent to that attained with their previous IGIV therapy and the next 12 months of therapy was considered the efficacy period.294 In the modified intention-to-treat (MITT) population (38 patients who completed the 3-month wash-in/wash-out period and received at least 1 subcutaneous infusion of Hizentra^® 20%), there were no serious bacterial infections (defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, or visceral abscess) and the annual rate of any infection was 2.76 infections per patient per year.294 Safety and efficacy of Hizentra^® 20% immune globulin subcutaneous also have been evaluated in an open-label, prospective, multicenter study in Europe that included 51 adult and pediatric patients with primary immunodeficiency who were previously receiving once-monthly IGIV (31 patients) or once-weekly immune globulin subcutaneous (20 patients) and were switched to once-weekly Hizentra^® 20%.294 During the efficacy period, there were no serious bacterial infections and the annual rate of any infection was 5.18 infections per patient per year.294

Safety and efficacy of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) for replacement therapy in patients with primary immunodeficiency were evaluated in an open-label, uncontrolled, prospective, multicenter US trial that included 83 adult and pediatric patients switched from a regimen of IGIV or another subcutaneous immune globulin preparation to Hyqvia^®.327 For each dose, the recombinant human hyaluronidase component (acts locally to temporarily increase permeability of subcutaneous tissue to increase dispersion and absorption of the immune globulin) was administered first and the immune globulin subcutaneous 10% component was administered within approximately 10 minutes at the same site.327 All patients (regardless of prior regimen) received Hyqvia^® in an initial dose ramp-up period that allowed them to adjust to the large volumes required for a full 3- to 4-week treatment regimen, after which Hyqvia^® was administered once every 3 or 4 weeks for the remainder of the trial.327 After 3 doses at full volume, dosage of the immune globulin component of Hyqvia^® was individually adjusted to achieve serum IgG levels comparable to those attained with their previous immune globulin therapy.327 During the 12 months of treatment after the ramp-up period, patients were assessed for several outcomes, including rate of infections.327 The overall rate of infections in patients treated with Hyqvia^® was 2.97 infections per patient per year.327 There were 2 acute serious bacterial infections during the 12-month efficacy period and, based on this, the annualized rate of acute serious bacterial infections was 0.025 infections per patient per year.327

Safety and efficacy of Xembify^® 20% administered subcutaneously for replacement therapy in patients with primary immunodeficiency were evaluated in an open-label, single-arm study that included 49 patients (35 adults and 14 pediatric patients 2-16 years of age).341 All patients received Gamunex-C^® 10% for 3-4 months (run-in phase) before treatment was switched to subcutaneous Xembify^® 20% (median weekly dose of Xembify^® 20% was 171 mg/kg [range: 71-276 mg/kg] given for a median duration of 24 weeks).341 The annual rate of serious bacterial infections during treatment with Xembify^® 20% was 0.05 per patient per year and the annual rate of any infection was 2.4 per patient per year.341

Neurologic and Neuromuscular Disorders

Chronic Inflammatory Demyelinating Polyneuropathy

Immune globulin subcutaneous (i.e., Hizentra^® 20%) is used for the treatment of CIDP in adults as maintenance therapy to prevent relapse of neuromuscular disability and impairment.294 Immune globulin subcutaneous is designated an orphan drug by FDA for the treatment of CIDP.148

Safety and efficacy of Hizentra^® 20% for maintenance therapy of CIDP were evaluated in a randomized, double-blind, placebo-controlled, phase 3 study (Polyneuropathy and Treatment with Hizentra^® [PATH]) that included adults with CIDP who had been previously treated with IGIV and had stable disease based on INCAT scores.294,343 A total of 172 patients were randomized 1:1:1 to receive low-dose Hizentra^® 20% (weekly dose of 0.2 g/kg), high-dose Hizentra^® 20% (weekly dose of 0.4 g/kg), or placebo.294,343 The primary end point was the percentage of patients who had CIDP relapse while receiving Hizentra^® 20% maintenance therapy or were withdrawn from the study for any other reason.294 Relapse was defined as at least a 1-point increase in adjusted INCAT score compared with baseline.294 Both the low- and high-dose Hizentra^® 20% regimens were superior to placebo based on the primary end point and there was no difference in efficacy between the dosage regimens.294,343 In the ITT population, 39% of those receiving the low-dose regimen, 33% of those receiving the high-dose regimen, and 63% of those receiving placebo had CIDP relapse or withdrew from the study;294,343 relapse was reported in 33, 19, and 56% of patients, respectively.294,343 Data indicate that 67% of those receiving the low-dose and 81% of those receiving the high-dose Hizentra^® 20% regimen remained relapse-free for up to 24 weeks, whereas only 44% of those in the placebo group remained relapse-free.294

Dermatomyositis

Immune globulin subcutaneous is designated an orphan drug by FDA for the treatment of dermatomyositis†.148

Reconstitution and Administration

Immune Globulin IM (IGIM)

Immune globulin IM (GamaSTAN^®) is administered by IM injection.154 IGIM should not be administered IV because of the risk of serious reactions (e.g., renal dysfunction, acute renal failure, hemolysis, transfusion-related acute lung injury).154

In adults and children, IM injections of IGIM preferably should be made into the deltoid muscle or anterolateral aspect of the thigh.154 Because of the risk of injury to sciatic nerves, the gluteal muscle should not be routinely used for IM injections.154

When the dose of IGIM is greater than 10 mL, the dose should be divided and injected into several muscle sites to reduce local pain and discomfort.154

Prior to administration, IGIM solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit.154 The plunger of the syringe should be drawn back before injection of IGIM to ensure that the needle is not in a blood vessel.154

Patients should be adequately hydrated prior to administration of IGIM.154

The recommended dosage of IGIM should not be exceeded in patients at increased risk of thrombosis (e.g., those with cardiovascular risk factors, advanced age, prolonged periods of immobilization, hypercoagulable disorders, previous thrombotic or thromboembolic event, concomitant use of estrogen-containing preparations, indwelling central vascular catheters, and/or known or suspected hyperviscosity).154

Immune Globulin IV (IGIV)

Immune globulin IV (Asceniv^® 10%,338 Bivigam^® 10%,324 Carimune^® NF,125 Flebogamma^® 5% DIF,282 Flebogamma^® 10% DIF,325 Gammagard^® Liquid 10%,266 Gammagard^® S/D [IgA less than 1 mcg/mL],280 Gammaked^® 10%,332 Gammaplex^® 5%,308 Gammaplex^® 10%,337 Gamunex^®-C 10%,265 Octagam^® 5%,263 Octagam^® 10%,326 Panzyga^® 10%,339 Privigen^® 10%292 ) is administered by IV infusion.

Certain IGIV preparations can be administered by IV infusion or subcutaneous infusion for the treatment of primary humoral immunodeficiency (Gammagard^® Liquid 10%,266 Gammaked^® 10%,332 Gamunex^®-C 10%265 ); all other IGIV preparations should only be administered by IV infusion.125,263,280,282,292,308,263,324,325,326,337,338,339

IGIV should be administered IV using a separate line and should not be mixed with other drugs or IV infusion fluids.125,263,265,266,280,282,292,308,324,325,326,332,337,338,339 In addition, different IGIV preparations should not be admixed.266,292,324,325,326,332,337,338,339

Prior to administration, IGIV solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit and should not be used if discolored or turbid or if particulate matter is present.263,265,266,282,292,308,324,325,326,332,337,338,339

The rate of infusion of IGIV should be individualized based on the preparation used and individual patient requirements.165,263,265,266,280,282,324,325,326,332,337,338,339 In general, IGIV infusions in patients receiving initial doses or switching from one IGIV preparation to another should be initiated at the lower end of the range of recommended rates; if the first few infusions are tolerated, the rate of infusion for subsequent infusions may be slowly increased to the maximum recommended rate.266,280,324,325,326,337,338,339

If adverse reactions occur during infusion of IGIV, the rate of infusion should be decreased or the infusion stopped until adverse reactions subside.263,265,266,282,292,308,324,325,326,337,338,339 In some cases when symptoms subside promptly, the infusion may then be resumed at a rate that is tolerated by the individual.265,266,282,292,324,325,326,337,338,339 A rapid infusion rate should not be used in patients with or at risk for renal dysfunction or thrombosis.125,280,282

Prior to initiation of the IGIV infusion, clinicians should ensure that patients, especially those with preexisting renal impairment, are not volume depleted and are adequately hydrated.125,263,265,266,282,292,308,324,325,326,332,337,338,339

Asceniv® 10%

Asceniv^® 10% is administered only by IV infusion.338

Asceniv^® 10% is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.338

Vials are for single use only.338

When large doses are to be administered, the contents of several vials of Asceniv^® 10% may be pooled into an empty, sterile IV infusion bag using aseptic technique.338

Asceniv^® 10% should be at room temperature before and during IV infusion.338

IV infusions of Asceniv^® 10% should be initiated at a rate of 0.5 mg/kg per minute (0.005 mL/kg per minute).338 If this rate is well tolerated for the first 15 minutes, the rate may be gradually increased every 15 minutes up to a maximum of 8 mg/kg per minute (0.08 mL/kg per minute).338 If adverse effects related to the rate of infusion occur, the IV infusion should be stopped or slowed.338 If symptoms subside promptly, the IV infusion may be resumed at a slower rate that is comfortable for the patient.338

In patients at increased risk of thrombosis or renal dysfunction, Asceniv^® 10% should be infused at the minimum IV infusion rate practicable.338 If renal function deteriorates, discontinuance of Asceniv^® 10% should be considered.338

Bivigam® 10%

Bivigam^® 10% is administered only by IV infusion.324

Bivigam^® 10% is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.324

Vials are for single use only.324

When large doses are to be administered, the contents of several vials of Bivigam^® 10% may be pooled into an empty, sterile IV infusion bag using aseptic technique.324 Partially used vials should be discarded.324

Bivigam^® 10% should be at room temperature during IV infusion.324

IV infusions of Bivigam^® 10% should be initiated at a rate of 0.5 mg/kg per minute (0.005 mL/kg per minute).324 If this rate is well tolerated for the first 10 minutes, the rate may be gradually increased every 20 minutes by 0.8 mg/kg per minute up to a maximum of 6 mg/kg per minute.324 If adverse effects related to the rate of infusion occur, the IV infusion should be stopped or slowed.324 If symptoms subside promptly, the IV infusion may be resumed at a slower rate that is comfortable for the patient.324

In patients at increased risk of thrombosis or renal dysfunction (including those 65 years of age or older), Bivigam^® 10% should be infused at the minimum IV infusion rate practicable.324 If renal function deteriorates, discontinuance of Bivigam^® 10% should be considered.324

Carimune® NF

Carimune^® NF is administered only by IV infusion.125

Carimune^® NF should be reconstituted according to the manufacturer's directions with 0.9% sodium chloride, 5% dextrose injection, or sterile water for injection to prepare a solution containing 30, 60, 90, or 120 mg of protein per mL (3, 6, 9, or 12% solution, respectively).125 The patient's fluid, electrolyte, and caloric requirements should be considered when selecting an appropriate diluent and concentration.125 After the diluent is added, vials should be swirled vigorously to dissolve the drug, but should not be shaken since this may cause foaming.125 Carimune^® NF generally dissolve within a few minutes, although in exceptional cases it may take up to 20 minutes for complete dissolution.125

The manufacturer of Carimune^® NF states that, although the drug may be filtered, filtering is not required.125 If a filter is used, filters with pore sizes of 15 µm or larger are less likely to slow the infusion, especially when higher concentrations of the drugs are administered; antibacterial filters (0.2 µm) may be used.125

If Carimune^® NF is reconstituted outside of sterile laminar airflow conditions, reconstituted solutions should be administered promptly and any partially used vials discarded.125 If the drug is reconstituted in a sterile laminar flow hood using aseptic technique and the reconstituted solution is stored under refrigeration, the IV infusion should be initiated within 24 hours after reconstitution.125

Prior to administration, solutions should be clear and at approximately room temperature.125 If large doses of Carimune^® NF are to be administered, the contents of several reconstituted vials of the identical concentration and diluent may be pooled into an empty, sterile glass or plastic IV infusion container using aseptic technique.125

Reconstituted Carimune^® NF should be administered through a separate IV line and should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.125

When Carimune^® NF is used for the treatment of primary immunodeficiency in individuals with previously untreated agammaglobulinemia or hypogammaglobulinemia, a solution containing 30 mg/mL should be used for the initial dose and given at an initial IV infusion rate of 0.5 mg/kg per minute.125 After 30 minutes, the infusion rate may be increased to 1 mg/kg per minute for the next 30 minutes; thereafter, the infusion rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg per minute as tolerated.125 If the initial IV infusion was well tolerated, higher concentrations may be used for subsequent infusions.125 (For information on concentrations of Carimune^® NF and corresponding infusion rates, see Table 1.) Use of an initial infusion rate exceeding 2 mg/kg per minute in patients with agammaglobulinemia or hypogammaglobulinemia who had not previously received IGIV or had not received a dose within the last 8 weeks has resulted in inflammatory reactions.125 (See Infusion Reactions under Cautions: Immune Globulin IV [IGIV].)

When Carimune^® NF is used for the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura or immune thrombocytopenia), a solution containing 60 mg/mL is recommended.125 The recommended initial IV infusion rate in patients with ITP is 0.5 mg/kg per minute.125 After 30 minutes, the infusion rate may be increased to 1 mg/kg per minute for the next 30 minutes; thereafter, the infusion rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg per minute as tolerated.125 (See Table 1.)

In patients at risk of developing renal dysfunction (e.g., adults older than 65 years of a individuals receiving nephrotoxic drugs; individuals with diabetes mellitus, volume depletion, paraproteinemia, or sepsis), Carimune^® NF should be infused at a rate less than 2 mg/kg per minute.125

In patients at increased risk of thrombosis (e.g., those with cardiovascular risk factors, advanced age, prolonged periods of immobilization, hypercoagulable disorders, history of venous or arterial thrombosis, concomitant use of estrogen-containing preparations, indwelling central vascular catheters, and/or hyperviscosity), Carimune^® NF should be infused at a rate less than 2 mg/kg per minute.125

Flebogamma® 5% DIF

Flebogamma^® 5% DIF is administered only by IV infusion.282

Flebogamma^® 5% DIF is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.282

If large doses are indicated, several vials of Flebogamma^® 5% DIF may be pooled into an empty, sterile IV container using aseptic technique.282 Partially used vials and administration sets should be discarded after use.282

IV infusions of Flebogamma^® 5% DIF should be initiated at a rate of 0.01 mL/kg per minute (0.5 mg/kg per minute).282 If tolerated during the first 30 minutes, the rate of infusion may be gradually increased to a maximum of 0.1 mL/kg per minute (5 mg/kg per minute).282

For individuals 65 years of age or older or at increased risk for renal dysfunction or thrombosis, the minimum infusion rate practicable should be used.282 The IV infusion rate for Flebogamma^® 5% DIF in geriatric patients should be less than 0.06 mL/kg per minute (less than 3 mg/kg per minute).282

Flebogamma® 10% DIF

Flebogamma^® 10% DIF is administered only by IV infusion.325

Flebogamma^® 10% DIF is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.325

Vials of Flebogamma^® 10% DIF are for single use only.325

When large doses are to be administered, the contents of several vials of Flebogamma^® 10% DIF may be pooled into an empty, sterile IV container using aseptic technique.325 Partially used vials and administration sets should be discarded.325

IV infusions of Flebogamma^® 10% DIF should be initiated at a rate of 0.01 mL/kg per minute (1 mg/kg per minute).325 If no adverse reactions occur during the first 30 minutes, the rate of infusion may be gradually increased to 0.04 mL/kg per minute (4 mg/kg per minute).325 If tolerated, the infusion rate may then be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute).325

For individuals 65 years of age or older or at risk for renal dysfunction or thrombosis, the minimum infusion rate practicable should be used.325 The IV infusion rate for Flebogamma^® 10% DIF in geriatric patients should be less than 0.04 mL/kg per minute (less than 4 mg/kg per minute).325

Gammagard® Liquid 10%

Gammagard^® Liquid 10% is administered by IV infusion.266 Alternatively, Gammagard^® Liquid 10% may be administered by subcutaneous infusion for the treatment of primary humoral immunodeficiency (see Gammagard Liquid 10% under Reconstitution and Administration: Immune Globulin Subcutaneous, in Dosage and Administration).266

If necessary, Gammagard^® Liquid 10% may be diluted with 5% dextrose injection;266 0.9% sodium chloride should not be used as a diluent.266

Gammagard^® Liquid 10% should not be mixed with other drugs or other IGIV preparations.266

Gammagard^® Liquid 10% should not be shaken.266

Use of an in-line filter is optional.266 The IV infusion line may be flushed with 0.9% sodium chloride injection.266

Gammagard^® Liquid 10% should be at room temperature during IV infusion;266 it should not be warmed in a microwave.266

Vials are for single use only.266

For the treatment of primary humoral immunodeficiency, IV infusions of Gammagard^® Liquid 10% should be given at an initial infusion rate of 0.5 mL/kg per hour (0.8 mg/kg per minute) for 30 minutes.266 The infusion rate may then be increased every 30 minutes (if tolerated) up to a maximum of 5 mL/kg per hour (8 mg/kg per minute).266

For maintenance therapy of multifocal motor neuropathy (MMN), IV infusions of Gammagard^® Liquid 10% should be given at an initial infusion rate of 0.5 mL/kg per hour (0.8 mg/kg per minute).266 The IV infusion rate may then be increased (if tolerated) up to a maximum of 5.4 mL/kg per hour (9 mg/kg per minute).266

For individuals older than 65 years of age or at risk for renal dysfunction or thrombosis, the minimum infusion rate practicable should be used.266 In such patients, the IV infusion rate should be less than 2 mL/kg per hour (less than 3.3 mg/kg per minute).266

Gammagard® S/D

Gammagard^® S/D (IgA less than 1 mcg/mL) is administered only by IV infusion.280

Gammagard^® S/D (IgA less than 1 mcg/mL) should be reconstituted according to the manufacturer's directions with the sterile water for injection diluent and transfer device provided to prepare a solution containing 50 mg of protein per mL (5%) or 100 mg of protein per mL (10%).280 Prior to reconstitution, the powder for injection and sterile water for injection diluent should be allowed to warm to room temperature.280 After the diluent is added, the vial should be gently rotated to dissolve the drug;280 to avoid foaming, the vial should not be shaken.280

If Gammagard^® S/D (IgA less than 1 mcg/mL) was reconstituted outside of sterile laminar airflow conditions, the IV infusion should be initiated within 2 hours after reconstitution (preferably as soon as possible).280 If the drug was reconstituted in a sterile laminar flow hood using aseptic technique and the reconstituted solution is stored under constant refrigeration (2-8°C), the reconstituted solution should be administered within 24 hours after reconstitution (preferably as soon as possible).280

When large doses are to be administered, the contents of several vials of Gammagard^® S/D (IgA less than 1 mcg/mL) may be pooled into an empty, sterile IV container using aseptic technique.280 Partially used vials should be discarded.280

Gammagard^® S/D (IgA less than 1 mcg/mL) should be infused with the administration set provided by the manufacturer which contains an integral airway and a filter with a pore size of 15 µm;280 if this administration set is not used, a similar filter must be used.280

The antecubital vein should be used for IV infusions of Gammagard^® S/D (IgA less than 1 mcg/mL) whenever possible, especially when a 10% solution is used;280 this may reduce discomfort at the infusion site.280

IV infusions of Gammagard^® S/D 5% (IgA less than 1 mcg/mL) should be initiated using a 5% solution at a rate of 0.5 mL/kg per hour and, if tolerated, the rate of IV infusion may be increased gradually to a maximum of 4 mL/kg per hour.280 Patients who tolerate the 5% solution at this maximum rate can be transferred to a 10% solution, initiated at an IV infusion rate of 0.5 mL/kg per hour.280 If tolerated, the infusion rate for the 10% solution may be increased gradually to a maximum of 8 mL/kg per hour.280 In general, it is recommended that the rate of IV infusion in patients beginning therapy with IGIV or switching from one IGIV product to another should be started at a slow rate and the rate increased to the maximum IV infusion rate only after the patient has tolerated several infusions at intermediate rates of infusion.280

For patients at risk of renal dysfunction (e.g., adults older than 65 years of a individuals receiving nephrotoxic drugs; individuals with diabetes mellitus, volume depletion, paraproteinemia, or sepsis) or patients at risk of thrombosis, Gammagard^® S/D (IgA less than 1 mcg/mL) should be administered at the minimum IV infusion rate practicable and the rate gradually titrated up to a reduced maximum rate of less than 3.3 mg/kg per minute (e.g., less than 4 mL/kg per hour as a 5% solution and less than 2 mL/kg per hour as a 10% solution).280 (See Cautions: Precautions and Contraindications.)

Gammaked® 10%

Gammaked^® 10% is administered by IV infusion.332 Alternatively, Gammaked^® 10% may be administered by subcutaneous infusion for the treatment of primary humoral immunodeficiency (see Gammaked^® 10% under Reconstitution and Administration: Immune Globulin Subcutaneous, in Dosage and Administration).332

Prior to administration, Gammaked^® 10% should be allowed to come to room temperature (this may take 60 minutes or longer);332 the solution should be clear to opalescent and colorless to pale yellow.332

If necessary, Gammaked^® 10% may be diluted with 5% dextrose injection; however, saline solutions are not compatible with the drug and should not be used as diluents.332

Gammaked^® 10% vials are for single use only and should not be shaken.332 When the 10-mL vial of Gammaked^® 10% (containing 1 g of protein) is used, the vial stopper should be penetrated only with an 18-gauge needle;332 when 25-, 50-, 100-, or 200-mL vials (containing 2.5, 5, 10, or 20 g of protein, respectively) are used, the vial stopper should be penetrated only with a 16-gauge needle or dispensing pin.332 Any vial that has been entered should be used promptly;332 partially used vials should be discarded.332 However, the manufacturer states that the contents of full vials may be pooled under aseptic conditions into empty, sterile infusion bags and infused within 8 hours after pooling.332

The infusion line can be flushed with either 0.9% sodium chloride injection or 5% dextrose injection.332 The infusion line should not be flushed with heparin because of the potential for incompatibility between Gammaked^® 10% and heparin.332

For primary humoral immunodeficiency or ITP, IV infusions of Gammaked^® 10% should be initiated at a rate of 1 mg/kg per minute (0.01 mL/kg per minute) for the first 30 minutes.332 If well tolerated, the IV infusion rate may be gradually increased to a maximum of 8 mg/kg per minute (0.08 mL/kg per minute).332 If adverse effects related to the rate of IV infusion occur, symptoms may disappear if the infusion is stopped or slowed.332

For the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), IV infusions of Gammaked^® 10% should be initiated at a rate of 2 mg/kg per minute (0.02 mL/kg per minute) for the first 30 minutes.332 If well tolerated, the IV infusion rate may be gradually increased to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute).332 If adverse effects related to the rate of IV infusion occur, symptoms may disappear if the infusion is stopped or slowed.332

In patients at increased risk for renal dysfunction or thrombosis, IV infusions of Gammaked^® 10% should be administered at the minimum infusion rate practicable (less than 8 mg/kg per minute [less than 0.08 mL/kg per minute]).332

Gammaplex® 5%

Gammaplex^® 5% is administered only by IV infusion.308

Prior to administration, Gammaplex^® 5% should be clear or slightly opalescent and at room temperature (up to 25°C).308

If large doses of Gammaplex^® 5% are to be administered, several bottles may be pooled using aseptic technique;308 the IV infusion should be started within 2 hours after pooling.308

Gammaplex^® 5% should not be shaken prior to administration.308

An infusion pump may be used to control the rate of administration.308

The solution should be used promptly after the single-use bottle has been entered;308 partially used bottles should be discarded.308

When Gammaplex^® 5% is used for the treatment of primary humoral immunodeficiency or ITP, the recommended initial IV infusion rate is 0.5 mg/kg per minute (0.01 mL/kg per minute).308 If this rate is well tolerated for the first 15 minutes, the rate may be gradually increased every 15 minutes to a maximum of 4 mg/kg per minute (0.08 mL/kg per minute).308

In patients at risk for renal dysfunction or thrombosis, Gammaplex^® 5% should be administered using the minimum IV infusion rate practicable.308 Gammaplex^® 5% should be discontinued if renal function deteriorates.308

Gammaplex® 10%

Gammaplex^® 10% is administered only by IV infusion.337

Prior to administration, Gammaplex^® 10% should be clear or slightly opalescent and at room temperature (up to 25°C).337

If large doses of Gammaplex^® 10% are to be administered, several vials may be pooled using aseptic technique.337

Gammaplex^® 10% should not be shaken prior to administration.337

An infusion pump may be used to control the rate of administration.337

The solution should be used promptly after the single-use vial has been entered;337 partially used vials should be discarded.337

When Gammaplex^® 10% is used the treatment of primary humoral immunodeficiency or ITP, the recommended initial IV infusion rate is 0.5 mg/kg per minute (0.005 mL/kg per minute).337 If this rate is well tolerated for the first 15 minutes, the rate may be gradually increased every 15 minutes to a maximum of 8 mg/kg per minute (0.08 mL/kg per minute).337

In patients at risk for renal dysfunction or thrombosis, Gammaplex^® 10% should be administered using the minimum IV infusion rate practicable.337 If renal function deteriorates, discontinuance of Gammaplex^® 10% should be considered.337

Gamunex®-C 10%

Gamunex^®-C 10% is administered by IV infusion.265 Alternatively, Gamunex^®-C 10% may be administered by subcutaneous infusion for the treatment of primary humoral immunodeficiency (see Gamunex^®-C 10% under Reconstitution and Administration: Immune Globulin Subcutaneous, in Dosage and Administration).265

Gamunex^®-C 10% should be administered at room temperature.265 If necessary, Gamunex^®-C 10% may be diluted with 5% dextrose injection; however, saline solutions are not compatible with the drug and should not be used as diluents.265

Gamunex^®-C 10% vials are for single use only.265 When the 10-mL vial of Gamunex^®-C 10% (containing 1 g of protein) is used, the vial stopper should be penetrated only with an 18-gauge needle;265 when 25-, 50-, 100-, 200, or 400-mL vials (containing 2.5, 5, 10, 20, or 40 g of protein, respectively) are used, the vial stopper should be penetrated only with a 16-gauge needle or dispensing pin.265 Any vial that has been entered should be used promptly; partially used vials should be discarded.265 However, the manufacturer states that the contents of full vials may be pooled under aseptic conditions into empty, sterile infusion bags and infused within 8 hours after pooling.265

The infusion line may be flushed with either 0.9% sodium chloride injection or 5% dextrose injection.265 The infusion line should not be flushed with heparin because of the potential for incompatibility between Gamunex^®-C 10% and heparin.265

For primary humoral immunodeficiency or ITP, IV infusions of Gamunex^®-C 10% should be initiated at a rate of 1 mg/kg per minute (0.01 mL/kg per minute) for the first 30 minutes.265 If tolerated, the IV infusion rate may be gradually increased to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute).265 If adverse effects related to the rate of IV infusion occur, symptoms may disappear if the infusion is stopped or slowed.265

For the treatment of CIDP, IV infusions of Gamunex^®-C 10% should be initiated at a rate of 2 mg/kg per minute (0.02 mL/kg per minute) for the first 30 minutes.265 If tolerated, the IV infusion rate may be gradually increased to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute).265 If adverse effects related to the rate of IV infusion occur, symptoms may disappear if the infusion is stopped or slowed.265

In patients at increased risk for renal dysfunction or thrombosis, IV infusions of Gamunex^®-C 10% should be administered at the minimum IV infusion rate practicable (less than 8 mg/kg per minute [less than 0.08 mL/kg per minute]).265

Octagam® 5%

Octagam^® 5% is administered only by IV infusion.263

Octagam^® 5% should not be diluted or mixed with other drugs, IV infusion fluids, or other IGIV preparations.263

Octagam^® 5% should be at room temperature during administration.263

The stopper of the single-use bottle of Octagam^® 5% should be penetrated with a 16-gauge or smaller needle;263 the needles should be inserted only once.263 The solution should be used promptly after the single-use bottle has been entered;263 partially used bottles should be discarded.263

If necessary, the contents of several single-use bottles of Octagam^® 5% may be pooled into a sterile IV infusion bag using aseptic technique;263 the solution should be infused within 8 hours after pooling.263

An infusion set is not provided with Octagam^® 5%;263 if an infusion set is used (not mandatory), the filter pore size must be 0.2-200 µm.263

The IV infusion line may be flushed with either 0.9% sodium chloride injection or 5% dextrose injection before or after administration of Octagam^® 5%.263

IV infusions of Octagam^® 5% should be given at a rate of 30 mg/kg per hour (0.5 mg/kg per minute or 0.01 mL/kg per minute) for the first 30 minutes.263 If tolerated, the rate of infusion may be increased to 60 mg/kg per hour (1 mg/kg per minute or 0.02 mL/kg per minute) for the second 30 minutes and, if further tolerated, increased to 120 mg/kg per hour (2 mg/kg per minute or 0.04 mL/kg per minute) for the third 30 minutes.263 The infusion rate can be increased to and maintained at 200 mg/kg per hour (maximum 3.33 mg/kg per minute or 0.07 mL/kg per minute) if tolerated.263

In patients at risk for renal dysfunction or thrombosis, IV infusions of Octagam^® 5% should be administered using the minimum infusion rate practicable.263 The maximum IV infusion rate in patients at risk for renal dysfunction is 200 mg/kg per hour (3.33 mg/kg per minute or 0.07 mL/kg per minute).263 Octagam^® 5% should be discontinued if renal function deteriorates.263

Octagam® 10%

Octagam^® 10% is administered only by IV infusion.326

Octagam^® 10% should not be diluted or mixed with other drugs, IV infusion fluids, or other IGIV preparations.326

Octagam^® 10% should be at room temperature during IV infusion.326

The stopper of the single-use bottle of Octagam^® 10% should be penetrated with a 16-gauge or smaller needle;326 the needles should be inserted only once.326 The solution should be used promptly after the single-use bottle has been entered;326 partially used bottles should be discarded.326

If necessary, the contents of several single-use bottles of Octagam^® 10% may be pooled into a sterile IV infusion bag using aseptic technique;326 the solution should be infused within 8 hours after pooling.326

An infusion set is not provided with Octagam^® 10%;326 if an infusion set is used (not mandatory), the filter pore size should be 0.2-200 µm.326

The IV infusion line may be flushed with either 0.9% sodium chloride injection or 5% dextrose injection before and after administration of Octagam^® 10%.326

IV infusions of Octagam^® 10% should be given at a rate of 60 mg/kg per hour (1 mg/kg per minute or 0.01 mL/kg per minute) for the first 30 minutes.326 If no adverse reactions occur, the rate of infusion may be increased to 120 mg/kg per hour (2 mg/kg per minute or 0.02 mL/kg per minute) for the second 30 minutes;326 if tolerated, the rate of infusion may be further increased to 240 mg/kg per hour (4 mg/kg per minute or 0.04 mL/kg per minute) for the third 30 minutes;326 and if further tolerated, increased to 480 mg/kg per hour (8 mg/kg per minute or 0.08 mL/kg per minute) for the fourth 30 minutes.326 The maximum IV infusion rate is 720 mg/kg per hour (maximum 12 mg/kg per minute or 0.12 mL/kg per minute).326

In patients at risk for renal dysfunction or thrombosis, IV infusions of Octagam^® 10% should be administered using the minimum infusion rate practicable.326 The maximum IV infusion rate in patients at risk for renal dysfunction or thrombosis is 200 mg/kg per hour (maximum 3.33 mg/kg per minute or 0.03 mL/kg per minute).326 Octagam^® 10% should be discontinued if renal function deteriorates.326

Panzyga® 10%

Panzyga^® 10% is administered only by IV infusion.339

Panzyga^® 10% should not be mixed with other drugs, IV infusion fluids, or other IGIV preparations.339

The stopper of the single-use bottle of Panzyga^® 10% should be penetrated with a 16-gauge or smaller needle;339 the needle should be inserted only once.339

If necessary, the contents of several single-use bottles of Panzyga^® 10% may be pooled into a sterile IV infusion bag using aseptic technique;339 the solution should be infused within 8 hours after pooling.339

Panzyga^® 10% should be at room or body temperature before IV infusion and should be administered using an in-line filter with a pore size of 0.2-200 µm.339

After IV infusion of Panzyga^® 10%, the infusion line should be flushed with 0.9% sodium chloride injection or 5% dextrose injection.339

For the treatment of primary humoral immunodeficiency, the recommended initial IV infusion rate of Panzyga^® 10% is 1 mg/kg per minute (0.01 mL/kg per minute) for the first 30 minutes.339 In patients who are receiving IGIV for the first time or received a dose of IGIV more than 8 weeks previously, the IV infusion rate may be gradually increased every 15-30 minutes to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute) as tolerated.339 The manufacturer recommends that the IV infusion rate in such patients be ramped up using sequential infusion rates of 1, 2, 4, and 8 mg/kg per minute (0.01, 0.02, 0.04, and 0.08 mL/kg per minute).339 In patients who are IGIV-experienced (i.e., previously received more than 3-6 IGIV infusions), the IV infusion rate may be gradually increased to a maximum of 12 or 14 mg/kg per minute (0.12 or 0.14 mL/kg per minute) as tolerated.339 The manufacturer recommends that the IV infusion rate in IGIV-experienced patients be ramped up using sequential infusion rates of 1, 4, 8, and 12 or 14 mg/kg per minute (0.01, 0.04, 0.08, and 0.12 or 0.14 mL/kg per minute).339

For the treatment of chronic ITP, the recommended initial IV infusion rate of Panzyga^® 10% is 1 mg/kg per minute (0.01 mL/kg per minute) for the first 30 minutes.339 If tolerated, the IV infusion rate may then be gradually increased every 15-30 minutes to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute) as tolerated.339

In patients at increased risk of thrombosis or renal dysfunction, Panzyga^® 10% should be infused at the minimum IV infusion rate practicable.339 The maximum IV infusion rate is 3.33 mg/kg per minute (0.03 mL/kg per minute).326 Panzyga^® 10% should be discontinued if renal function deteriorates.339

Privigen® 10%

Privigen^® 10% is administered only by IV infusion.292

Privigen^® 10% should be administered at room temperature (up to 25°C).292 The solution should be used promptly after the vial has been entered;292 partially used vials should be discarded.292

If necessary, Privigen^® 10% may be diluted with dextrose injection.292

If large doses are to be administered, several vials of Privigen^® 10% may be pooled using aseptic technique;292 the IV infusion should be started within 8 hours after pooling.292

Privigen^® 10% should not be shaken prior to administration.292

The IV infusion line may be flushed with either 0.9% sodium chloride injection or 5% dextrose injection.292

An infusion pump may be used to control the rate of administration.292

For the treatment of primary humoral immunodeficiency, the recommended initial IV infusion rate of Privigen^® 10% is 0.5 mg/kg per minute (0.005 mL/kg per minute).292 If tolerated, the rate may be gradually increased to a maximum of 8 mg/kg per minute (0.08 mL/kg per minute).292

For the treatment of chronic ITP, the recommended initial IV infusion rate of Privigen^® 10% is 0.5 mg/kg per minute (0.005 mL/kg per minute).292 If no adverse reactions occur, the IV infusion rate may be gradually increased to a maximum of 4 mg/kg per minute (0.04 mL/kg per minute).292

For the treatment of CIDP, IV infusions of Privigen^® 10% should be initiated at a rate of 0.5 mg/kg per minute (0.005 mL/kg per minute).292 If tolerated, the IV infusion rate may be gradually increased to a maximum rate of 8 mg/kg per minute (0.08 mL/kg per minute).292

Patients who have not previously received Privigen^® 10% (or another immune globulin preparation), patients who have not received the drug within the past 8 weeks, and patients switching from another immune globulin preparation to Privigen^® 10% may be at risk of developing inflammatory reactions if a rapid IV infusion rate (e.g., greater than 4 mg/kg per minute [greater than 0.04 mL/kg per minute]) is used.292 In such patients, Privigen^® 10% should be initiated using a slow IV infusion rate (e.g., 0.5 mg/kg per minute or slower [0.005 mL/kg per minute or slower]) and the rate gradually increased to the maximum IV infusion rate tolerated.292

In patients at risk of renal dysfunction or thrombosis, IV infusions of Privigen^® 10% should be administered using the minimum IV infusion rate practicable.292 Privigen^® 10% should be discontinued if renal function deteriorates.292

Immune Globulin Subcutaneous

Cutaquig® 16.5%

Cutaquig^® 16.5% is administered only by subcutaneous infusion.340

Cutaquig^® 16.5% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.340

Cutaquig^® 16.5% is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other immune globulin preparations.340

Vials of Cutaquig^® 16.5% are for single use only.340 Partially used vials should be discarded.340

Subcutaneous infusions of Cutaquig^® 16.5% should be made into the abdomen, thighs, upper arms, and/or upper leg/hips using an infusion pump;340 scars, tattoos, and any areas that are injured or inflamed should be avoided.340

The dose may be divided and infused simultaneously in up to 6 different infusion sites that are at least 2 inches apart.340 For patients who have not previously received immune globulin subcutaneous, the maximum volume per infusion site is 25 mL; after the first 5 doses of Cutaquig^® 16.5%, the volume may be gradually increased to a maximum of 40 mL per infusion site as tolerated.340 Subcutaneous infusion sites should be rotated for each subsequent dose.340

For the treatment of primary humoral immunodeficiency, the first 6 subcutaneous infusions of Cutaquig^® 16.5% should be given at a rate of 15-20 mL/hour at each infusion site.340 For subsequent subcutaneous infusions, the infusion rate may be increased as tolerated to a maximum of 25 mL/hour at each infusion site.340

The manufacturer's instructions provided with Cutaquig® 16.5% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 340

Cuvitru® 20%

Cuvitru^® 20% is administered only by subcutaneous infusion.331

Cuvitru^® 20% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.331

Cuvitru^® 20% is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other immune globulin preparations.331

Vials of Cuvitru^® 20% are for single use only.331

Subcutaneous infusions of Cuvitru^® 20% should be made into the abdomen, thighs, upper arms, and/or lateral hip;331 bony areas, visible blood vessels, scars, and any areas with inflammation (irritation) or infection should be avoided.331

The dose may be divided and infused simultaneously in up to 4 different sites that are at least 4 inches apart;331 a multi-needle administration set can be used to facilitate simultaneous subcutaneous infusion at multiple sites.331 The number of sites to be used depends on the volume of the dose and can be calculated by dividing the total volume to be infused by the maximum volume per site.331 For the first 2 subcutaneous infusions, the maximum volume per site is 20 mL in those weighing less than 40 kg or 60 mL in those weighing 40 kg or more;331 for subsequent infusions, the maximum volume per site is 60 mL regardless of weight.331 Subcutaneous infusion sites should be rotated for each subsequent dose.331

For the treatment of primary humoral immunodeficiency, the first 2 subcutaneous infusions of Cuvitru^® 20% should be given at a rate of 10-20 mL/hour at each infusion site.331 For subsequent subcutaneous infusions, the infusion rate may be increased as tolerated to a maximum of 60 mL/hour at each infusion site.331

The manufacturer's instructions provided with Cuvitru® 20% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 331

Gammagard Liquid 10%

Gammagard^® Liquid 10% may be administered by subcutaneous infusion in patients with primary humoral immunodeficiency.266 Gammagard^® Liquid 10% also may be administered by IV infusion (see Gammagard Liquid 10% under Reconstitution and Administration: Immune Globulin IV [IGIV], in Dosage and Administration).266

Gammagard^® Liquid 10% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.266

Subcutaneous infusions of Gammagard^® Liquid 10% should be made into the abdomen, thighs, upper arms, and/or lower back using an infusion pump;266 bony prominences should be avoided.266

To determine the number of subcutaneous infusion sites needed, the weekly dose (in mL) should be divided by 30 or 20 (i.e., divide by recommended volume per site based on patient weight).266 Infusion sites should be located at least 2 inches apart and should be changed for each weekly dose.266 A maximum of 8 simultaneous infusion sites should be used.266

In patients weighing 40 kg or more, initial subcutaneous infusions should be given using a volume of 30 mL per infusion site and an infusion rate of 20 mL/hour per site.266 For maintenance doses in these patients, a volume of 30 mL per site and a subcutaneous infusion rate of 20-30 mL/hour per site should be used.266

In patients weighing less than 40 kg, initial subcutaneous infusions should be given using a volume of 20 mL per infusion site and an infusion rate of 15 mL/hour per site.266 For maintenance doses in these patients, a volume of 20 mL per site and a subcutaneous infusion rate of 15-20 mL/hour per site should be used.266

The manufacturer's instructions provided with Gammagard® Liquid 10% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 266

Gammaked® 10%

Gammaked^® 10% may be administered by subcutaneous infusion in patients with primary humoral immunodeficiency.332 Gammaked^® 10% also may be administered by IV infusion (see Gammaked^® 10% under Reconstitution and Administration: Immune Globulin IV [IGIV], in Dosage and Administration).332

Gammaked^® 10% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.332

Prior to administration, Gammaked^® 10% should be allowed to come to room temperature (this may take 60 minutes or longer);332 the solution should be clear to opalescent and colorless to pale yellow.332

Vials are for single use only and should not be shaken.332

The solution should be used promptly after the vial has been entered;332 any partially used vials should be discarded.332

Subcutaneous infusions of Gammaked^® 10% should be made into the abdomen, thighs, upper arms, and/or lateral hip using an infusion pump.332

Depending on the total volume required, each subcutaneous dose of Gammaked^® 10% may be divided and infused into multiple sites.332 A maximum of 8 different infusion sites may be used simultaneously in adults (4 infusion sites used simultaneously in most adults) and a maximum of 6 different infusion sites may be used simultaneously in children.332 Infusion sites should be located at least 2 inches apart.332

For the treatment of primary humoral immunodeficiency in adults, subcutaneous infusions of Gammaked^® 10% should be given at a rate of 20 mL/hour at each infusion site.332

For the treatment of primary humoral immunodeficiency in pediatric patients 2 years of age or older weighing 25 kg or more, subcutaneous infusions of Gammaked^® 10% should be initiated at a rate of 15 mL/hour at each infusion site.332 The subcutaneous infusion rate may then be increased up to 20 mL/hour at each infusion site.332

For the treatment of primary humoral immunodeficiency in pediatric patients 2 years of age or older weighing less than 25 kg, subcutaneous infusions of Gammaked^® 10% should be given at a rate of 10 mL/hour at each infusion site.332

The manufacturer's instructions provided with Gammaked® 10% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 332

Gamunex®-C 10%

Gamunex^®-C 10% may be administered by subcutaneous infusion in patients with primary humoral immunodeficiency.265 Gamunex^®-C 10% also may be administered by IV infusion (see Gamunex^®-C 10% under Reconstitution and Administration: Immune Globulin IV [IGIV], in Dosage and Administration).265

Gamunex^®-C 10% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.265

Prior to administration, Gamunex^®-C 10% should be at room temperature.265 The solution should not be shaken prior to administration.265

Subcutaneous infusions of Gamunex^®-C 10% should be made into the abdomen, thighs, upper arms, and/or lateral hip using an infusion pump.265

Depending on the total volume required, each subcutaneous dose of Gamunex^®-C 10% may be divided and infused into multiple sites.265 A maximum of 8 different infusion sites may be used simultaneously in adults (4 infusion sites used simultaneously in most adults) and a maximum of 6 different infusion sites may be used simultaneously in children.265 Infusion sites should be located at least 2 inches apart.265

For the treatment of primary humoral immunodeficiency in adults, subcutaneous infusions of Gamunex^®-C 10% should be given at a rate of 20 mL/hour at each infusion site.265

For the treatment of primary humoral immunodeficiency in pediatric patients 2 years of age or older weighing 25 kg or more, subcutaneous infusions of Gamunex^®-C 10% should be initiated at a rate of 15 mL/hour at each infusion site.265 The subcutaneous infusion rate may then be increased up to 20 mL/hour at each infusion site.265

For the treatment of primary humoral immunodeficiency in pediatric patients 2 years of age or older weighing less than 25 kg, subcutaneous infusions of Gamunex^®-C 10% should be given at a rate of 10 mL/hour at each infusion site.265

The manufacturer's instructions provided with Gamunex®-C 10% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 265

Hizentra® 20%

Hizentra^® 20% is administered only by subcutaneous infusion.294

Hizentra^® 20% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.294

Prefilled syringes and vials of Hizentra^® 20% are for single use only and should not be shaken.294 The manufacturer's instructions should be consulted for specific information on preparing and using the single-use prefilled syringes and vials.294

Subcutaneous infusions of Hizentra^® 20% should be made in the abdomen, thighs, upper arms, and/or lateral hips using an infusion pump.294

Depending on the total volume required, each subcutaneous dose of Hizentra^® 20% may be divided and infused into multiple infusion sites.294 A maximum of 8 different infusion sites and more than one infusion device may be used simultaneously.294 Infusion sites should be located at least 2 inches apart and should be changed for each infusion session.294

For the treatment of primary humoral immunodeficiency, subcutaneous infusions of Hizentra^® 20% should be initiated using a maximum volume of 15 mL at each infusion site and a maximum infusion rate of 15 mL/hour at each infusion site.294 For subsequent infusions, the volume may be increased up to 25 mL at each infusion site and the subcutaneous infusion rate may be increased up to 25 mL/hour at each infusion site as tolerated.294

For the treatment of CIDP, subcutaneous infusions of Hizentra^® 20% should be initiated using a maximum volume of 20 mL at each infusion site and a maximum infusion rate of 20 mL/hour at each infusion site.294 For subsequent infusions, the volume may be increased up to 50 mL at each infusion site and the subcutaneous infusion rate may be increased up to 50 mL/hour at each infusion site as tolerated.294

The manufacturer's instructions provided with Hizentra® 20% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 294

Hyqvia® (Immune Globulin Subcutaneous 10% with Recombinant Human Hyaluronidase)

Immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) is commercially available as a kit that contains a vial of immune globulin subcutaneous 10% copackaged with a vial of recombinant human hyaluronidase.327 Both components are administered only by subcutaneous infusion and are administered sequentially at the same infusion site.327

The recombinant human hyaluronidase component and the immune globulin subcutaneous 10% component should not be mixed together in the same container;327 the individual components should not be mixed with or administered with other drugs or infusion fluids.327

Subcutaneous infusions of the Hyqvia^® components should be made using an appropriate infusion pump and subcutaneous needle set.327 The manufacturer's instructions provided with Hyqvia® and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 327

For each dose of Hyqvia^®, the recombinant human hyaluronidase component (acts locally to temporarily increase permeability of subcutaneous tissue to increase dispersion and absorption of the immune globulin component) must be administered first.327 Within approximately 10 minutes after completion of the subcutaneous infusion of the recombinant human hyaluronidase component, the appropriate dose of the immune globulin subcutaneous 10% component should then be administered using the same subcutaneous infusion site and the same needle set.327

Hyqvia^® may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the components by subcutaneous infusion after appropriate training and with medical follow-up as necessary.327

Subcutaneous infusions of Hyqvia^® should be made in the abdomen and/or thighs;327 bony prominences or scarred, infected, or inflamed areas should be avoided.327 Administration sites should be rotated on opposite sides of the body between successive infusions.327

A maximum volume of 600 mL may be administered at each subcutaneous infusion site in patients weighing 40 kg or more, or a maximum volume of 300 mL may be administered at each subcutaneous infusion site in those weighing less than 40 kg.327

If necessary because of the total volume required and/or tolerability, the immune globulin subcutaneous 10% dose may be divided and administered using 2 infusion sites on opposite sides of the body.327 When 2 administration sites are used, the dose of recombinant human hyaluronidase must be divided and half administered at each site prior to the immune globulin component.327

Subcutaneous infusions of the recombinant human hyaluronidase component of Hyqvia^® should be initiated at a rate approximately 1-2 mL/minute at each infusion site or as tolerated.327

Subcutaneous infusions of the immune globulin 10% component of Hyqvia^® should be administered using variable rates for the first 4 or 5 infusions (ramp-up period).327 Time intervals and number of rate changes should be adjusted as needed.327

The manufacturer's literature should be consulted for specific information on recommended infusion rates and time intervals for subcutaneous administration of Hyqvia ^®during the ramp-up period. 327

Xembify® 20%

Xembify^® 20% is administered only by subcutaneous infusion.341

Xembify^® 20% may be self-administered in the home or other appropriate setting if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.341

Xembify^® 20% is administered undiluted and should not be mixed with other drugs, IV infusion fluids, or other immune globulin preparations.341

Vials of Xembify^® 20% are for single use only.341 Partially used vials should be discarded.341

Subcutaneous infusions of Xembify^® 20% should be made into the abdomen, thighs, upper arms, sides, back, and/or upper lateral hip area using an infusion pump;341 bony areas, scars, blood vessels, and any areas with inflammation or superficial infection should be avoided.341

The dose may be divided and infused simultaneously in up to 6 different infusion sites that are at least 2 inches apart.341 The maximum volume per infusion site is 25 mL.341 Subcutaneous infusion sites should be rotated for each subsequent dose.341

For the treatment of primary humoral immunodeficiency, subcutaneous infusions of Xembify^® 20% should be given at a maximum rate of 25 mL/hour at each infusion site.341

The manufacturer's instructions provided with Xembify® 20% and with the infusion pump should be consulted for specific information regarding subcutaneous administration. 341

Dosage for Immune Globulin IM (IGIM)

Hepatitis A Virus Infection

If IGIM is used for preexposure prophylaxis of hepatitis A virus (HAV) infection in adults154,186 or children†186 who will be traveling to countries with intermediate or high levels of endemic HAV, the manufacturer and the US Public Health Service (USPHS) Advisory Committee on Immunization Practices (ACIP) recommend a single dose of 0.1 or 0.2 mL/kg of IGIM in those who will be staying in such areas for up to 1 or 2 months, respectively.154,186 If the period of exposure to HAV infection in such areas will be 2 months or longer, 0.2 mL/kg of IGIM should be administered once every 2 months.154,186 Unless contraindicated, preexposure vaccination with an age-appropriate schedule of hepatitis A virus vaccine inactivated (hepatitis A vaccine) before an expected exposure to HAV is preferred in adults and children 12 months of age or older.186 (See Hepatitis A Virus Infection under Uses: Immune Globulin IM [IGIM].)

If IGIM is used for postexposure prophylaxis of HAV infection in infants younger than 12 months of age†, adults older than 40 years of age, immunocompromised individuals, individuals with chronic liver disease, or whenever preexposure vaccination with hepatitis A vaccine is contraindicated, a single dose of 0.1 mL/kg of IGIM154,186 should be administered as soon as possible after exposure (ideally within 2 weeks).154,186 Efficacy of IGIM for HAV postexposure prophylaxis if administered more than 2 weeks after exposure has not been established.186 (See Hepatitis A Virus Infection under Uses: Immune Globulin IM [IGIM].)

Healthcare professionals should consider that IGIM dosages currently recommended for preexposure or postexposure prophylaxis of HAV are higher than those previously recommended.186 A change in dosage recommendations was made in 2017 based on data indicating that HAV immunoglobulin G antibody (anti-HAV IgG) potency of IGIM commercially available in the US is lower than in the past, most likely because decreasing prevalence of previous HAV infection among plasma donors resulted in lower anti-HAV antibody levels in donor plasma used to prepare IGIM.186

If combined active and passive immunization is used for preexposure prophylaxis or postexposure prophylaxis to provide long-term protection against HAV, the first dose of hepatitis A vaccine may be administered concurrently with the dose of IGIM at a separate site using a separate syringe.154,186

Measles

If IGIM is used for postexposure prophylaxis of measles in susceptible individuals, the manufacturer recommends that most individuals receive a single dose of 0.25 mL/kg administered within 6 days after exposure.154 If a susceptible child who is immunocompromised is exposed to measles, the manufacturer recommends that IGIM be given as a single dose of 0.5 mL/kg (up to 15 mL) immediately after the exposure.154

Whenever IGIM is indicated for postexposure prophylaxis of measles, ACIP and the American Academy of Pediatrics (AAP) recommend a single dose of 0.5 mL/kg (up to 15 mL) given within 6 days after exposure.105,133 ACIP states that the optimal dose of IGIM needed to provide protection against measles infection is unknown.133

Active immunization with a vaccine containing measles virus vaccine live (e.g., measles, mumps, and rubella virus vaccine live; MMR) should then be initiated 6 months after administration of IGIM in individuals 12 months of age or older, unless the vaccine is contraindicated (see Measles, Mumps, Rubella, and Varicella Vaccines under Drug Interactions: Live Vaccines).105,133

ACIP and AAP state that individuals currently receiving immune globulin therapy replacement therapy who received an IGIV dose of 400 mg/kg or greater within 3 weeks prior to measles exposure or received immune globulin subcutaneous in a dosage of 200 mg/kg or greater for 2 consecutive weeks prior to measles exposure should be sufficiently protected against measles.105,133 (See Measles under Dosage and Administration: Dosage for Immune Globulin IV [IGIV].)

Rubella

If IGIM is used to modify rubella in susceptible pregnant women exposed to the disease, the manufacturer recommends that 0.55 mL/kg be administered as a single dose.154 However, routine use of IGIM is not recommended.105,131,154 (See Rubella under Uses: Immune Globulin IM [IGIM].)

Varicella

If IGIM is used as an alternative to varicella-zoster immune globulin (VZIG) for postexposure prophylaxis of varicella infection, the manufacturer recommends that a single dose of 0.6-1.2 mL/kg be administered promptly.154

IGIV (not IGIM) usually is recommended for postexposure prophylaxis when VZIG is unavailable.105,156 (See Varicella under Dosage and Administration: Dosage for Immune Globulin IV [IGIV].)

Dosage for Immune Globulin IV (IGIV)

Primary Immunodeficiency Diseases

The minimum serum concentration of IgG necessary for protection in patients with primary humoral immunodeficiency varies among patients and has not been established in controlled clinical studies.266 Clinical response should be monitored and dosage of IGIV should be individualized since there are interindividual differences in the half-life of IgG among patients with primary immunodeficiencies.263,265,266,282,308,324,337,339 Dosage should be adjusted to achieve the desired trough serum IgG concentration and/or clinical response.263,265,266,282,308,324,337,338,339

If a patient with primary humoral immunodeficiency is exposed to measles or is at increased risk of measles exposure, some manufacturers state that it may be prudent to administer an extra IGIV dose or increase the IGIV dose, respectively.263,282,292,308,325,337,339 (See Measles under Dosage and Administration: Dosage for Immune Globulin IV [IGIV].)

Asceniv® 10%

The usual IV dosage of Asceniv^® 10% for replacement therapy in adults and adolescents 12 years of age or older with primary humoral immunodeficiency is 300-800 mg/kg given by IV infusion once every 3-4 weeks.338

Starting with the second IV infusion, dosage should be adjusted proportionally and trough IgG concentrations of 600 mg/dL or greater should be targeted.338 Dosage adjustment may be required in patients who fail to maintain trough serum IgG concentrations of at least 500 mg/dL with a target of 600 mg/dL.338

Bivigam® 10%

The usual IV dosage of Bivigam^® 10% for replacement therapy in adults and children 6 years of age or older with primary humoral immunodeficiency is 300-800 mg/kg given by IV infusion once every 3-4 weeks.324

Starting with the second IV infusion, dosage of Bivigam^® 10% should be adjusted over time to achieve and maintain trough serum IgG concentrations exceeding 600 mg/dL.324 In patients who fail to maintain trough serum IgG concentrations of at least 500 mg/dL, dosage should be adjusted to achieve a target trough serum IgG concentration of 600 mg/dL.324

Carimune® NF

The usual IV dosage of Carimune^® NF for replacement therapy in adults and children with primary immunodeficiency is 400-800 mg/kg given by IV infusion once every 3-4 weeks.125

Flebogamma® 5% DIF

The usual IV dosage of Flebogamma^® 5% DIF for replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency is 300-600 mg/kg given by IV infusion once every 3-4 weeks.282

Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.282 The manufacturer states that data are not available to date from randomized, controlled studies to determine an optimum target trough serum IgG concentration.282

Flebogamma® 10% DIF

The usual IV dosage of Flebogamma^® 10% DIF for replacement therapy in adults with primary immunodeficiency is 300-600 mg/kg given by IV infusion once every 3-4 weeks.325

Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.325 The manufacturer states that data are not available to date from randomized, controlled studies to determine an optimum target trough serum IgG concentration.325

Gammagard® Liquid 10%

The usual IV dosage of Gammagard^® Liquid 10% for replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency is 300-600 mg/kg given by IV infusion once every 3-4 weeks.266

Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.266 The manufacturer states that data are not available to date from randomized, controlled studies to determine an optimum target trough serum IgG concentration.266

Gammagard® S/D

The recommended IV dosage of Gammagard^® S/D (IgA less than 1 mcg/mL) for the treatment of primary immunodeficiency in adults and children 2 years of age or older is 300-600 mg/kg given by IV infusion once every 3-4 weeks.280

Dosage should be adjusted over time based on clinical response.280 The manufacturer states that data are not available to date from randomized, controlled studies to determine an optimum target trough serum IgG concentration.280

Gammaked® 10%

The recommended IV dosage of Gammaked^® 10% for replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency is 300-600 mg/kg (3-6 mL/kg) given by IV infusion once every 3-4 weeks.332 Dosage may be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.332

Gammaplex® 5%

The recommended IV dosage of Gammaplex^® 5% for replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency is 300-800 mg/kg (6-16 mL/kg) given by IV infusion once every 3-4 weeks.308 Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.308

If a patient misses a dose, the missed dose should be given as soon as possible and scheduled doses should be resumed every 3 or 4 weeks as applicable.308

Gammaplex® 10%

The recommended IV dosage of Gammaplex^® 10% for replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency is 300-800 mg/kg (3-8 mL/kg) given by IV infusion once every 3-4 weeks.337 Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.337

If a patient misses a dose, the missed dose should be given as soon as possible and scheduled doses should be resumed every 3 or 4 weeks as applicable.337

Gamunex®-C 10%

The recommended IV dosage of Gamunex^®-C 10% for replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency is 300-600 mg/kg (3-6 mL/kg) given by IV infusion once every 3-4 weeks.265 Dosage may be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.265

Octagam® 5%

The recommended IV dosage of Octagam^® 5% for replacement therapy in adults and pediatric patients with primary humoral immunodeficiency disease is 300-600 mg/kg (6-12 mL/kg) given by IV infusion once every 3-4 weeks.263 Dosage may be adjusted over time to achieve the desired trough IgG concentration and clinical response.263

If a patient misses a dose, the missed dose should be given as soon as possible and scheduled doses should be resumed every 3 or 4 weeks as applicable.263

Panzyga® 10%

The recommended IV dosage of Panzyga^® 10% for replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency is 300-600 mg/kg (3-6 mL/kg) given by IV infusion once every 3-4 weeks.339 Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.339

Privigen® 10%

The recommended IV dosage of Privigen^® 10% for replacement therapy in adults and children 3 years of age and older with primary humoral immunodeficiency disease is 200-800 mg/kg (2-8 mL/kg) given by IV infusion once every 3-4 weeks.292 Dosage should be adjusted over time to achieve the desired trough serum IgG concentration and clinical response.292 There are no data from randomized, controlled studies to date to determine an optimum target trough IgG concentration.292

If a patient misses a dose, the missed dose should be given as soon as possible and scheduled doses should be resumed every 3 or 4 weeks as applicable.292

Idiopathic Thrombocytopenic Purpura (ITP)

Carimune® NF

The usual IV dosage of Carimune^® NF for initial induction therapy in adults and children with ITP (also known as immune thrombocytopenic purpura or immune thrombocytopenia) is 400 mg/kg given by IV infusion once daily for 2-5 consecutive days.125

In the treatment of acute ITP of childhood, if an initial platelet count response to the first 2 doses is adequate (30,000-50,000/mm³), therapy may be discontinued after the second day of the 5-day regimen.125

In the treatment of chronic ITP in adults and children, if the platelet count decreases to less than 30,000/mm³ and/or clinically important bleeding becomes apparent following initial induction therapy with Carimune^® NF, a maintenance dose of 400 mg/kg may be given as a single infusion.125 If an adequate response does not occur, the maintenance dose may be increased to 800-1000 mg/kg given as a single infusion.125

Flebogamma® 10% DIF

The recommended IV dosage of Flebogamma^® 10% DIF for the treatment of chronic ITP in adults and children 2 years of age or older is 1 g/kg given by IV infusion once daily for 2 consecutive days.325

Gammagard® S/D

The usual IV dosage of Gammagard^® S/D (IgA less than 1 mcg/mL) for the treatment of chronic ITP in adults is 1 g/kg given by IV infusion as a single dose.280 The need for additional doses can be determined by clinical response and platelet count.280 If required, up to 3 doses may be given on alternate days.280

Gammaked® 10%

The usual IV dosage of Gammaked^® 10% for the treatment of ITP in adults and pediatric patients is 1 g/kg (10 mL/kg) given by IV infusion once daily on 2 consecutive days (total dose of 2 g/kg);332 if an adequate increase in platelet count is obtained at 24 hours after the initial dose of 1 g/kg (10 mL/kg) of the 2-dose regimen, the second 1-g/kg dose may be withheld.332 Alternatively, 400 mg/kg (4 mL/kg) may be given by IV infusion once daily for 5 consecutive days (total dose of 2 g/kg).332

The high-dose regimen of Gammaked^® 10% (1 g/kg given on 2 consecutive days) is not recommended in patients with expanded fluid volumes or when fluid volume may be a concern.332

Gammaplex® 5%

The usual IV dosage of Gammaplex^® 5% in adults with ITP is 1 g/kg (20 mL/kg) given by IV infusion once daily for 2 consecutive days (total dosage of 2 g/kg).308 The risks and benefits of this high-dose regimen should be carefully considered before using it in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload.308

Adequate data are not available regarding the platelet response to a lower-dose regimen of Gammaplex^® 5% (i.e., 400 mg/kg per day for 5 consecutive days).308

Gammaplex® 10%

The usual IV dosage of Gammaplex^® 10% in adults with ITP is 1 g/kg (10 mL/kg) given by IV infusion once daily for 2 consecutive days (total dosage of 2 g/kg).337 The risks and benefits of this high-dose regimen should be carefully considered before using it in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload.337

Adequate data are not available regarding the platelet response to a lower-dose regimen of Gammaplex^® 10% (i.e., 400 mg/kg daily for 5 consecutive days).337

Gamunex®-C 10%

The usual IV dosage of Gamunex^®-C 10% for the treatment of ITP in adults and pediatric patients is 1 g/kg (10 mL/kg) given by IV infusion on 2 consecutive days (total dose of 2 g/kg);265 if an adequate increase in platelet count is obtained at 24 hours after the initial dose of 1 g/kg (10 mL/kg) of the 2-dose regimen, the second 1-g/kg dose may be withheld.265 Alternatively, 400 mg/kg (4 mL/kg) may be given by IV infusion once daily for 5 consecutive days (total dose of 2 g/kg).265

The high-dose regimen of Gamunex^®-C 10% (1 g/kg given on 2 consecutive days) is not recommended in patients with expanded fluid volumes or when fluid volume may be a concern.265

Octagam® 10%

The usual IV dosage of Octagam^® 10% in adults with chronic ITP is 1 g/kg (10 mL/kg) given by IV infusion once daily for 2 consecutive days (total dose of 2 g/kg).326

Panzyga® 10%

The usual IV dosage of Panzyga^® 10% in adults with chronic ITP is 1 g/kg (10 mL/kg) given by IV infusion once daily on 2 consecutive days (total dose of 2 g/kg).339

Privigen® 10%

The recommended IV dosage of Privigen^® 10% in adults and adolescents 15 years of age and older with chronic ITP is 1 g/kg (10 mL/kg) given by IV infusion once daily for 2 consecutive days (total dose of 2 g/kg).292 The risks and benefits of this high-dose regimen should be carefully considered before using it in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload.292

Individuals with B-cell Chronic Lymphocytic Leukemia (CLL)

The usual IV dosage of Gammagard^® S/D (IgA less than 1 mcg/mL) for prevention of bacterial infections in adults with B-cell CLL who have hypogammaglobulinemia and/or recurrent bacterial infections is 400 mg/kg given by IV infusion once every 3-4 weeks.280

Kawasaki Disease

For initial treatment of the acute phase of Kawasaki disease, AAP, American Heart Association (AHA), and American College of Chest Physicians (ACCP) recommend that a single dose of 2 g/kg of IGIV be given by IV infusion (usually over 10-12 hours) initiated as soon as possible after the disease is diagnosed or strongly suspected (optimally within 7-10 days of disease onset).105,299,300 IGIV is used in conjunction with appropriate aspirin therapy (e.g., 80-100 mg/kg daily for up to 14 days and/or until the patient has been afebrile for 48-72 hours; may be followed by low-dose aspirin therapy).105,299,300

If there is no response (i.e., fever persists or recurs 36 hours or longer after the IGIV dose), AHA and AAP state that retreatment with a second IGIV dose of 2 g/kg and continued aspirin therapy is a reasonable option.299 Use of additional or alternative anti-inflammatory or immunosuppressive agents may be necessary in IGIV-resistant patients.105,299,300 Specialized references should be consulted for information on management of Kawasaki disease in such patients.299,300

Gammagard® S/D

For initial treatment of Kawasaki disease in adults or pediatric patients, the manufacturer recommends that Gammagard^® S/D (IgA less than 1 mcg/mL) be given by IV infusion as a single dose of 1 g/kg or, alternatively, in a dosage of 400 mg/kg once daily for 4 consecutive days beginning within 7 days of fever onset.280 Gammagard^® S/D is used in conjunction with appropriate aspirin therapy.280

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Gammaked® 10%

For the treatment of CIDP in adults, a loading dose of Gammaked^® 10% of 2 g/kg (20 mL/kg) should be given by IV infusion in divided doses over 2-4 consecutive days.332 Then, a maintenance dosage of 1 g/kg (10 mL/kg) may be given as a single IV infusion once every 3 weeks or, alternatively, as 2 doses of 0.5 g/kg (5 mL/kg) given by IV infusion on 2 consecutive days once every 3 weeks.332

Gamunex®-C 10%

For the treatment of CIDP in adults, a loading dose of Gamunex^®-C 10% of 2 g/kg (20 mL/kg) should be given by IV infusion in divided doses over 2-4 consecutive days.265 Then, a maintenance dosage of 1 g/kg (10 mL/kg) may be given as a single IV infusion once every 3 weeks or, alternatively, as 2 doses of 0.5 g/kg (5 mL/kg) given by IV infusion on 2 consecutive days once every 3 weeks.265 In clinical studies in patients with CIDP, Gamunex^®-C 10% has been continued for up to 48 weeks.298

Privigen® 10%

For the treatment of CIDP in adults, a total loading dose of Privigen^® 10% of 2 g/kg (20 mL/kg) should be given by IV infusion in divided doses over 2-5 consecutive days.292 Then, a maintenance dosage of 1 g/kg (10 mL/kg) may be given as a single IV infusion once every 3 weeks or, alternatively, as 2 divided doses given by IV infusion on 2 consecutive days once every 3 weeks.292

Privigen^® 10% maintenance therapy in patients with CIDP has not been studied for periods longer than 6 months.292 After a response is obtained during the initial treatment period, not all patients require indefinite maintenance therapy with Privigen^® 10% to remain free of CIDP symptoms.292 The patient's response and demonstrated need for continued Privigen^® 10% therapy beyond 6 months should be assessed.292

Multifocal Motor Neuropathy

Although optimum dosage of IGIV has not been established for use in patients with multifocal motor neuropathy (MMN) when disability is severe enough to warrant treatment, the European Federation of Neurological Societies (EFNS) and the Peripheral Nerve Society (PNS) suggest an initial dosage of 2 g/kg given in divided doses over 2-5 consecutive days.310,311 If the initial regimen is effective, these clinicians state that maintenance therapy can be considered using an IGIV dosage of 1 g/kg once every 2-4 weeks or 2 g/kg once every 1-2 months.310,311 The frequency of IGIV maintenance therapy should be guided by response.310,311

Gammagard® Liquid 10%

The manufacturer states that the usual maintenance dosage of Gammagard^® Liquid 10% for adults with MMN ranges from 500 mg/kg to 2.4 g/kg given by IV infusion once every month.266 Dosage adjustment may be required to achieve the desired clinical response and avoid worsening of muscle weakness.266 In a clinical trial, 9% of patients experienced neurologic decompensation that required an increase in dosage.266

Guillain-Barré Syndrome

Although safety and efficacy and optimum dosage of IGIV for the treatment of Guillain-Barré syndrome† (GBS) have not been established,312,317,318 EFNS and others recommend a dosage of 0.4 g/kg daily for 5 days.301,310,312 It is unclear whether IGIV is effective when initiated more than 2 weeks after symptom onset.317

If relapse of GBS† occurs after an initial response, EFNS states that retreatment with an IGIV dosage of 2 g/kg given in divided doses over 2-5 consecutive days can be considered.310 Retreatment also can be considered in those who do not respond to the initial regimen;310 however, other clinicians state that it is unclear whether retreatment is beneficial in such patients.305,318

Infections in HIV-infected Individuals

If IGIV is used for prevention of serious bacterial infections in HIV-infected infants and children† who have hypogammaglobulinemia (IgG less than 400 mg/dL), AAP, US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and other experts recommend that IGIV be given in a dosage of 400 mg/kg once every 2-4 weeks.156 IGIV should be discontinued if hypogammaglobulinemia resolves.156

Infections in Hematopoietic Stem Cell Transplant Recipients

If IGIV is used to prevent bacterial infections (e.g., Streptococcus pneumoniae sinopulmonary infections) in allogeneic hematopoietic stem cell transplant (HSCT) recipients† who experience severe hypogammaglobulinemia (IgG less than 400 mg/dL) within the first 100 days after transplant, some clinicians recommend that adults and adolescents receive 500 mg/kg once weekly and that pediatric patients receive 400 mg/kg once monthly.262 However, whenever IGIV is used for prophylaxis in hypogammaglobulinemic allogeneic HSCT recipients, it is recommended that dosage be individualized to maintain trough serum IgG concentrations exceeding 400-500 mg/dL and that trough serum IgG concentrations be monitored regularly (e.g., approximately every 2 weeks).262

Measles

If IGIV is used for postexposure prophylaxis of measles† in susceptible individuals (see Measles under Uses: Immune Globulin IV [IGIV]), ACIP and AAP recommend 400 mg/kg administered as a single dose within 6 days after exposure.105,133

Active immunization with a vaccine containing measles virus vaccine live (e.g., MMR) should then be initiated 8 months after administration of IGIV in individuals 12 months of age or older, unless the vaccine is contraindicated (see Measles, Mumps, Rubella, and Varicella Vaccines under Drug Interactions: Live Vaccines).105,133

ACIP and AAP state that individuals currently receiving immune globulin replacement therapy who received an IGIV dose of 400 mg/kg or greater within 3 weeks prior to measles exposure or received immune globulin subcutaneous in a dosage of 200 mg/kg or greater for 2 consecutive weeks prior to measles exposure should be sufficiently protected against measles.105,133

If a patient with primary humoral immunodeficiency receiving IGIV is exposed to measles, some manufacturers state that it may be prudent to administer an extra dose of IGIV as soon as possible and within 6 days after the exposure and that a dose of 400 mg/kg should provide serum levels of measles antibody that are greater than 240 mIU/mL for at least 2 weeks.263,282,292,308,325,337,339 These manufacturers state that if a patient with primary humoral immunodeficiency is receiving IGIV in a dosage less than 530 mg/kg once every 3-4 weeks and is at risk of measles exposure, the dose should be increased to at least 530 mg/kg since this should provide serum levels of measles antibody that are 240 mIU/mL for at least 22 days after the IGIV dose.263,282,292,308,325,337,339

Tetanus

If IGIV is used as an alternative to tetanus immune globulin (TIG) for the treatment of tetanus† when TIG is unavailable, a dosage of 200-400 mg/kg has been recommended.105

Toxic Shock Syndrome

When used as an adjunct in the treatment of staphylococcal or streptococcal toxic shock syndrome†, IGIV has been given in dosages of 150-400 mg/kg once daily for 5 days or, alternatively, a single dose of 1-2 g/kg has been used.105 Because the half-life of IGIV may be shortened in these patients, some clinicians suggest that more than a single dose may be needed.105 However, the optimal dosage regimen of IGIV in patients with toxic shock syndrome has not been identified.105

Varicella

If IGIV is used as an alternative to VZIG for postexposure prophylaxis of varicella infection† in individuals who do not have evidence of immunity and are at high risk for severe disease and complications (see Varicella under Uses: Immune Globulin IV [IGIV]), the recommended dosage is 400 mg/kg administered as a single dose (ideally within 96 hours after varicella exposure).105,156 IGIV may not be necessary in patients receiving replacement therapy with IGIV (i.e., 400 mg/kg or greater given at regular intervals) if the last dose was administered within 3 weeks prior to varicella exposure.105,146,156

Dosage for Immune Globulin Subcutaneous

Primary Immunodeficiency Diseases

Clinical response should be monitored and dosage of immune globulin subcutaneous should be individualized based on clinical response and trough serum IgG concentrations.265,266,294,327,331,332,340,341

ACIP and AAP state that individuals currently receiving immune globulin replacement therapy who received an IGIV dose of 400 mg/kg or greater within 3 weeks prior to measles exposure or received immune globulin subcutaneous in a dosage of 200 mg/kg or greater for 2 consecutive weeks prior to measles exposure should be sufficiently protected against measles.105,133

Cutaquig® 16.5%

For replacement therapy in adults with primary humoral immunodeficiency disease, Cutaquig^® 16.5% is administered subcutaneously once weekly.340

When switching patients from IGIV or a different immune globulin subcutaneous preparation to Cutaquig^® 16.5%, the patient should have received at least 3 months of prior treatment with IGIV or immune globulin subcutaneous and the first dose of Cutaquig^® 16.5% should be given 1 week after the last dose of the prior immune globulin.340

The initial dose of Cutaquig^® 16.5% should be calculated based on the dosage of IGIV or immune globulin subcutaneous that the patient was previously receiving.340

The manufacturer's literature should be consulted for specific information regarding initial and subsequent dosage of Cutaquig® 16.5%. 340

If a patient receiving Cutaquig^® 16.5% is exposed to measles, the manufacturer states that it may be prudent to administer a dose of IGIV as soon as possible and within 6 days after the exposure and that an IGIV dose of 400 mg/kg should provide serum levels of measles antibody that are greater than 240 mIU/mL for at least 2 weeks.340 If a patient is receiving Cutaquig^® 16.5% in a weekly dosage less than 245 mg/kg and is at risk of measles exposure, the manufacturer states that the weekly dosage should be increased to at least 245 mg/kg.340

Cuvitru® 20%

For replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency disease, Cuvitru^® 20% is administered subcutaneously at regular intervals ranging from once daily up to once every 2 weeks (biweekly).331

In patients switching from IGIV or immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®), the first dose of Cuvitru^® 20% should be given 1 week after the last dose of the other immune globulin.331

The initial dose of Cuvitru^® 20% can be calculated based on the monthly dose of the prior immune globulin regimen.331

The manufacturer's literature should be consulted for specific information regarding initial and subsequent dosage of Cuvitru® 20%. 331

Gammagard® Liquid 10%

For replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency disease, Gammagard^® Liquid 10% is administered subcutaneously once weekly.266

The initial weekly subcutaneous dose of Gammagard^® Liquid 10% should be given approximately 1 week after the last IGIV dose.266 The initial dose is calculated by dividing the patient's previous IGIV dose (in g) by the number of weeks between IGIV doses (i.e., divide by 3 or 4 depending on whether the patient was receiving IGIV every 3 or 4 weeks), then multiplying this value by a dose adjustment factor of 1.37.266

The maintenance weekly subcutaneous dose of Gammagard^® Liquid 10% is based on clinical response and target trough IgG concentrations.266

The manufacturer's literature should be consulted for specific information on how to adjust dosage of Gammagard® Liquid 10% based on trough serum IgG concentrations. 266

Gammaked® 10%

For replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency disease, Gammaked^® 10% is administered subcutaneously once weekly.332

The initial weekly subcutaneous dose of Gammaked^® 10% should be given 1 week after the last IGIV dose.332 The initial dose is calculated by dividing the patient's previous IGIV dose (in g) by the number of weeks between IGIV doses (i.e., divide by 3 or 4 depending on whether the patient was receiving IGIV every 3 or 4 weeks), then multiplying this value by a dose adjustment factor of 1.37.332 This dose can be converted to mL by multiplying the calculated dose (in g) by 10.332

The weekly dose of Gammaked^® 10% may be adjusted over time to achieve the desired trough serum IgG concentrations and clinical response.332

The manufacturer's literature should be consulted for specific information on how to adjust dosage of Gammaked ^®10% based on trough serum IgG concentrations and for specific information regarding dosage requirements for patients switching from another immune globulin subcutaneous preparation to Gammaked ^®10%. 332

Gamunex®-C 10%

For replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency disease, Gamunex^®-C 10% is administered subcutaneously once weekly.265

The initial weekly subcutaneous dose of Gamunex^®-C 10% should be given 1 week after the last IGIV dose.265 The initial dose is calculated by dividing the patient's previous IGIV dose (in g) by the number of weeks between IGIV doses (i.e., divide by 3 or 4 depending on whether the patient was receiving IGIV every 3 or 4 weeks), then multiplying this value by a dose adjustment factor of 1.37.265 This dose can be converted to mL by multiplying the calculated dose (in g) by 10.265

Adjustment of the weekly dose of Gamunex^®-C 10% may be required over time to achieve the desired trough serum IgG concentrations and clinical response.265

The manufacturer's literature should be consulted for specific information on how to adjust dosage of Gamunex ^®-C 10% based on trough serum IgG concentrations and for specific information regarding dosage requirements for patients switching from another immune globulin subcutaneous preparation to Gamunex ^®-C 10%. 265

Hizentra® 20%

For replacement therapy in adults and children 2 years of age or older with primary humoral immunodeficiency disease, Hizentra^® 20% is administered subcutaneously at regular intervals ranging from once daily up to once every 2 weeks (biweekly).294

Patients should have been receiving IGIV for at least 3 months before being switched to Hizentra^® 20%.294 The initial dose of Hizentra^® 20% should be given 1 week after the last IGIV dose.294 The initial weekly dose of Hizentra^® 20% should be calculated by dividing the patient's previous IGIV dose (in g) by the number of weeks between IGIV doses (e.g., divide by 3 or 4 depending on whether the patient was receiving IGIV every 3 or 4 weeks), then multiplying this value by a dose adjustment factor of 1.37.294

The manufacturer's literature should be consulted for specific information regarding initial and subsequent dosage of Hizentra® 20% .294

If a patient receiving Hizentra^® 20% is at risk of measles exposure (i.e., susceptible traveler to an area outside the US where measles is endemic, measles outbreak in US), the minimum weekly dosage of Hizentra^® 20% should be at least 200 mg/kg for 2 consecutive weeks;294 if the patient is receiving a biweekly regimen, a single dose of at least 400 mg/kg should be given.294 If the patient has been exposed to measles, a single dose of at least 400 mg/kg should be administered as soon as possible after the exposure.294

Hyqvia® (Immune Globulin Subcutaneous 10% with Recombinant Human Hyaluronidase)

Immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) is commercially available as a kit that contains a vial of immune globulin subcutaneous 10% copackaged with a vial of recombinant human hyaluronidase.327 Although dosage of the recombinant human hyaluronidase component is the same for all patients, dosage of the immune globulin subcutaneous 10% component must be individualized.327

For replacement therapy in adults with primary immunodeficiency, Hyqvia^® is administered subcutaneously once every 3 to 4 weeks after an initial ramp-up period that incrementally changes the dosage regimen from a 1-week regimen to a 3- or 4-week regimen and allows the patient to become accustomed to the large volumes required for a full monthly dose.327

For each dose of Hyqvia^®, the entire contents of the vial containing recombinant human hyaluronidase (2.5 mL containing 160 units/mL) should be administered first.327 The appropriate dose of the immune globulin subcutaneous 10% component should then be administered within approximately 10 minutes at the same subcutaneous infusion site using the same needle set.327 (See Hyqvia^® [Immune Globulin Subcutaneous 10% with Recombinant Human Hyaluronidase] under Reconstitution and Administration: Immune Globulin Subcutaneous, in Dosage and Administration.)

In patients already receiving an immune globulin preparation, the first dose of Hyqvia^® for the ramp-up period should be administered approximately 1 week after the last dose of the previous immune globulin preparation.327 The target dose of the immune globulin subcutaneous 10% component of Hyqvia^® after the ramp-up period should be the same as the immune globulin dose the patient was previously receiving.327

In patients who are immune globulin naive or have been receiving a different immune globulin subcutaneous preparation, the target dose of the immune globulin subcutaneous 10% component of Hyqvia^® after the initial dose ramp-up period should be 300-600 mg/kg once every 3-4 weeks.327

Dosage adjustment of the immune globulin 10% component may be required over time to achieve the desired clinical response and trough serum IgG concentrations.327

The manufacturer's literature should be consulted for specific information on the ramp-up schedule, including dosage of the immune globulin 10% component and dosing intervals. 327The manufacturer's literature also should be consulted for specific information on how to adjust dosage of the immune globulin 10% component based on trough serum IgG concentrations. 327

Xembify® 20%

For replacement therapy in adults and pediatric patients 2 years of age or older with primary humoral immunodeficiency disease, Xembify^® 20% is administered subcutaneously once weekly.341 Alternatively, the weekly dose can be divided and given in 2-7 doses during the week.341

When switching patients from IGIV to Xembify^® 20%, the initial dose of Xembify^® 20% should be calculated based on the previous monthly (or every 3 weeks) dosage of IGIV and should be given 1 week after the last IGIV dose.341 When switching patients from a different immune globulin subcutaneous preparation to Xembify^® 20%, the initial weekly dose of Xembify^® 20% should be the same as the previously weekly dose of prior immune globulin subcutaneous treatment.341 Subsequent doses should be based on clinical response and target trough IgG concentrations.341

The manufacturer's literature should be consulted for specific information regarding initial and subsequent dosage of Xembify® 20%. 341

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Hizentra® 20%

When Hizentra^® 20% is used for maintenance treatment to prevent relapse in adults with CIDP, the initial dose should be administered subcutaneously 1 week after the last IGIV dose.294 The recommended dosage of Hizentra^® 20% for such maintenance therapy is a weekly dose of 0.2 g/kg (1 mL/kg) administered by subcutaneous infusion in 1 or 2 sessions over 1 or 2 consecutive days.294 Data from the clinical study evaluating use of Hizentra^® 20% for maintenance therapy in CIDP patients transitioning from IGIV indicate that a weekly dose of 0.4 g/kg (2 mL/kg) also is safe and effective when used to prevent CIDP relapse.294

If CIDP symptoms worsen, discontinuing Hizentra^® 20% and reinitiating IGIV treatment should be considered.294 If improvement and stabilization are observed during IGIV retreatment, discontinuing IGIV and reinitiating Hizentra^® 20% using a weekly dose of 0.4 g/kg administered by subcutaneous infusion in 2 sessions over 1 or 2 consecutive days can be considered.294 If CIDP symptoms worsen on the weekly subcutaneous dose of 0.4 g/kg, discontinuance of Hizentra^® 20% and reinitiation of IGIV should be considered.294

Use of Hizentra^® 20% maintenance therapy in adults with CIDP has been systematically studied for a duration of 6 months and for an additional 12 months in a follow-up study.294 Use of the drug for maintenance therapy for a longer duration should be individualized based on the patient's response and need for continued therapy.294

Immune Globulin IM (IGIM)

The most common adverse reaction reported for immune globulin IM (IGIM) is fatigue.154 Headache, nausea, and fever have also been reported.154 Injection site reactions (pain, inflammation) have occurred.154

Hypersensitivity reactions manifested as rash, flushing, and dyspnea or severe systemic reactions (including anaphylactic reactions) have been reported in patients hypersensitive to IGIM.154 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Thrombosis

Thrombosis may occur following treatment with immune globulin, including IGIM.154

Risk factors for thrombosis in patients receiving IGIM may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogen-containing preparations, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors.154 Thrombosis may occur in the absence of known risk factors.154 (See Thrombosis Precautions under Cautions: Precautions and Contraindications.)

Immune Globulin IV (IGIV)

Adverse reactions to immune globulin IV (IGIV) have been reported in 10% or less of individuals receiving the drug. Certain adverse reactions to IGIV, including severe reactions, may be related to the rate of administration rather than the dose and may be relieved by decreasing the rate of administration or by temporarily stopping the infusion.263,265,266,280,308,324,332,337,338,339 Patients who have not previously received IGIV or have not received IGIV within the previous 8 weeks may be at higher risk of developing adverse reactions (e.g., transfusion reactions, systemic reactions resembling an inflammatory response or infection) if the immune globulin is administered by rapid IV infusion.125,282,292,325

Infusion site reactions (pain, irritation);265,266,280,282,292 mild chest, hip, joint, or back pain;263,265,282,308 arthralgia125,263,265,282 or myalgia;125,308 diarrhea;265,266,282 nausea;263,265,266,282,292,308 vomiting;263,265,266,282,308 chills;263,266,282,292,308 fever;263,265,266,282,292,308 asthenia;265 malaise;282 fatigue;266,282,292,308 insomnia;308 dizziness;263,265,266 headache;263,265,266,282,292,308 immediate anaphylactoid and hypersensitivity reactions;125 allergic and cutaneous reactions263,282 such as rash,125 erythema,125 pruritus,125 urticaria,125,265 eczema,125 or dermatitis;125 flushing; hypertension or changes in blood pressure;263,292,308 palpitations;282 tachycardia;282 increased liver function test results;263,265,282 asthma;265,282 wheezing;282 otic pain;265 upper respiratory tract infection;308 cough (increased or productive);265,266,282 bronchitis;282 rhinitis/nasal congestion;308 sinusitis;282,308 and pharyngitis265 have been reported following administration of IGIV. Reversible increases in liver function test results also have been reported.263

In clinical studies evaluating IGIV in adults and children with idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura or immune thrombocytopenia), the most common adverse effects were headache,125,265,265,292,308,325,332,339 fever,265,292,308,325,332,339 chills,325 GI effects (nausea,265,292,308,325,332,339 vomiting,265,292,325,332,339 diarrhea,325 dyspepsia265,332 ), dizziness,325,339 hypotension,325 hypertension,325 increased heart rate,325 pain (abdominal or back),265,325,332 dehydration,308 rash,265,332 pruritus,308 ecchymosis,265,332 and anemia.292,339

In clinical studies evaluating IGIV in adults with chronic inflammatory demyelinating polyneuropathy (CIDP), the most common adverse effects were headache,265,292,332 fever,265,332 chills,265,332 nausea,265,292,332 hypertension,265,292,332 pain (extremity),292 arthralgia,265,332 influenza-like illness,292 leukopenia,292 rash,265,292,332 and asthenia.265,292,332

Infusion Reactions

Occasionally, IGIV causes a precipitous fall in blood pressure and clinical manifestations of anaphylaxis, even in patients without a history of sensitivity to immune globulin.125,265,266,282 These reactions generally appear 0.5-1 hour after initiation of the infusion and include flushing of the face, tightness in the chest, chills, fever, dizziness, nausea, vomiting, diaphoresis, and hypotension or hypertension.125 These reactions appear to be related to the rate of administration of IGIV.266 Individuals receiving IGIV for the first time or restarting IGIV after a treatment hiatus of more than 8 weeks may be at higher risk for the development of fever, chills, nausea, and vomiting.125,282,325 (See Administration Precautions under Cautions: Precautions and Contraindications.)

Hypertensive urgency with elevated systolic blood pressure (180 mm Hg or greater) and/or elevated diastolic blood pressure (greater than 120 mm Hg) has been reported during and/or shortly following infusion of IGIV (Privigen^® 10%.)292 These blood pressure elevations were reported more often among patients with a history of hypertension and resolved or significantly improved within hours with either observation alone or changes in oral antihypertensive therapy.292

Thrombosis

Thrombotic events, including some fatalities, have been reported in patients receiving IGIV and include chest pain, myocardial infarction, congestive heart failure, cerebral vascular accident or infarction, ischemic encephalopathy, severe headache requiring hospitalization, pulmonary embolism, retinal vein occlusion, and peripheral deep-vein thrombosis.125,252,253,254,255,257,258,263,265,266,294,308,324,325,326,332,337,338,339 Although the precise etiology of these events has not been fully elucidated, immune globulin-induced alterations of blood rheology (e.g., activation of platelets, increases in blood viscosity, elevated levels of activated coagulation factor XI [XIa]) and infusion-related hypertensive effects appear to contribute to the development of such thrombotic complications.252,253,256,260,329

Patients at risk for thrombotic events may include those with a history of atherosclerosis, cardiovascular risk factors, impaired cardiac output, coagulation or hypercoagulable disorders (e.g., factor V Leiden), prolonged periods of immobilization, advanced age, acquired or inherited thrombotic disorder, previous thrombotic or thromboembolic event, known or suspected hyperviscosity, indwelling central vascular catheters, and/or those receiving estrogen-containing preparations.125,263,265,266,292,294,308,332,337,338,339 The risk of such complications also appears to be increased in patients with a history of cardiovascular disease and/or thrombosis who receive IGIV by rapid IV infusion.252,253,255,258,259,260,292,339 Thrombosis may occur in patients without known risk factors.125,154,263,265,324,325,326,328,332,337,338,339 (See Thrombosis Precautions under Cautions: Precautions and Contraindications.)

Renal Effects

Renal dysfunction, acute renal failure, osmotic nephrosis, and death have been reported in patients receiving IGIV.125,249,251,263,265,282,292,308,324,325,326,332,337,338,339 In some patients with IGIV-associated acute renal failure, renal histopathology findings suggested osmotic injury to the proximal renal tubules (acute tubular necrosis, vacuolar degeneration, osmotic nephrosis).249 Increases in serum creatinine and BUN have occurred as soon as 1-2 days following infusion of IGIV,125,265 predominately with preparations stabilized with sucrose.265 Progression to oliguria or anuria (requiring dialysis) has been observed,125,265 although some patients have improved spontaneously following discontinuance of IGIV.265 Many of the reported fatalities related to nephrotoxicity occurred in patients with serious underlying conditions.249,251

Approximately 55% of reported cases of renal dysfunction have involved patients receiving IGIV for the treatment of ITP;249 less than 5% involved patients receiving the drug for primary immunodeficiency diseases.249 The increased rate of renal dysfunction among patients with ITP may be related to the fact that IGIV is administered in higher dosages and is given for several consecutive days for the treatment of ITP instead of the intermittent dosing regimen usually used for primary immunodeficiency diseases.249 Further study is needed to determine if other factors (e.g., age, baseline glomerular filtration rate) are associated with the increased rate of renal dysfunction reported in patients receiving IGIV for ITP.249

There is some evidence that IGIV preparations stabilized with sucrose (e.g., Carimune^® NF), are associated with a greater risk of developing IGIV-associated renal dysfunction125,249,263,265,266,292 since approximately 88% of reports of such adverse effects in the US have involved use of these preparations.249 The degree of risk may depend on the amount of sucrose contained in the formulation and hyperosmolality after reconstitution.249

To reduce the risk of acute renal failure in patients receiving IGIV, patients should be adequately hydrated prior to administration of the drug, recommended dosage and rate of IV infusion should not be exceeded, and renal function should be monitored.125,249,263,265,266,282,292,308,324 In addition, if the drug is used in patients considered at risk of acute renal failure (e.g., adults older than 65 years of age, individuals with any degree of preexisting renal insufficiency, individuals receiving nephrotoxic drugs, individuals with diabetes mellitus, volume depletion, paraproteinemia, or sepsis), a reduction in dose, concentration, and/or rate of administration should be considered.125,249,263,265,266,292 (See Renal Precautions under Cautions: Precautions and Contraindications.)

Hyperproteinemia, Increased Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV.263,265,266,280,282,292,308,324,325,326,332,337,338,339 The hyponatremia is likely to be pseudohyponatremia, as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap.263,265,266,292,308,325

If hyponatremia occurs, it is critical to distinguish true hyponatremia from pseudohyponatremia.263,265,266,292,308,324,325,326,332,337,338,339 Treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and may predispose to thromboembolic events.263,265,266,292,308,324,332,338,339

Aseptic Meningitis Syndrome

Aseptic meningitis syndrome has been reported in patients receiving IGIV therapy.125,211,263,265,266,282,292,294,308,324,325,326,332,337,338,339 The syndrome, which may occur more frequently in patients receiving high doses (e.g., 2 g/kg) and/or rapid infusion of immune globulin, usually is evident within several hours to 2 days after administration and is characterized by severe headache (including migraine), nuchal rigidity, drowsiness, lethargy, fever, photophobia, painful eye movements, and nausea and vomiting.125,211,212,263,265,266,282,292,308,324,332,337,338,339 Aseptic meningitis syndrome may occur more frequently in female patients.266,280 In addition, although information is limited, patients with a history of migraine may be more susceptible to aseptic meningitis syndrome and may have severe symptoms requiring additional hospitalization and treatment with opiate analgesics.211 The cause of aseptic meningitis syndrome in patients receiving immune globulin is not known.211 It has been suggested that the syndrome may result from an allergic hypersensitivity reaction associated with distribution of components of the preparation into the CSF; alternatively, IgG antibodies present in immune globulin, which are allogeneic, may accumulate in the CNS and initiate reactions resulting in aseptic meningitis.211 The syndrome has been reported with various commercially available preparations and does not appear to be related to a specific formulation.211,212

Patients with signs and symptoms of aseptic meningitis should receive a thorough neurologic examination, including CSF analysis, to rule out other causes of meningitis.125,263,266,282,292,308,324,332,337,338,339 CSF analysis frequently reveals protein levels (up to several hundred mg/dL) and pleocytosis (up to several thousand cells per mm³), predominantly from the granulocytic series,125,211,212,263,266,282,308,324,332,337,338,339 but negative culture results.265,266,292,324,332,338,339

Discontinuance of immune globulin therapy has resulted in resolution of aseptic meningitis syndrome within several days (3-5 days) without sequelae.125,211,212,263,265,266,282,294,308,324,332,337,338,339

Hemolysis

IGIV may contain blood group antibodies which can act as hemolysins and induce in vivo coating of erythrocytes with immunoglobulin, causing a positive direct antiglobulin reaction and hemolysis.125,263,265,266,282,292,308,324,325,326,332,337,338,339 Acute intravascular hemolysis has been reported and delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced erythrocyte sequestration.125,263,265,266,282,292,308,324,325,326,332,337,338,339 Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV.263,292,308,325,326,337,339

Risk factors that may be associated with the development of hemolysis following IGIV administration include use of high doses (e.g., 2 g/kg or greater, given either as a single dose or in divided doses over several days) and non-O blood group.263,265,266,282,292,308,325,326,332,337,339 Although other individual patient factors have been hypothesized to increase the risk of hemolysis following IGIV administration, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), the role of such factors is uncertain.263,265,266,282,292,308,325,326,332,337,339 Hemolysis has been reported following administration of IGIV for a variety of indications, including primary humoral immunodeficiency and ITP.263,292,308,325,326,337,339 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (noncardiogenic pulmonary edema) has been reported in patients receiving IGIV.125,263,265,266,282,292,308,324,325,326,332,337,338,339 This typically occurs within 1-6 hours after IV infusion and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever.125,263,265,266,282,292,308,324,332,337,338,339 Patients should be managed using oxygen therapy with adequate ventilatory support.125,263,265,266,308,324,332,337,338,339 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Immune Globulin Subcutaneous

Adverse effects reported in 5% or more of patients receiving immune globulin subcutaneous (Cutaquig^® 16.5%, Cuvitru^® 20%, Gammagard^® Liquid 10%, Gammaked^® 10%, Gamunex^®-C 10%, Hizentra^® 20%, Hyqvia^®, Xembify^® 20%) include infusion site reactions (e.g., erythema, pain, swelling, induration, edema, pruritus, heat, bruising, hematoma, nodule, scab),265,266,294,327,331,340,341 headache,265,266,294,327,331,332,340 migraine headache,265,266,294,332 fever,265,266,327,332,340 fatigue,265,266,294,327,331,332 cough,294,341 upper respiratory tract infection,265,294,332 asthma,266,340 GI effects (e.g., nausea, vomiting, diarrhea, upper abdominal pain, stomatitis),265,266,294,327,331,332,340,341 increased heart rate,266 increased systolic blood pressure,266 pain (back pain, extremity pain),266,294,332 arthralgia,265,332 cough,294 dermatitis,340 rash,294 and pruritus.294

Thrombosis

Thrombotic events have been reported in patients receiving immune globulin preparations, including immune globulin subcutaneous, and have included chest pain, myocardial infarction, congestive heart failure, cerebral vascular accident or infarction, ischemic encephalopathy, severe headache requiring hospitalization, pulmonary embolism, retinal vein occlusion, and peripheral deep-vein thrombosis.125,252,253,254,255,257,258,263,265,266,294,308,324,325,326,327,332,340,341 Although the precise etiology of these events has not been fully elucidated, immune globulin-induced alterations of blood rheology (e.g., activation of platelets, increases in blood viscosity) and infusion-related hypertensive effects appear to contribute to the development of such thrombotic complications.252,253,256,260,266,294,327,332

Patients at risk for thrombotic events may include those with multiple cardiovascular risk factors, coagulation or hypercoagulable disorders, prolonged periods of immobilization, advanced age, previous thrombotic or thromboembolic event, known or suspected hyperviscosity, indwelling central vascular catheters, and/or those receiving estrogen-containing preparations.265,266,294,327,332,340,341 Thrombotic events may also occur in the absence of known risk factors.265,266,294,327,332,340,341 (See Thrombosis Precautions under Cautions: Precautions and Contraindications.)

Aseptic Meningitis Syndrome

Aseptic meningitis syndrome has been reported with immune globulin subcutaneous.266,294,331,332,340,341 The syndrome, which may occur more frequently in patients receiving high doses (e.g., 2 g/kg) and/or rapid infusion of immune globulin, usually is evident within several hours to 2 days after administration and is characterized by severe headache (including migraine), nuchal rigidity, drowsiness, lethargy, fever, photophobia, painful eye movements, and nausea and vomiting.294,327,331,332,340,341 (See Aseptic Meningitis Syndrome under Immune Globulin IV [IGIV], in Cautions.)

Other Serious Adverse Effects

Other serious adverse effects reported with IGIV (e.g., anaphylactic and hypersensitivity reactions, infusion reactions, renal dysfunction or acute renal failure, hemolysis, transfusion-related acute lung injury) also may occur with immune globulin subcutaneous.266,294,327,331,340,341 (See Cautions: Immune Globulin IV [IGIV].)

Immunogenicity of Recombinant Human Hyaluronidase

In clinical studies evaluating immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®), 18% of patients developed nonneutralizing antibodies to the recombinant human hyaluronidase component (anti-rHuPH20 antibodies).327 The clinical importance of these anti-recombinant human hyaluronidase antibodies is not known.327 Animal studies indicate that antibodies to recombinant human hyaluronidase cross the placenta and are transferred to offspring during lactation.327 There also is the potential for these antibodies to cross-react with endogenous human hyaluronidase, which is expressed in adult male testes, epididymis, and sperm.327 (See Cautions: Pregnancy, Fertility, and Lactation.)

Precautions and Contraindications

IGIM, IGIV, and immune globulin subcutaneous are contraindicated in individuals with a history of anaphylactic or severe systemic hypersensitivity reactions to immune globulin or any ingredient in the formulation.125,154,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

IGIM, IGIV, and immune globulin subcutaneous also are contraindicated in IgA-deficient individuals with antibodies against IgA and a history of hypersensitivity.125,154,263,265,266,282,292,294,308,324,325,327,331,332,337,338,339,340,341 (See IgA Deficiency under Precautions and Contraindications: Sensitivity Reactions, in Cautions.)

Flebogamma^® 5% DIF and Flebogamma^® 10% DIF should not be used in patients with hereditary fructose intolerance since these IGIV preparations contain sorbitol, which presents a risk to individuals with hereditary fructose intolerance.282,325 Symptoms of hereditary fructose intolerance include recurrent vomiting, abdominal pain, and hypoglycemia and the condition is usually diagnosed in young children who become symptomatic after breast-feeding when fructose or sucrose is introduced into the diet.282,325

Gammaplex^® 5% contains sorbitol and is contraindicated in patients with hereditary fructose intolerance and in neonates and infants for whom sucrose or fructose tolerance has not been established.308

Hizentra^® 20% and Privigen 10% contain l-proline as a stabilizer and these preparations are contraindicated in individuals with hyperprolinemia (type I or II).292,294

Hyqvia^® (immune globulin subcutaneous 10% with recombinant human hyaluronidase) is contraindicated in patients with known systemic hypersensitivity to human albumin (contained in the hyaluronidase component).327

Octagam^® 5% is contraindicated in individuals with acute hypersensitivity reactions to corn.263 (See Corn Allergy under Precautions and Contraindications: Sensitivity Reactions, in Cautions.)

Administration Precautions

IGIV occasionally causes a precipitous fall in blood pressure and the clinical manifestations of anaphylaxis, even in patients who previously tolerated IGIV.265,266,282,325 Some severe reactions appear to be related to the rate of administration of the drug;266,282 the recommended rate of infusion should not be exceeded.265,266,282 If flushing, changes in blood pressure or pulse, or other infusion reactions occur, the infusion should be slowed or temporarily stopped.125,266 If symptoms subside, the infusion may be resumed at a rate that is comfortable for the patient.125,266

Patients who have not previously received IGIM, IGIV, or immune globulin subcutaneous, have not received immune globulin within the preceding 8 weeks, or are being switched from another preparation of immune globulin are at risk of developing reactions including fever, chills, nausea, and vomiting.125,282,292,325

Thrombosis Precautions

The fact that thrombotic events, including chest pain, myocardial infarction, congestive heart failure, cerebral vascular accident or infarction, ischemic encephalopathy, severe headache requiring hospitalization, pulmonary embolism, retinal vein occlusion, and peripheral deep-vein thrombosis, have been reported in patients receiving immune globulin should be considered.125,154,252,253,254,255,256,257,258,259,263,265,266,282,292,294,308,324,325,326,327,328,329,331,332,337,338,339,340,341 (See Thrombosis under Cautions: Immune Globulin IV [IGIV].)

Prior to immune globulin therapy, all patients with risk factors for thrombosis should be carefully evaluated.252,253,255,256,257,259,260,308,328,329,331,332,337,338,341 This includes those with a history of atherosclerosis, cardiovascular risk factors, impaired cardiac output, coagulation or hypercoagulable disorders (e.g., factor V Leiden), prolonged periods of immobilization, advanced age, acquired or inherited thrombotic disorder, history of venous or arterial thrombosis, known or suspected hyperviscosity, indwelling central vascular catheters, and/or treatment with estrogen-containing preparations.125,154,263,265,266,282,292,294,308,324,325,326,327,328,329,331,332,337,338,340,341 However, thrombosis may occur in patients with no known risk factors.125,154,263,265,266,282,292,294,308,324,325,326,327,328,331,332,337,338,339,340,341

For all patients, the potential risks and benefits of immune globulin should be weighed against those of alternative therapies.125,263,265,266,292,308,328

When immune globulin is used in patients at risk for thrombosis, the minimum dose and minimum infusion rate practicable should be used and patients should be monitored closely for signs and symptoms of thrombosis.125,154,263,265,266,282,292,294,308,324,325,326,327,328,329,331,332,337,338,339,340,341 In addition, all patients should be adequately hydrated prior to administration of immune globulin.125,154,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Because of the possible increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.125,154,263,265,266,282,292,294,308,324,325,326,327,328,329,331,332,337,338,339,340,341

Patients receiving immune globulin should be advised to immediately inform a clinician if symptoms of thrombosis occur, including pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, unexplained rapid pulse, chest pain or discomfort that worsens on deep breathing, numbness or weakness on one side of the body, changes in mental status/confusion, numbness in the face or extremities, weakness or paralysis, severe headache, and/or visual disturbances.154,125,154,263,265,266,282,294,308,324,325,326,327,328,331,332,337,338,339,340,341

Renal Precautions

Because renal dysfunction, acute renal failure, osmotic nephrosis, and death have been reported in patients receiving immune globulin,125,249,251,263,265,266,282,292,308,324,325,326,331,332,337,337,339,340,341 urine output and renal function (BUN and serum creatinine concentrations) should be assessed prior to and at appropriate intervals during therapy with IGIV or immune globulin subcutaneous, especially in patients considered at increased risk of acute renal failure.125,249,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341 In addition, all patients should be adequately hydrated prior to administration of immune globulin.125,249,251,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Patients considered at increased risk of developing acute renal failure include, but are not limited to, those with any degree of preexisting renal insufficiency, diabetes mellitus, hypovolemia, volume depletion, sepsis, or paraproteinemia; those receiving concomitant nephrotoxic drugs; and/or those older than 65 years of age.125,249,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341 Particular caution should be observed if immune globulin is administered to patients considered at increased risk of developing acute renal failure, and reduction in dosage, concentration, and/or rate of administration should be considered in such patients.125,249,263,265,324,325,326,331,332,337,338,339,340,341

When immune globulin is used in patients at risk for renal dysfunction, the minimum dose and minimum infusion rate practicable should be used and patients should be monitored closely for signs and symptoms of renal dysfunction.125,154,263,265,266,282,292,294,308,324,325,326,327,328,329,331,332,337,338,339,340,341 (See Dosage and Administration: Reconstitution and Administration.) If renal function deteriorates, consideration should be given to discontinuing immune globulin therapy.125,249,263,265,266,282,292,308,324,325,326,331,332,337,338,339,340,341

Because renal dysfunction has been reported more frequently with IGIV preparations stabilized with sucrose (Carimune^® NF) than with other IGIV preparations,125,249,261,263,265,266,282,292 the benefits of such preparations should be carefully weighed against the potential risk of IGIV-associated renal dysfunction.249 If a sucrose-containing IGIV preparation is used, it has been recommended that the rate of infusion of these preparations not exceed 3 mg of sucrose/kg per minute (maximum infusion rate that will deliver 2 mg IgG/kg per minute for Carimune^® NF).125,249,261

Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest renal damage) to their clinician.125,249,263,265,266,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Sensitivity Reactions

Severe hypersensitivity reactions, including anaphylaxis, may occur rarely following administration of IGIM, IGIV, or immune globulin subcutaneous in patients hypersensitive to immune globulin or some component of the preparation.154,263,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

IgA-deficient individuals with antibodies against IgA may be at increased risk of severe hypersensitivity and anaphylactoid reactions if they receive immune globulin.154,263,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341 (See IgA Deficiency under Precautions and Contraindications: Sensitivity Reactions, in Cautions.)

If a severe hypersensitivity reaction occurs, the immune globulin should be discontinued immediately and appropriate therapy should be instituted as indicated.154,263,266,292,294,308,324,325,326,327,331,332,337,338,339,340,341 Epinephrine and antihistamines should be readily available in case anaphylaxis or an anaphylactoid reaction occurs.125,154,263,265,266,282,292,308,331,332,337,338,339,340

Patients should be advised about the early signs of hypersensitivity (e.g., hives, generalized urticaria, chest tightness, wheezing, hypotension, anaphylaxis) and the importance of immediately contacting a clinician if allergic symptoms occur.263,265,266,294,308,324,325,326,327,337,338,339,340,341

IGIM should be used with caution in patients with a history of systemic allergic reactions to immune globulin preparations.154 The manufacturer of IGIM states that intradermal sensitivity testing should not be performed because intradermal injection of concentrated buffered immune globulin solution causes a localized area of inflammation in most patients because of chemical irritation and this may be misinterpreted as evidence of hypersensitivity.154 Such misinterpretation may result in beneficial therapy being withheld from a patient who is not hypersensitive to immune globulin.154

IgA Deficiency

IGIM, IGIV, and immune globulin subcutaneous should not be used in IgA-deficient individuals with antibodies against IgA and a history of hypersensitivity.125,263,265,266,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Individuals with selective IgA deficiency or individuals in whom IgA deficiency exists as a component of an immunodeficiency disease may have serum antibodies to IgA or may develop such antibodies following administration of immune globulin or other blood products containing IgA.125,154,263,265,266,280,282,292,308,337,338,339,340,341 Severe hypersensitivity reactions (e.g., anaphylaxis) could result following administration of immune globulin in individuals with antibodies to IgA.125,154,263,265,266,282,292,294,308,327,337,338,339,340,341

All commercially available preparations of IGIV and immune globulin subcutaneous contain trace amounts of IgA, but the amount varies among the different preparations.125,262,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341 The concentration of IgA that will not provoke a reaction to IgA is not known.280

Asceniv^® 10% contains 200 mcg/mL or less of IgA.338

Bivigam^® 10% contains 200 mcg/mL or less of IgA.324

Carimune^® NF contains trace amounts of IgA.125

Cutaquig^® 16.5% contains 600 mcg/mL or less of IgA.340

Cuvitru^® 20% contains an average of 80 mcg/mL of IgA.331

Flebogamma^® 5% DIF contains less than 50 mcg/mL of IgA.262

Flebogamma^® 10% DIF contains less than 32 mcg/mL of IgA.325

Gammagard^® Liquid 10% contains an average of 37 mcg/mL of IgA.266

Gammagard^® S/D is available in a formulation containing less than 1 mcg/mL of IgA.280

Gammaked^® 10% contains an average of 46 mcg/mL of IgA.332

Gammaplex^® 5% contains trace amounts of IgA (less than 10 mcg/mL).308

Gammaplex^® 10% contains trace amounts of IgA (less than 20 mcg/mL).337

Gamunex^®-C 10% contains an average of 46 mcg/mL of IgA.265

Hizentra^® 20% contains 50 mcg/mL or less of IgA.294

Hyqvia^®: The immune globulin component contains an average of 37 mcg/mL of IgA.327

Octagam^® 5% contains 200 mcg/mL or less of IgA.263

Octagam^® 10% contains an average of 106 mcg/mL of IgA.326

Panzyga^® 10% contains an average of 100 mcg/mL of IgA.339

Privigen^® 10% contains 25 mcg/mL or less of IgA.292

Xembify^® 20% contains IgA (amount not specified).341

Corn Allergy

Some IGIV preparations (i.e., Octagam^® 5%, Octagam^® 10%) contain maltose, a disaccharide sugar derived from corn.263,326 Hypersensitivity reactions may occur if these preparations are used in patients with corn allergy.263,326 The manufacturer states that Octagam^® 5% should be avoided in patients with known corn allergies and is contraindicated in those with acute hypersensitivity reactions to corn.263

Risk of Transmissible Agents in Plasma-derived Preparations

Because IGIM, IGIV, and immune globulin subcutaneous are prepared from pooled human plasma, they are potential vehicles for transmission of human viruses (e.g., hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV]) and theoretically may carry a risk of transmitting the causative agents of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).125,154,210,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Although donor plasma used to prepare immune globulin is screened for certain viruses (e.g., HBV, HIV type 1 and type 2 [HIV-1, HIV-2], HCV, human parvovirus [B19V]) and the manufacturing process for the various immune globulin preparations includes different procedures (e.g., cold ethanol precipitation, column chromatography, solvent/detergent [S/D] treatment, pasteurization/heat treatment, incubation at low pH, octanoic acid fractionation, caprylate precipitation, caprylate incubation, filtration) that further reduce the risk of transmission of infectious agents, a potential for transmission of infectious agents still remains.125,154,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341

Patients receiving immune globulin should be informed that the preparation is prepared from human plasma and may carry a risk of transmitting infectious agents.154,263,265,266,280,282,292,308,324,325,326,332,337,338,339,340,341

Any infections that possibly may have been transmitted by immune globulin preparations should be reported to the appropriate manufacturer.125,154,227,263,266,280,282,292,294,308,324,325,326,337,338,339,340,341

Risk of Hepatitis and Human Immunodeficiency Virus Infection

Although HCV infection was reported in a few individuals who received immune globulin preparations prepared outside the US and a US IGIV preparation (subsequently removed from the market) was implicated in the transmission of the virus,228,229 donors and/or donor units used for commercially available immune globulin preparations are screened for HCV and undergo various procedures during manufacture to reduce the risk of transmission of viral infection.154,228,263,265,266,282,292,294,308,325,326,331,332,337,338,339,340,341

Epidemiologic and laboratory evidence indicate that commercially available preparations of IGIM, IGIV, and immune globulin subcutaneous do not have a discernible risk of transmitting HIV infection.116,117,119,120,121,123,127 In addition to the screening of all donor units for antibody to HIV and rejection of all repeatedly reactive units, the manufacturing processes for immune globulin include purification steps that provide an extremely high margin of safety in removal of HIV infectivity.116 Although some IGIM or IGIV produced in 1982-1985 may have contained antibody to HIV,116,117,118,120,122 all immune globulin produced since April 1985 should be free of the antibody.116,118

Risk of Creutzfeldt-Jakob Disease or Variant Creutzfeldt-Jakob Disease

Because IGIM, IGIV, and immune globulin subcutaneous are prepared from human blood, they theoretically may carry a risk of transmitting the causative agent of CJD or vCJD.210,263,292,294,308,325,326,327,331,332,337,338,339 Although no cases of transmission of CJD or vCJD through plasma-derived preparations have been documented to date,210 an ongoing epidemiologic review being conducted in the United Kingdom identified several probable cases of vCJD acquired through transfusion of non-leukoreduced human red blood cell (RBC) concentrate.210,271 FDA has issued specific guidelines for industry intended to reduce the possible risk of transmission of CJD and vCJD by blood and blood components, including recommendations for screening blood and plasma donors for risk factors for these diseases.210

Other Precautions and Contraindications

Whenever use of immune globulin is being considered, the potential risks and benefits should be weighed against those of alternative therapies and discussed with the patient.308,337

Because aseptic meningitis syndrome has been reported rarely, patients receiving immune globulin should be instructed to immediately inform their clinician if signs or symptoms of aseptic meningitis occur (e.g., severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea and vomiting).263,265,292,294,308,327,331,332,337,338,339,340,341 Patients with signs and symptoms of aseptic meningitis should receive a thorough neurologic examination, including CSF analysis, to rule out other causes of meningitis.125,263,266,282,292,294,308,327,331,332,337,338,339,340,341 (See Aseptic Meningitis Syndrome under Cautions: Immune Globulin IV [IGIV].)

Because hemolysis has been reported (see Hemolysis under Cautions: Immune Globulin IV [IGIV]), patients receiving immune globulin (especially those with risk factors and those with preexisting anemia and/or cardiovascular or pulmonary compromise) should be closely monitored for clinical signs and symptoms of hemolysis (e.g., increased heart rate, swelling, fatigue, difficulty breathing, yellowing of skin or eyes, dark-colored urine).125,263,265,266,282,292,294,308,325,326,327,331,332,337,338,339,340,341 In higher risk patients, appropriate laboratory testing (e.g., hemoglobin or hematocrit) performed prior to IGIV infusion and within approximately 36-96 hours after the infusion should be considered.263,265,266,282,292,308,325,326,332,337,339 Patients should be instructed to immediately inform their clinician if signs or symptoms of hemolysis occur (e.g., increased heart rate, fatigue, yellowing of skin or eyes, dark-colored urine).263,265,266,292,294,308,325,326,331,332,337,341 If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit occur, additional confirmatory laboratory tests should be performed.263,265,266,282,292,308,325,326,332,337,338,339,340,341 If a blood transfusion is indicated for a patient who developed hemolysis with clinically compromising anemia after receiving immune globulin, adequate cross-matching should be performed to avoid exacerbating on-going hemolysis.263,265,266,282,292,294,308,325,326,332,337,338,339

Because transfusion-related acute lung injury (noncardiogenic pulmonary edema) has been reported (see Transfusion-related Acute Lung Injury under Cautions: Immune Globulin IV [IGIV]), patients receiving immune globulin should be monitored for adverse pulmonary reactions.125,263,265,266,292,294,308,327,331,332,337,338,339,340,341 Patients should be instructed to immediately inform their clinician if signs or symptoms of transfusion-related acute lung injury occur (e.g., difficulty breathing, severe respiratory distress, chest pain, pulmonary edema, hypoxia, blue lips or extremities, fever) and advised that such effects typically occur within 1-6 hours following infusion of immune globulin.263,265,266,292,294,308,327,331,332,337,338,339,341 If transfusion-related acute lung injury is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in the product and in patient serum.125,263,265,266,282,292,294,308,327,331,332,337,338,339,340,341 Patients should be managed using oxygen therapy with adequate ventilatory support.125,263,265,266,292,294,308,327,331,332,337,338,339,340,341

Because of the risk of volume overload, the manufacturers of Gammaplex^® 5%, Gammaplex^® 10%, and Privigen^® 10% state that the relative risks and benefits of the high-dose IGIV regimens (1 g/kg daily for 1-2 days) used for treatment of chronic ITP should be carefully considered before these preparations are used in individuals at increased risk of volume overload.292,308,337 The manufacturers of Gammaked^® 10% and Gamunex^®-C 10% state that high-dose regimens for treatment of ITP should not be used in patients with expanded fluid volumes or when fluid volume may be a concern.265,332

Because hypertensive urgency has been reported during and/or shortly following infusion of IGIV (Privigen^® 10%), patients should be evaluated for a history of hypertension and current antihypertensive treatment.292 Blood pressure should be monitored prior to, during, and following infusion of IGIV.292

Patients should be advised that immune globulin may interfere with the immune response to certain live viral vaccines (e.g., measles, mumps and rubella virus vaccine live [MMR], fixed-combination vaccine containing MMR and varicella virus vaccine live [MMRV], varicella virus vaccine live) and instructed to inform clinicians administering vaccines about any current or recent immune globulin therapy.154,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,339,340,341 (See Drug Interactions: Live Vaccines.)

The fact that immune globulin preparations that contain maltose (e.g., Cutaquig^® 16.5%, Octagam^® 5%, Octagam^® 10%) may cause falsely elevated results in blood glucose determinations that use nonspecific methods based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye oxidoreductase should be considered if blood glucose testing is indicated in a patient receiving one of these preparations.263,267,326,340 Falsely elevated glucose determinations in patients receiving parenteral products containing maltose have resulted in inappropriate administration of insulin and life-threatening hypoglycemia and there also is a risk that such falsely elevated glucose determinations may mask true hypoglycemic states.263,267,326,340 (See Laboratory Test Interferences: Tests for Glucose.)

Gammagard^® S/D (IgA less than 1 mcg/mL) contains approximately 8.5 mg of sodium chloride per mL.280 The amount of sodium in the preparations should be considered when determining dietary sodium in patients on a low-sodium diet since hypernatremia may occur.280

Pediatric Precautions

Immune Globulin IM

Safety and efficacy of IGIM have not been established in pediatric patients;154 however, passive immunization with IGIM is recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) in pediatric patients† under certain circumstances using the same dosages recommended for adults.105,133,186,231 (See Uses: Immune Globulin IM [IGIM].)

Immune Globulin IV

Asceniv^® 10% has been evaluated for the treatment of primary immunodeficiency in a limited number of pediatric patients (5 adolescents 12-16 years of age and 6 children younger than 12 years).338 Safety, efficacy, and pharmacokinetic profiles in adolescents are comparable to those demonstrated in adults.338 Data are insufficient regarding safety, efficacy, and pharmacokinetics of Asceniv^® 10% in pediatric patients younger than 12 years of age and safety and efficacy have not been studied in those younger than 3 years of age.338

Safety and efficacy of Bivigam^® 10% have not been established in pediatric patients younger than 6 years of age.324 Only limited data are available regarding the safety and efficacy of Bivigam^® 10% in pediatric patients.324

Studies using high doses of Carimune^® NF in pediatric patients with acute or chronic ITP did not reveal any specific differences in safety in pediatric patients versus adults.125

Flebogamma^® 5% DIF has been evaluated for the treatment of primary immunodeficiency in pediatric patients 2 years of age or older;282 pediatric-specific dosage was not required to achieve desired serum IgG concentrations.282 Safety and efficacy of Flebogamma^® 5% DIF have not been established in pediatric patients younger than 2 years of age.282

Safety and efficacy of Flebogamma^® 10% DIF have not been established for the treatment of primary immunodeficiency in pediatric patients.325 Flebogamma^® 10% DIF has been evaluated in a limited number of children and adolescents with chronic ITP;325 treatment-emergent adverse effects were reported more frequently in pediatric patients than in adults.325 Safety and efficacy of Flebogamma^® 10% DIF have not been established for the treatment of ITP in pediatric patients younger than 2 years of age.325

Safety and efficacy of Gammagard^® Liquid 10% for the treatment of primary immunodeficiency have not been established in pediatric patients younger than 2 years of age.266 Clinical studies evaluating Gammagard^® Liquid 10% administered by IV infusion for replacement therapy in patients with primary immunodeficiency included pediatric patients 2 years to less than 16 years of a 266 safety and efficacy profiles in these pediatric patients were similar to those reported in adults and pediatric-specific dosage was not required to achieve desired serum IgG concentrations.266 Safety and efficacy of Gammagard^® Liquid 10% have not been established for the treatment of multifocal motor neuropathy (MMN) in pediatric patients.266

Clinical studies evaluating Gammagard^® S/D (IgA less than 1 mcg/mL) for the treatment of primary immunodeficiency did not include sufficient numbers of pediatric patients 16 years of age or younger to determine whether they respond differently than adults.280 Safety and efficacy of Gammagard^® S/D (IgA less than 1 mcg/mL) for the treatment of ITP in pediatric patients have not been established.280 Safety and efficacy of Gammagard^® S/D (IgA less than 1 mcg/mL) for the treatment of Kawasaki disease in pediatric patients have been established;280 the majority of patients in clinical studies were younger than 5 years of age.280

Gammaked^® 10% administered by IV infusion can be used for the treatment of primary immunodeficiency or ITP in pediatric patients;332 pediatric-specific dosage is not necessary to achieve desired serum IgG concentrations.332 Safety and efficacy of Gammaked^® 10% have not been established for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in pediatric patients.332

Safety and efficacy of Gammaplex^® 5% for the treatment of primary humoral immunodeficiency have not been established in pediatric patients younger than 2 years of age.308 In pediatric patients 2-16 years of age, safety and efficacy have been established in those with primary humoral immunodeficiency;308 pediatric-specific dosage was not required to achieve desired serum IgG concentrations in this age group.308 Gammaplex^® 5% has been evaluated for the treatment of ITP in only a limited number of pediatric patients;308 data were insufficient to determine whether efficacy for treatment of ITP in pediatric patients differs from that in adults.308

Gammaplex^® 10% has been evaluated for the treatment of primary humoral immunodeficiency in a limited number of pediatric patients 3-15 years of a 337 pediatric-specific dosage was not required to achieve desired serum IgG concentrations in this age group.337 Safety and pharmacokinetics of Gammaplex^® 10% in pediatric patients 3 years of age or older are similar to those in adults.337 Safety and efficacy of Gammaplex^® 10% have not been established for the treatment of ITP in pediatric patients.337

Safety and efficacy of Gamunex^®-C 10% given by IV infusion were evaluated in a limited number of children and adolescents with primary immunodeficiency or chronic ITP.265 The pharmacokinetics, efficacy, and safety were similar to that reported in adults (except vomiting and fever were reported more frequently in pediatric patients);265 no pediatric-specific dosage requirements were necessary to achieve desired serum IgG concentrations.265 Safety and efficacy of Gamunex^®-C 10% given by IV infusion have not been established for the treatment of CIDP in pediatric patients.265

Octagam^® 5% was evaluated in a limited number of children 6-16 years of age.263 There were no obvious differences in pharmacokinetics, efficacy, or safety between pediatric patients and adults and no pediatric-specific dosage requirements were necessary to achieve desired serum IgG concentrations.263

Safety and efficacy of Octagam^® 10% have not been established for the treatment of ITP in pediatric patients.326

Panzyga^® 10% was evaluated for the treatment of primary humoral immunodeficiency in a limited number of pediatric patients 2-15 years of age.339 Pharmacokinetics, efficacy, and safety in these pediatric patients were similar to those in adults and pediatric-specific dosage was not necessary to achieve targeted serum IgG concentrations.339 Safety and efficacy of Panzyga^® 10% have not been established for the treatment of ITP in pediatric patients.339

Safety and efficacy of Privigen^® 10% for the treatment of primary humoral immunodeficiency have not been established in pediatric patients younger than 3 years of age.292 Privigen^® 10% has been evaluated in a limited number of children and adolescents with primary immunodeficiency;292 there were no apparent differences in safety and efficacy compared with adults and no pediatric-specific dosage requirements were necessary to achieve desired serum IgG concentrations.292 Safety and efficacy of Privigen^® 10% have not been established for the treatment of ITP in pediatric patients younger than 15 years of age.292 Safety and efficacy of Privigen^® 10% have not been established for the treatment of CIDP in pediatric patients younger than 18 years of age.292

Immune Globulin Subcutaneous

Safety and efficacy of Cutaquig^® 16.5% have not been established in pediatric patients younger than 17 years of age.340 Only a limited number of pediatric patients were included in the clinical study evaluating Cutaquig^® 16.5% for replacement therapy in patients with primary immunodeficiency.340

Cuvitru^® 20% can be used for the treatment of primary immunodeficiency in pediatric patients 2 years of age or older;331 in clinical studies, safety and efficacy profiles in this age group were similar to those reported in adults and pediatric-specific dosage was not necessary to achieve desired serum IgG concentrations.331 Safety and efficacy of Cuvitru^® 20% have not been established in pediatric patients younger than 2 years of age.331

Safety and efficacy of Gammagard^® Liquid 10% for the treatment of primary immunodeficiency have not been established in pediatric patients younger than 2 years of age.266 Clinical studies evaluating Gammagard^® Liquid 10% administered by subcutaneous infusion for replacement therapy in patients with primary immunodeficiency included pediatric patients 2 years to less than 16 years of a 266 safety and efficacy profiles in these pediatric patients were similar to those reported in adults and pediatric-specific dosage was not required to achieve desired serum IgG concentrations.266

Safety and efficacy of Gammaked^® 10% administered by subcutaneous infusion have not been established for the treatment of primary immunodeficiency in pediatric patients younger than 2 years of age.332 Safety and efficacy of Gammaked^® 10% administered subcutaneously have not been established for the treatment of ITP or CIDP in pediatric patients.332

Safety and efficacy of Gamunex^®-C 10% administered by subcutaneous infusion have not been established for the treatment of primary humoral immunodeficiency in pediatric patients younger than 2 years of age.265 Safety and efficacy of Gamunex^®-C 10% administered subcutaneously have not been established for the treatment of ITP or CIDP in pediatric patients.265

Safety and efficacy of Hizentra^® 20% have not been established for the treatment of primary immunodeficiency in pediatric patients younger than 2 years of age.294 In pediatric patients 2-16 years of age, safety and efficacy have been established for the treatment of primary immunodeficiency.294 In clinical studies evaluating Hizentra^® 20% for the treatment of primary immunodeficiency, there were no differences in safety and efficacy profiles in pediatric patients compared with adults;294 pediatric-specific dosage was not required to achieve desired serum IgG concentrations.294 Safety and efficacy of Hizentra^® 20% have not been established for the treatment of CIDP in pediatric patients younger than 18 years of age.294

Safety of Hyqvia^® (immune globulin subcutaneous 10% with recombinant human hyaluronidase) has not been established in pediatric patients.327

Xembify^® 20% was evaluated for the treatment of primary humoral immunodeficiency in a limited number of pediatric patients 2-16 years of age.341 Efficacy and safety in these pediatric patients were similar to those in adults and no pediatric-specific dosage requirements were necessary to achieve targeted serum IgG concentrations.341

Geriatric Precautions

Geriatric patients older than 65 years of age receiving immune globulin are at increased risk of acute renal failure or thrombotic events.125,263,265,266,282,292,308,326,327,332,337,338,339,340,341

Safety and efficacy of IGIM have not been established in geriatric patients.154

Immune globulin should be used with caution in patients 65 years of age or older.265,266,282,292,308,324,325,332,337 In general, selection of immune globulin dosage for geriatric patients should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.263,338,340,341 Recommended dosage should not be exceeded125,265,266,280,282,292,308,324,325,326,331,337,339 and the minimum practicable infusion rate should be used for IGIV or immune globulin subcutaneous.125,263,265,266,280,282,292,308,324,325,326,331,332,337,339 (See Dosage and Administration: Reconstitution and Administration.)

Clinical studies of IGIV did not include a sufficient number of patients 65 years of age or older to determine whether geriatric individuals respond differently than younger patients.263,265,266,280,282,292,308,324,325,326,332,337,338,339 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.263,338

Clinical studies evaluating immune globulin subcutaneous (Cutaquig^® 16.5%, Xembify^® 20%) did not include a sufficient number of patients 65 years of age or older to determine whether geriatric individuals respond differently than younger patients.340,341 Clinical studies evaluating safety and efficacy of immune globulin subcutaneous (Cuvitru^® 20%, Gammagard^® Liquid 10%, Hizentra^® 20%, Hyqvia^®) included only a limited number of patients 65 years of age or older;266,294,327,331 no overall differences in safety or efficacy were observed in these patients compared with younger patients.266,294,331

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with IGIM, IGIV, or immune globulin subcutaneous and it is not known whether immune globulins can cause fetal harm when administered to pregnant women.125,154,263,265,266,280,282,292,294,308,324,325,326,327,331,332,337,338,340,341 Some manufacturers state that immune globulin should be used during pregnancy only when clearly needed.125,265,266,280,282,292,294,308,324,325,326,327,331,332,337

ACIP states that there are no known risks associated with use of immune globulins for passive immunization in pregnant women.134

Intact immune globulins, such as those contained in IGIV, cross the placenta in increasing amounts after 30 weeks of gestation.125,265,266,280,282,292,294,308,325,326,327,331,337,338,340,341 Results of studies in pregnant women with ITP who received IGIV prior to delivery indicate that the platelet response and clinical effects of IGIV were similar in the mother and neonate.125

Animal reproduction studies have been performed with the recombinant human hyaluronidase component of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®).327 In mice and rabbits, antibodies to recombinant human hyaluronidase (anti-rHuPH20 antibodies) that developed in the mother were not associated with adverse effects on pregnancy; these antibodies crossed the placenta and were transferred to offspring in utero.327 It is not known whether anti-recombinant human hyaluronidase antibodies that develop in women cause fetal harm.327 The manufacturer states that Hyqvia^® should be used during pregnancy only if clearly needed,327

Fertility

It is not known if immune globulin affects fertility.125,263,265,280,282,292,294,308,324,325,326,331,332,337,338,340,341

The manufacturer of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) states that animal studies do not indicate direct or indirect harmful effects of recombinant human hyaluronidase with respect to reproductive potential at the doses used for facilitating administration of immune globulin 10% and reproduction in animals was not affected by antibodies to hyaluronidase.327 Some patients receiving immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) have developed antibodies to recombinant human hyaluronidase and these antibodies potentially could cross-react with endogenous human hyaluronidase, which is expressed in adult male testes, epididymis, and sperm.327 It is not known whether these anti-recombinant human hyaluronidase antibodies interfere with human fertility.327

Lactation

IGIV and immune globulin subcutaneous have not been evaluated in nursing women.265,280,282,292,294,308,324,325,327,331,332,337,338,340,341

It is not known whether immune globulin is distributed into milk following IM, IV, or subcutaneous administration, affects milk production, or affects the breast-fed infant.154,263,265,266,280,281,282,325,326,332

Immune globulin should be used with caution in nursing women.266 The benefits of breast-feeding and the importance of immune globulin to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.154,263,265,325,266,280,282,292,294,325,327,331,332,338,340,341

The manufacturer of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) states that data are not available regarding use in nursing women.327 In lactating animals, maternal antibodies bound to recombinant human hyaluronidase (anti-rHuPH20 antibodies) were transferred to nursing offspring;327 no adverse effects on pregnancy or offspring development were associated with these antibodies.327 The possible effects of these antibodies to recombinant human hyaluronidase that may be transferred to infants are unknown.327

Live Vaccines

Antibodies present in immune globulin may interfere with the immune response to certain live virus vaccine, including measles, mumps, and rubella virus vaccine live (MMR) and varicella virus vaccine live.105,125,134,154,263,265,266,292,294,308,324,325,326,327,331,332,337,338,339,340,341 These vaccines should not be administered simultaneously with or for specified intervals before or after administration of immune globulin.105,125,134,186,263,265,292,326,327,331,332

There is no evidence that immune globulin preparations interfere with the immune response to influenza virus vaccine live intranasal, rotavirus vaccine live oral, typhoid vaccine live oral, yellow fever vaccine, zoster vaccine live, poliovirus vaccine live oral (OPV; no longer commercially available in the US), and these live vaccines may be given simultaneously with or at any interval before or after immune globulin.105,134

Measles, Mumps, Rubella, and Varicella Vaccines

Antibodies present in immune globulin can interfere with the immune response to measles and rubella antigens contained in MMR and measles, mumps, rubella, and varicella virus vaccine live (MMRV) for at least 3 months or longer.105,125,134,154,263,266,294,308,324,326,327,331,332 Although specific information regarding the effect of immune globulin preparations on the immune response to mumps antigen contained in MMR or MMRV or varicella antigen contained in varicella virus vaccine live or MMRV are not available, there is potential for similar interference since immune globulin preparations contain antibodies to these viruses.105,134 The duration of interference with the immune response to vaccines containing measles, mumps, rubella, and/or varicella antigens following administration of immune globulin depends on the amount of antigen-specific antibody contained in the immune globulin preparation.105,134 Based on the assumption that passively acquired antibody has an estimated half-life of 30 days and data indicating that an IgG dose of 80 mg/kg interferes with the immune response to measles virus vaccine live for 5 months, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) have made the following recommendations concerning administration of live viral vaccines.105,134

Immune globulin IM (IGIM): Administration of vaccines containing measles or varicella antigens (MMR, MMRV, or varicella virus vaccine live) should be deferred for 6 months following administration of IGIM used for hepatitis A virus (HAV) preexposure or postexposure prophylaxis134,186 or for measles prophylaxis in immunocompetent individuals.105,134

Immune globulin IV (IGIV): Administration of vaccines containing measles or varicella antigens (MMR, MMRV, or varicella virus vaccine live) should be deferred for 8 months following administration of IGIV used for replacement therapy in patients with primary immunodeficiencies,105,134 measles prophylaxis,105,134 or varicella postexposure prophylaxis.134,269 In patients receiving IGIV for the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura or immune thrombocytopenia), administration of vaccines containing measles or varicella antigens should be deferred for 8 months in those receiving IGIV doses of 400 mg/kg and deferred for 10-11 months in those receiving IGIV doses of 800 mg/kg or greater.105,134 Vaccines containing measles or varicella antigens should be deferred for 11 months following administration of IGIV used for the treatment of Kawasaki disease.105,134

Immune globulin and MMR, MMRV, or varicella virus vaccine live should not be administered simultaneously.134 If simultaneous administration (at a separate site) is deemed necessary (e.g., because of imminent exposure to measles) or if a dose of MMR, MMRV, or varicella virus vaccine live is given after immune globulin at an interval shorter than that recommended, ACIP and AAP state that the vaccine dose should be repeated after the recommended interval, unless serologic testing is feasible and indicates an adequate antibody response to the live virus vaccine.105,134 In general, vaccine virus replication and stimulation of immunity occur within 1-2 weeks after administration of a live virus vaccine.134,142 Therefore, if immune globulin is administered less than 14 days after MMR, MMRV, or varicella virus vaccine live, an additional dose of vaccine should be given after the recommended interval previously specified, unless there is serologic evidence of an adequate antibody response to the vaccine.105,134

Inactivated Vaccines and Toxoids

ACIP and AAP state that administration of inactivated vaccines and toxoids simultaneously with (at different sites) or at any interval before or after administration of immune globulin preparations should not have a clinically important effect on the immune response to the vaccines or toxoids.105,134

Hepatitis A Virus Vaccine Inactivated

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) may be administered simultaneously with immune globulin at a separate site using a different syringe.105,186,194,195,208,289 Although there is evidence that geometric mean concentrations (GMCs) of anti-HAV antibodies in adults who received immune globulin concomitantly with the first dose of hepatitis A vaccine were lower than GMCs in those who received hepatitis A vaccine alone, there was no difference in the proportion of vaccinees who subsequently had protective levels of antibody.186,195,208,289 The effect of reduced GMCs on long-term protection against HAV is unknown.186

Laboratory Test Interferences

Immunohematology and Serologic Tests

Because immune globulin can contain blood group antibodies (e.g., anti-A, anti-B, anti-D), positive direct or indirect antiglobulin (Coombs') test results may occur in patients receiving the drug.125,263,265,266,280,282,292,294,308,325,326,327,331,332,337,338,340,341 This reaction may interfere with hematologic studies or transfusion cross-matching procedures.265,327,331,332

Patients receiving immune globulin may have transitory increases in various passively acquired antibodies that could cause false-positive serologic test results and misinterpretation of these test results.263,265,266,292,325,326,338,340,341

Tests for Fungus

False-positive readings in assays used for the diagnosis of fungal infections may occur in patients receiving immune globulin if the tests depend on detection of beta-d-glucans.266,280,331 Interference with these assays may persist during the weeks following infusion of immune globulin.266,280,331

Tests for Glucose

Immune globulin preparations that contain maltose (e.g., Cutaquig^® 16.5%, Octagam^® 5%, Octagam^® 10%) may cause falsely elevated results in blood glucose determinations that use nonspecific methods based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye oxidoreductase.263,267,326,340 Such falsely elevated glucose determinations in patients receiving parenteral products containing maltose have resulted in inappropriate administration of insulin and life-threatening hypoglycemia.263,267,326,340 In addition, there is a risk that true cases of hypoglycemia may go untreated if a hypoglycemic state is masked by falsely elevated blood glucose determinations.263,267,326,340 Therefore, only glucose-specific test methods that are not affected by maltose (e.g., methods that use glucose dehydrogenase nicotine adenine dinucleotide [GDH-NAD], glucose oxidase, glucose hexokinase) should be used to measure blood glucose concentrations in patients receiving immune globulin preparations that contain maltose.263,267,326,340 If blood glucose determinations are indicated in a patient receiving an immune globulin preparation that contains maltose, the product information for the blood glucose testing system (including glucose test strips) should be carefully reviewed to determine if the testing system is appropriate.263,267,326,340 If any uncertainty exists, the manufacturer of the glucose testing system should be contacted to determine if the system will provide accurate blood glucose determinations in this situation.263,267,326,340

Pharmacology

Immune globulin IM (IGIM), immune globulin IV (IGIV), and immune globulin subcutaneous provide a broad spectrum of opsonic and neutralizing IgG antibodies against a wide variety of bacterial and viral agents.125,263,265,266,282,292,294,308,324,325,327,331,332,337,338,339,340,341 These IgG antibodies are used to provide passive immunity by increasing an individual's antibody titer and antigen-antibody reaction potential and prevent or modify certain infectious diseases in susceptible individuals.105 The mechanism of action of immune globulin in the treatment of primary humoral immunodeficiency has not been fully elucidated.263,265,282,292,294,308,324,325,331,332,337,338,339,340,341

The mechanism by which IGIV increases platelet counts in the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura or immune thrombocytopenia) has not been fully elucidated.125,130,139,140,142,265,292,308,325,326,332,337,339 It has been suggested that IGIV may saturate Fc (crystallizable fragment) receptors on cells of the reticuloendothelial system, resulting in a decrease in Fc-mediated phagocytosis of antibody-coated cells.130,139,142 This Fc-receptor blockade may occur in bone marrow, spleen, and other parts of the reticuloendothelial system140 and may occur through competition for Fc receptors by increased serum concentrations of IgG or by circulating immune complexes.139,142 Altered Fc-receptor affinity for IgG or suppression of antiplatelet antibody production may also be involved.139,140,142

The mechanism of action of IGIV in the treatment of Kawasaki disease is not known, but possibly may include modulation of cytokine production, neutralization of bacterial superantigens or other etiologic agents, augmentation of T-cell suppressor activity, suppression of antibody synthesis, and provision of anti-idiotypic antibodies.299 IGIV and aspirin appear to have additive anti-inflammatory effects in the treatment of Kawasaki disease.299

The mechanism of action of IGIV in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) has not been fully elucidated.265,332

Pharmacokinetics

Following IM administration of immune globulin IM (IGIM), serum concentrations of IgG peak within 2 days.154 IgG present in IGIM is rapidly and evenly distributed between intravascular and extravascular spaces.125,263,280

Following IV infusion of immune globulin IV (IGIV), there is an immediate post-infusion peak in serum IgG concentrations followed by a biphasic decline.125,263,265,266,280 There is an initial rapid decline in serum IgG concentrations associated with equilibration between plasma and extravascular fluid compartments that is followed by a second phase characterized by a slower and constant rate of elimination.125,263,265,266,280

Peak serum concentrations of IgG attained with immune globulin subcutaneous are lower than those attained with IGIV, but trough IgG concentrations generally are higher than those attained with IGIV.265,266,294,331 In addition, in contrast to the biphasic IgG concentrations reported with IGIV, once-weekly administration of immune globulin subcutaneous results in relatively stable IgG concentrations.265,294,331 Peak serum IgG concentrations in patients receiving once-weekly immune globulin subcutaneous occur approximately 3 days (range: 0-7 days) after a dose.266,294,331

In studies evaluating immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®), peak serum concentrations of IgG were lower but trough IgG concentrations generally were comparable to those attained with IGIV.327 In addition, the area under the plasma concentration-time curve (AUC) of IgG was 20% higher than that attained with immune globulin subcutaneous administered without recombinant human hyaluronidase.327 Peak serum IgG concentrations in patients receiving Hyqvia^® occurred 5 days (range: 3.3-5.1 days) after a dose.327

The half-life of IgG in individuals with normal serum IgG concentrations is reportedly about 18-25 days.154,266 The half-life of IGIV preparations in patients with immunodeficiencies has been reported to range from 12-59 days.263,266,280,282,292,308,324,325,338 High IgG concentrations and hypermetabolism associated with fever and infection have been reported to coincide with a shortened IgG half-life.263,266,280 Following IV administration of IGIV once every 3 or 4 weeks in patients with primary humoral immunodeficiency, the elimination half-life of IgG was approximately 35 days.265,266

Immune globulins can cross the placenta in increasing amounts after 30 weeks' gestation.125,265,266,292,325,331 It is not known whether IGIM or IGIV is distributed into milk.266,266,281,292

Chemistry and Stability

Chemistry

Immune globulin is a sterile, nonpyrogenic preparation of globulins containing many antibodies normally present in adult human blood.154,263,265,266,282,294,308,324,325,326,327,331,332,337,338,339,340,341 Immune globulin is commercially available for IM administration as immune globulin IM (IGIM),154 for IV administration as immune globulin IV (IGIV),125,280,282,308,263,265,266,292,324,325,326,332,337,338,339 and for subcutaneous administration as immune globulin subcutaneous.265,266,294,327,331,332,340,341

IGIM, IGIV, and immune globulin subcutaneous meet standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration (FDA). IGIM and IGIV are prepared by cold alcohol fractionation of pooled plasma from healthy individuals. Plasma donors and plasma used in the preparation of commercially available immune globulin have been tested and shown to be negative for certain human blood-borne viruses and all commercially available preparations of IGIM, IGIV, and immune globulin subcutaneous undergo at least one heat-treatment, filtration, and/or chemical (solvent/detergent) procedure during the manufacturing process to reduce virus infectious potential.125,154,228,280,282,294,308,324,325,326,327,331,332,337,338,339,340,341 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications.)

Immune Globulin IM

Immune globulin IM (IGIM) is commercially available as GamaSTAN^®.154

GamaSTAN®

GamaSTAN^® is a sterile solution containing 15-18% protein stabilized in 0.16-0.26 M glycine.154 GamaSTAN^® occurs as a colorless to pale yellow or light brown solution that is clear or slightly opalescent, has a pH of 4.1-4.8, and does not contain thimerosal or any other preservative.154 GamaSTAN^® has been purified using cold ethanol fractionation, caprylate precipitation and filtration, caprylate incubation, anion-exchange chromatography, nanofiltration, and low pH incubation.154

Immune Globulin IV

Immune globulin IV (IGIV) is commercially available as Asceniv^® 10%,338 Bivigam^® 10%,324 Carimune^® NF,125 Flebogamma^® 5% DIF,282 Flebogamma^® 10% DIF,325 Gammagard^® Liquid 10%,266 Gammagard^® S/D,280 Gammaked^® 10%,332 Gammaplex^® 5%,308 Gammaplex^® 10%,337 Gamunex^®-C 10%,265 Octagam^® 5%,263 Octagam^® 10%,326 Panzyga^® 10%,339 and Privigen^® 10%.292 The various manufacturers of IGIV use different methods to isolate and purify immune globulin after cold alcohol fractionation and different methods to reduce the viral infectious potential of the preparations.125,263,265,282,292,308,324,332,338,339

Asceniv® 10%

Asceniv^® 10% is a sterile solution containing 10% protein, of which not less than 96% is IgG.338 The preparation contains 200 mcg/mL or less of IgA.338 During manufacture, Asceniv^® 10% undergoes various procedures, including cold alcohol fractionation, solvent-detergent treatment, and filtration, to reduce the virus infectious potential of the preparation.338

Asceniv^® 10% is a clear or slightly opalescent, colorless to pale yellow liquid with a pH of 4-4.6.338 Asceniv^® 10% contains 0.2-0.29 M glycine, 0.15-0.25% polysorbate 80, and 0.1-0.14 M sodium chloride, but does not contain preservatives.338

Bivigam® 10%

Bivigam^® 10% is a sterile solution containing 10% protein, of which not less 96% is IgG.324 The preparation contains 200 mcg/mL or less of IgA.324 During manufacture, Bivigam^® 10% undergoes cold alcohol fractionation, solvent-detergent treatment, nanofiltration, and low pH incubation to reduce the virus infectious potential of the preparation.324

Bivigam^® 10% is a clear or slightly opalescent, colorless to pale yellow solution with a pH of 4-4.6.324 Bivigam^® 10% contains 0.2-0.29 M glycine, 0.15-0.25% polysorbate 80, and 0.1-0.14 M sodium chloride, but does not contain preservatives or sucrose.324

Carimune® NF

Carimune^® NF is a sterile, lyophilized preparation of immune globulin that has been modified at acid pH in the presence of trace amounts of pepsin to make it suitable for IV administration.125 Carimune^® NF contains not less than 96% IgG;125 the distribution of the IgG subclasses corresponds to that of normal serum.125 Most immunoglobulins contained in the preparation are monomeric (7S) IgG and the remainder are dimeric IgG, small amounts of polymeric IgG, traces of IgA and IgM, and immunoglobulin fragments.125 Carimune^® NF contains 1.67 g of sucrose as a stabilizing agent and also contains small amounts (less than 20 mg) of sodium chloride per gram of protein.125 Carimune^® NF undergoes filtration procedures during manufacturer to reduce the risk of transmission of viral infections.125 The manufacturing process also includes nanofiltration (removing viruses via size-exclusion); this is performed prior to the viral inactivation step in order to reduce the potential viral load before inactivation is performed.125 Treatment with pepsin at pH 4 rapidly inactivates enveloped viruses.125

Following reconstitution as directed with a neutral unbuffered diluent, Carimune^® NF solutions have a pH of 6.4-6.8.125 Carimune^® NF that has been reconstituted to a concentration of 30-120 mg of protein per mL with 0.9% sodium chloride injection, 5% dextrose injection, or sterile water for injection has a calculated osmolality of 498-1074, 444-1020, or 192-768 mOsm/kg, respectively.125

Flebogamma® 5% DIF

Flebogamma^® 5% DIF contains at least 97% IgG and trace amounts of IgA (typically less than 50 mcg/mL) and IgM.282 The distribution of IgG subclasses is approximately 66.6% IgG₁, 28.5% IgG₂, 2.7% IgG₃, and 2.2% IgG₄.282 Flebogamma^® 5% DIF undergoes several procedures during manufacture to reduce the risk of transmission of viral infections.282 The manufacturing process includes cold alcohol fractionation, polyethylene glycol precipitation, ion exchange chromatography, pasteurization, solvent-detergent treatment, and double sequential nanofiltration.282

Flebogamma^® 5% DIF is a clear or slightly opalescent and colorless to pale yellow liquid.282 The pH of Flebogamma^® 5% DIF is 5-6282 and the osmolality is 240-370 mOsm/kg.282 Flebogamma^® 5% DIF contains sorbitol as a stabilizing agent, polyethylene glycol, and trace amounts of sodium, but does not contain preservatives or sucrose.282

Flebogamma® 10% DIF

Flebogamma^® 10% DIF contains at least 97% IgG and trace amounts of IgA (typically less than 32 mcg/mL) and IgM.325 The distribution of IgG subclasses is approximately 66.6% IgG₁, 27.9% IgG₂, 3.0% IgG₃, and 2.5% IgG₄.325 Flebogamma^® 10% DIF undergoes several procedures during manufacture to reduce the risk of transmission of viral infections.325 The manufacturing process includes cold alcohol fractionation, polyethylene glycol precipitation, ion exchange chromatography, low pH treatment, pasteurization, solvent-detergent treatment, and nanofiltration.325

Flebogamma^® 10% DIF occurs as a clear or slightly opalescent and colorless to pale yellow solution with a pH of 5-6 and an osmolality of 240-370 mOsm/L.325 Flebogamma^® 10% DIF contains sorbitol as a stabilizing agent, polyethylene glycol, and trace amounts of sodium, but does not contain preservatives or sucrose.325

Gammagard® Liquid 10%

Gammagard^® Liquid 10% is a sterile solution of IgG.266 At least 98% is IgG;266 the distribution of the IgG subclasses corresponds to that of normal plasma and the Fc and Fab functions are maintained.266 The average IgA concentration in this preparation is 37 mcg/mL and IgM is present in only trace amounts.266 During manufacture, Gammagard^® Liquid 10% undergoes a chemical (solvent/detergent) procedure, nanofiltration, and low pH incubation at elevated temperatures to reduce the virus infectious potential of the preparation.266

Gammagard^® Liquid 10% is a clear or slightly opalescent and colorless or pale yellow solution with a pH of 4.6-5.1.266 The solution has an osmolality of 240-300 mOsm/kg, which is similar to physiologic osmolality (285-295 mOsm/kg).266 Gammagard^® Liquid 10% contains 0.25 M glycine as a stabilizing and buffering agent, but does not contain preservatives, sodium, or sucrose.266

Gammagard® S/D

Gammagard^® S/D is a sterile, lyophilized preparation of immune globulin that has been purified using ultrafiltration and ion exchange adsorption.280 In addition, the preparation undergoes a chemical (solvent/detergent) procedure during manufacture to reduce the risk of transmission of viral infection.280

Following reconstitution as directed, Gammagard^® S/D contains approximately 50 mg of protein per mL, of which not less than 90% is IgG.280 The distribution of the IgG subclasses on average corresponds to that of normal plasma.280 Gammagard^® S/D is commercially available as a formulation that contains less than 1 mcg/mL of IgA.280

The manufacturing process for Gammagard^® S/D isolates IgG without additional chemical or enzymatic modification and the Fc portion is maintained intact.280 The preparation also contains glycine, dextrose, polyethylene glycol, polysorbate 80, and human albumin.280

Reconstituted solutions of Gammagard^® S/D contain approximately 8.5 mg of sodium chloride per mL and have a pH of 6.4-7.2.280 The reconstituted solution is clear to slightly opalescent and colorless to pale yellow.280 Gammagard^® S/D does not contain preservatives or sucrose.280

Gammaked® 10%

Gammaked^® 10% is a sterile solution containing 9-11% protein stabilized in 0.16-0.24 M glycine.332 Not less than 98% of the protein content of Gammaked^® 10% has the electrophoretic mobility of IgG.332 The distribution of the IgG subclasses in Gammaked^® 10% is approximately 63% IgG₁, 30% IgG₂, 5% IgG₃, and 3% IgG₄, which is similar to that of normal serum.332 The preparation contains trace amounts of fragments, IgA (average 46 mcg/mL), and IgM.332 Gammaked^® 10% has been purified using caprylate precipitation and filtration and anion-exchange chromatography.332 Various steps used in the manufacturing process (caprylate precipitation/cloth filtration, caprylate incubation, depth filtration, column chromatography, incubation in the final container at pH 4-4.3) reduce the risk of transmission of viral infections.332 Gammaked^® 10% does not contain preservatives or sucrose.332

Gammaked^® 10% is a clear to opalescent and colorless to pale yellow solution and has a pH of 4-4.5 and an osmolality of 258 mOsm/kg of solvent.332 Gammaked^® 10% has a buffering capacity of 35 mEq/L.332 A dose of 1 g/kg represents an acid load of 0.35 mEq/kg.332 Because the total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood or 3.6 mEq/kg, the acid load delivered with a Gammaked^® 10% dose of 1 g/kg would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.332

Gammaplex® 5% and Gammaplex® 10%

Gammaplex^® 5% and Gammaplex 10% are sterile solutions of polyclonal human IgG for IV administration.308,337 Gammaplex^® 5% and Gammaplex^® 10% are prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography.308,337 The manufacturing process for these preparations includes several steps (solvent/detergent treatment, filtration steps, terminal low pH incubation) to reduce the risk of transmission of viral infections.308,337

Gammaplex^® 5% has a purity of at least 95% IgG308 and contains less than 10 mcg/mL of IgA.308 The IgG subclass distribution is approximately 64% IgG₁, 30% IgG₂, 5% IgG₃, and 1% IgG₄.308 Gammaplex^® 5% has an osmolality of not less than 240 mOsm/kg (typically 420-500 mOsm/kg) and a pH of 4.8-5.1.308 The preparation contains sorbitol, glycine, and polysorbate 80 as stabilizers.308 Gammaplex^® 5% does not contain any carbohydrate stabilizers (e.g., sucrose, maltose) or preservatives.308

Gammaplex^® 10% has a purity of at least 98% IgG337 and contains less than 20 mcg/mL of IgA.337 The IgG subclass distribution in Gammaplex^® 10% reflects that of normal plasma.337 Gammaplex^® 10% has an osmolality of not less than 240 mOsm/kg (typically 280 mOsm/kg) and a pH of 4.9-5.3.337 The preparation contains glycine and polysorbate 80 as stabilizers.337 Gammaplex^® 10% does not contain any carbohydrate stabilizers (e.g., sucrose, maltose) or preservatives.337

Gamunex®-C 10%

Gamunex^®-C 10% is a sterile solution containing 9-11% protein stabilized in 0.16-0.24 M glycine.265 Not less than 98% of the protein content of Gamunex^®-C 10% has the electrophoretic mobility of IgG.265 The distribution of the IgG subclasses in Gamunex^®-C 10% is approximately 63% IgG₁, 30% IgG₂, 5% IgG₃, and 3% IgG₄, which is similar to that of normal serum.265 The preparation contains trace amounts of fragments, IgA (average 46 mcg/mL), and IgM.265 Gamunex^®-C 10% has been purified using caprylate precipitation and filtration and anion-exchange chromatography; the protein has not been modified using heat, chemical, or enzymatic modification steps.265 Various steps used in the manufacturing process (caprylate precipitation/cloth filtration, caprylate incubation, depth filtration, column chromatography, incubation in the final container at low pH [pH 4-4.3 for at least 21 days at 23-27°C]) reduce the risk of transmission of viral infections.265 Gamunex^®-C 10% does not contain preservatives or sucrose.265

The pH of Gamunex^®-C 10% is 4-4.5 and the osmolality is 258 mOsm/kg of solvent.265 Gamunex^®-C 10% has a buffering capacity of 35 mEq/L.265 A dose of 1 g/kg represents an acid load of 0.35 mEq/kg.265 Because the total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood or 3.6 mEq/kg, the acid load delivered with a Gamunex^®-C 10% dose of 1 g/kg would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.265

Octagam® 5%

Octagam^® 5% is a sterile solution containing 5% protein stabilized with 10% maltose.263 Octagam^® 5% contains approximately 50 mg of protein per mL, of which not less than 96% is IgG, and contains aggregates (3% or less), monomers and dimers (90% or greater), and fragments (3 % or less).263 The distribution of the IgG subclasses in Octagam^® 5% is approximately 65% IgG₁, 30% IgG₂, 3% IgG₃, and 2% IgG₄;263 only trace amounts of IgA (no more than 200 mcg/mL) and IgM are present.263 In addition, the Fc portion is maintained intact.263 Octagam^® 5% is prepared using cold ethanol fractionation and is purified using ultrafiltration and chromatography;263 the protein has not been chemically or enzymatically modified.263 Octagam^® 5% undergoes a chemical (solvent/detergent) procedure during manufacture to reduce the risk of transmission of viral infections.263

The pH of Octagam^® 5% is 5.1-6 and the osmolality is 310-380 mOsm/kg.263 Octagam^® 5% does not contain preservatives or sucrose.263

Octagam® 10%

Octagam^® 10% is a sterile solution containing 10% protein stabilized with 9% maltose.326 Octagam^® 10% contains approximately 100 mg of protein per mL, of which not less than 96% is IgG, and contains aggregates (3% or less), monomers and dimers (94% or greater), and fragments (3% or less).326 The distribution of the IgG subclasses in Octagam^® 10% is approximately 65% IgG₁, 30% IgG₂, 3% IgG₃, and 2% IgG₄;326 the preparation contains only trace amounts of IgA (average 106 mcg/mL) and IgM.326 In addition, the Fc portion is maintained intact.326 Octagam^® 10% is prepared using cold ethanol fractionation and is purified using ultrafiltration and chromatography;326 the protein has not been chemically or enzymatically modified.326 Octagam^® 10% undergoes a chemical (solvent/detergent) procedure during manufacture to reduce the risk of transmission of viral infections.326

The pH of Octagam^® 10% is 4.5-5 and the osmolality is 310-380 mOsm/kg.326 Octagam^® 10% does not contain preservatives or sucrose.326

Panzyga® 10%

Panzyga^® 10% is a sterile preparation of highly purified human IgG for IV administration.339 Panzyga^® 10% is prepared from large pools of human plasma using cold ethanol fractionation followed by various purification steps.339 Panzyga^® 10% contains approximately 100 mg of protein per mL, of which not less than 96% is IgG, and contains aggregates (3% or less), monomers and dimers (90% or greater), and fragments (3% or less);339 the Fc portion is maintained intact.339 The distribution of the IgG subclasses in Panzyga^® 10% is approximately 65% IgG₁, 28% IgG₂, 3% IgG₃, and 4% IgG₄.339 On average, the preparation contains 100 mcg/mL of IgA and lower amounts of IgM.339 The manufacturing process for Panzyga^® 10% includes solvent/detergent treatment, ion-exchange chromatography, and nanofiltration steps that reduce the risk of transmission of viral infections.339

Panzyga^® 10% has a pH of 4.5-5 and an osmolality of 240-310 mOsm/kg.339 The preparation contains glycine (15-19.5 mg/mL) as a stabilizer, but does not contain preservatives or sucrose.339

Privigen® 10%

Privigen^® 10% is a sterile solution of polyvalent human IgG for IV administration.292 Privigen^® 10% is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography.292 The IgG proteins are not subjected to heating or to chemical or enzymatic modification.292 The Fc and Fab functions of the IgG molecule are retained.292 Privigen^® 10% does not activate the complement system or prekallikrein in an unspecific manner.292 The manufacturing process for Privigen^® 10% includes an immunoaffinity chromatography step to specifically reduce blood group A and B antibodies (isoagglutinins A and B).292 The manufacturing process also includes several steps (incubation at pH 4, filtration steps) to reduce the risk of transmission of viral infections.292

Privigen^® 10% has a purity of at least 98% IgG, consisting primarily of monomers.292 Privigen^® 10% contains IgA (not exceeding 25 mcg/mL).292 The IgG subclass distribution in Privigen^® 10% reflects that of normal plasma.292 Privigen^® 10% has an osmolality of approximately 320 mOsm/kg (range: 240-440) and a pH of 4.8 (range: 4.6-5).292 Privigen^® 10% contains approximately 250 mmol/L (range: 210-290) of l-proline (a nonessential amino acid) as a stabilizer and trace amounts of sodium.292 Privigen^® 10% does not contain any carbohydrate stabilizers (e.g., sucrose, maltose) or preservatives.292

Immune Globulin Subcutaneous

Immune globulin subcutaneous is commercially available as Cutaquig^® 16.5%,340 Cuvitru^® 20%,331 and Hizentra^® 20%,294 and also is commercially available as immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®).327 In addition, certain IGIV preparations also can be administered subcutaneously (i.e., Gammagard^® Liquid 10%, Gammaked^® 10%, Gamunex^®-C 10%).265,266,332

Cutaquig® 16.5%

Cutaquig^® 16.5% is a sterile solution containing 16.5% protein, of which not less than 96% is IgG.340 The distribution of the IgG subclasses in Cutaquig^® 16.5% is approximately 70% IgG₁, 25% IgG₂, 3% IgG₃, and 2% IgG₄.340 The preparation contains aggregates (3% or less), monomers and dimers (94% or greater), and fragments (3% or less) and the Fc portion is maintained intact.340 Cutaquig^® 16.5% contains 600 mcg/mL or less of IgA.340 The manufacturing process includes several procedures, including cold ethanol fractionation, ultrafiltration, chromatography, solvent/detergent treatment, and incubation at low pH, to reduce the risk of transmission of infectious agents.340

Cutaquig^® 16.5% is a clear and colorless or slightly opalescent or pale yellow solution and has a pH of 5-5.5 and an osmolality of 310-380 mOsm/kg.340 Cutaquig^® 16.5% contains maltose (79 mg/mL), but does not contain any preservatives or sucrose.340

Cuvitru® 20%

Cuvitru^® 20% is a sterile solution containing 20% protein, of which not less than 98% is IgG.331 The distribution of the IgG subclasses is similar to that of normal plasma;331 the Fc and Fab functions are maintained.331 The preparation contains trace amounts of IgA (average 80 mcg/mL).331 The manufacturing process includes several procedures, including cold ethanol fractionation, cation and anion exchange chromatography, solvent/detergent treatment, incubation at low pH, and nanofiltration, to reduce the risk of transmission of infectious agents.331

Cuvitru^® 20% is a clear and colorless or pale yellow or light brown solution and has a pH of 4.6-5.1 and an osmolality of 280-292 mOsm/kg.331 Cuvitru^® 20% contains glycine as a stabilizing and buffering agent, but does not contain any preservatives, sodium, or sucrose.331

Hizentra® 20%

Hizentra^® 20% is a sterile solution containing 20% protein, of which not less than 98% is IgG.294 The distribution of the IgG subclasses is similar to that of normal plasma.294 The preparation contains trace amounts of IgA (50 mcg/mL or less).294 The manufacturing process for Hizentra^® 20% includes cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography.294 The Fc and Fab functions of the IgG molecule are retained since the process does not include heating or chemical or enzymatic modification.294 The manufacturing process includes steps to reduce the risk of virus transmission, including incubation at pH 4, virus filtration based on size exclusion, and depth filtration.294 Several of the manufacturing processes (e.g., octanoic acid fractionation, depth filtration, virus filtration) have been shown to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE).294

Hizentra^® 20% occurs as a clear, pale yellow to light brown solution and has a pH of 4.6-5.2.294 The preparation contains approximately 250 mmol/L (range: 210-290 mmol/L) of l-proline (a nonessential amino acid) as a stabilizer, polysorbate 80 (8-30 mg/L), and trace amounts of sodium.294 Hizentra^® 20% does not contain any carbohydrate stabilizers (e.g., sucrose, maltose) or preservatives.294

Hyqvia® (Immune Globulin Subcutaneous 10% with Recombinant Human Hyaluronidase)

Immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®) is commercially available as a kit that contains a vial of immune globulin subcutaneous 10% copackaged with a vial of recombinant human hyaluronidase.327 The recombinant human hyaluronidase component is administered prior to the immune globulin component and acts locally to temporarily increase permeability of subcutaneous tissue to increase dispersion and absorption of the immune globulin.327

The immune globulin subcutaneous 10% component of Hyqvia^® is a sterile preparation of highly purified and concentrated IgG antibodies (not less than 98% IgG) with a distribution of IgG subclasses similar to that of normal plasma;327 Fc and Fab portions are maintained intact and prekallikrein activator activity is not detectable.327 The preparation contains an average of 37 mcg/mL of IgA and trace amounts of IgM.327 The immune globulin is prepared from large pools of human plasma by a combination of cold ethanol fractionation and cation and anion exchange chromatography and undergoes solvent/detergent treatment, nanofiltration, and low pH incubation at elevated temperatures to reduce the risk of transmission of viral infections.327 The immune globulin subcutaneous 10% component of Hyqvia^® is a clear or slightly opalescent and colorless or pale yellow solution with a pH of 4.6-5.1 and an osmolality of 240-300 mOsm/kg.327 The immune globulin component contains glycine as a stabilizing and buffering agent, but does not contain preservatives, sodium, or sucrose.327

The recombinant human hyaluronidase component of Hyqvia^® is prepared from mammalian cells using recombinant DNA technology.327 It is a clear and colorless solution with a pH of 7.4 and an osmolality of 290-350 mOsm/kg.327 Each vial contains 160 units/mL of recombinant human hyaluronidase and also contains sodium chloride, sodium phosphate dibasic dihydrate, human albumin, edentate disodium dihydrate, and calcium chloride dihydrate;327 sodium hydroxide is added to adjust pH.327 The solution does not contain preservatives.327

Xembify® 20%

Xembify^® 20% is a sterile solution containing 16.5% protein, of which not less than 98% is IgG.341 The distribution of the IgG subclasses in Xembify^® 20% is similar to that of normal serum.341 The manufacturing process includes several procedures, including cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography, to reduce the risk of transmission of infectious agents.341

Xembify^® 20% is a clear and colorless or slightly opalescent or pale yellow solution and has a pH of 4,1-4.8 and an osmolality of 280-404 mOsm/kg.341 Xembify^® 20% contains 0.16-0.26 M glycine and 10-40 mcg/mL of polysorbate 80, but does not contain preservatives.341

Stability

Immune Globulin IM

IGIM (GamaSTAN^®) should be refrigerated at 2-8°C and should not be frozen.154

Immune Globulin IV

Partially used vials or bottles of IGIV preparations should be discarded.125,263,265,282,308,337,338,339,340,341

Because of the potential for incompatibility, the commercially available lyophilized preparations of IGIV (Carimune^® NF, Gammagard^® S/D) should be reconstituted only with the diluent provided or specified by the manufacturers.125 Although certain immune globulin preparations may be diluted with compatible infusion fluids specified by the manufacturer (Gammagard^® Liquid 10%,266 Gammaked^® 10%,332 Gamunex^®-C 10%,265 Privigen^® 10%292 ), other immune globulin preparations should not be diluted.282,324,325,326,338,340,341 IGIV should not be admixed with other drugs.125,263,265,280,282,292,308,324,325,326,337,338,339,340,341

Asceniv® 10%

Asceniv^® 10% should be stored at 2-8°C.338 Asceniv^® 10% should not be frozen or heated and should be discarded if it has been frozen or heated.338 Vials are for single use only;338 partially used vials should be discarded.338

Bivigam® 10%

Bivigam^® 10% should be stored at 2-8°C.324 Bivigam^® 10% should not be frozen or heated and should be discarded if it has been frozen or heated.324 Vials are for single use only;324 partially used vials should be discarded.324

Carimune® NF

Carimune^® NF lyophilized powder for injection should be stored at room temperature not exceeding 30°C.125 Carimune^® NF solutions should be administered promptly if the drug is reconstituted outside of sterile laminar airflow conditions.125 If the drug is reconstituted in a sterile laminar flow hood using aseptic technique, reconstituted solutions may be stored for up to 24 hours under refrigeration.125 Carimune^® NF solutions should not be frozen.125

Flebogamma® 5% DIF

Flebogamma^® 5% DIF should be stored at 2-25°C and is stable for up to 24 months as indicated by the expiration date on the outer carton and container label.282 Flebogamma^® 5% DIF should not be frozen and should be discarded if frozen.282 Any partially used vials should be discarded.282 To protect Flebogamma^® 5% from light, it should be stored in the original carton until used.282

Flebogamma® 10% DIF

Flebogamma^® 10% DIF should be stored at 2-25°C and is stable for up to 24 months as indicated by the expiration date on the outer carton and container label.325 Flebogamma^® 10% DIF should not be frozen and should be discarded if frozen.325 Vials are for single use only;325 partially used vials should be discarded.325 To protect Flebogamma^® 10% from light, it should be stored in the original carton until used.325

Gammagard® Liquid 10%

Gammagard^® Liquid 10% may be stored at 2-8°C for up to 36 months as indicated by the expiration date on the outer carton and container label.266 Alternatively, Gammagard^® Liquid 10% may be stored at room temperature (up to 25°C) for up to 24 months as indicated by the expiration date on the outer carton and container label.266 Gammagard^® Liquid 10% should not be frozen.266 Gammagard^® Liquid 10% vials are for single use only;266 any partially used vials should be discarded.266

Gammagard® S/D

Prior to reconstitution, Gammagard^® S/D (IgA less than 1 mcg/mL) lyophilized powder for injection should be stored at a temperature not exceeding 25°C and should not be frozen.280 If reconstitution is performed outside of sterile laminar airflow conditions, administration should begin within 2 hours of reconstitution.280 If reconstitution is performed in a sterile laminar flow hood using aseptic technique, the manufacturer states that the reconstituted solution may be stored in the original glass container or in Viaflex IV bags for up to 24 hours at 2-8°C.280 Partially used vials of Gammagard^® S/D (IgA less than 1 mcg/mL) should be discarded.280

Gammaked® 10%

Gammaked^® 10% may be stored at 2-8°C for 36 months after the date of manufacture.332 The drug also may be stored at room temperature (up to 25°C) for up to 6 months at any time during the 36 months, but then must be used immediately or discarded.332 Gammaked^® 10% should not be frozen and should be discarded if frozen.332 To protect Gammaked^® 10% from light, vials should be stored in the original carton until used.265

Vials of Gammaked^® 10% that have been entered should be promptly used;332 partially used vials should be discarded.332 If the contents of full vials are pooled under aseptic conditions, the solution should be used within 8 hours of pooling.332

Gammaplex® 5% and Gammaplex® 10%

Gammaplex^® 5% and Gammaplex^® 10% should be stored at 2-25°C for up to 36 months after the date of manufacture.308,337 Gammaplex^® 5% and Gammaplex^® 10% should not be frozen and should be discarded if frozen.308 To protect these preparations from light, they should be stored in the original carton until used.308,337

Bottles of Gammaplex^® 5% or vials of Gammaplex^® 10% that have been entered should be promptly used;308,337 partially used bottles or vials should be discarded.308,337 If the contents of bottles of Gammaplex^® 5% are pooled under aseptic conditions, the IV infusion should be started within 2 hours of pooling.308

Gamunex®-C 10%

Gamunex^®-C 10% may be stored at 2-8°C for 36 months after the date of manufacture.265 The drug also may be stored at room temperature (up to 25°C) for up to 6 months at any time during the 36 months, but then must be used immediately or discarded.265 Gamunex^®-C 10% should not be frozen and should be discarded if frozen.265 To protect Gamunex^®-C 10% from light, vials should be stored in the original carton until used.265

Vials of Gamunex^®-C 10% that have been entered should be promptly used;265 partially used vials should be discarded.265 If the contents of full vials are pooled under aseptic conditions, the solution should be used within 8 hours of pooling.265

Octagam® 5%

Octagam^® 5% may be stored at 2-25°C for 24 months after the date of manufacture.263 Octagam^® 5% should not be frozen and should be discarded if frozen.263

Octagam^® 5% single-use bottles that have been entered should be used promptly;263 partially used bottles should be discarded.263

Octagam® 10%

Octagam^® 10% may be stored at 2-8°C for 24 months after the date of manufacture.326 Within the first 12 months from the date of manufacture, Octagam^® 10% may be stored for up to 9 months at room temperature (up to 25°C), but then must be used immediately or discarded.326 Octagam^® 10% should not be frozen and should be discarded if frozen.326

Octagam^® 10% single-use bottles that have been entered should be used promptly;326 partially used bottles should be discarded.326

Panzyga® 10%

Panzyga^® 10% should be stored at 2-8°C for up to 24 months after the date of manufacture.339 The drug also may be stored at room temperature (up to 25°C) for up to 9 months at any time during the 24 months, but then must be used immediately or discarded.339 Panzyga^® 10% should not be frozen and should be discarded if it has been frozen.339

Privigen® 10%

Privigen^® 10% is stable for up to 36 months when stored at room temperature (up to 25°C) as indicated by the expiration date on the outer carton and vial label.292 Privigen^® 10% should not be frozen and should be discarded if it has been frozen.292 Privigen^® 10% should be protected from light.292

Immune Globulin Subcutaneous

Cutaquig® 16.5%

Cutaquig^® 16.5% should be stored at 2-8°C for up to 24 months after the date of manufacture.340 The drug also may be stored at room temperature (up to 25°C) for up to 6 months at any time during the 24 months, but then must be used immediately or discarded.340 To protect the preparation from light, vials should be stored in the original carton until used.340 Cutaquig^® 16.5% should not be frozen and should be discarded if it has been frozen.340

Cuvitru® 20%

Cuvitru^® 20% should be stored at 2-8°C and is stable for up to 36 months.331 Alternatively, Cuvitru^® 20% can be stored at room temperature (up to 25°C) for up to 12 months, but should not be returned to refrigeration.331 Cuvitru^® 20% should not be frozen.331 To protect Cuvitru^® 20% from light, it should be stored in the original carton until used.331

Cuvitru^® 20% vials are for single use only;331 any partially used vials should be discarded.331

Hizentra® 20%

Hizentra^® 20% should be stored at room temperature (up to 25°C) and is stable for up to 30 months as indicated by the expiration date on the outer carton of the prefilled syringe or vial label.294 Hizentra^® 20% should not be frozen and should be discarded if it has been frozen.294 To protect Hizentra^® 20% from light, it should be stored in the original carton until used.294

Partially used vials of Hizentra^® 20% should be discarded.294

Hyqvia® (Immune Globulin Subcutaneous 10% with Recombinant Human Hyaluronidase)

The kit containing immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia^®; vial of immune globulin subcutaneous 10% copackaged with a vial of recombinant human hyaluronidase) can be stored at 2-8°C for up to 36 months.327 Alternatively, the kit can be stored at room temperature (up to 25°C) for up to 3 months during the first 24 months from the date of manufacture printed on the carton.327 If the kit is removed from refrigeration and subsequently stored at room temperature (up to 25°C), it should be used within 3 months after removal to room temperature (but within the expiration date on the carton and vial labels) and should not be returned to refrigeration.327 The vials of immune globulin subcutaneous 10% and vials of recombinant human hyaluronidase should be stored in the original carton to protect from light and should not be frozen.327

Xembify® 20%

Xembify^® 20% should be stored at 2-8°C.341 Alternatively, Xembify^® 20% may be stored at room temperature (up to 25°C) for up to 6 months at any time prior to the expiration date, but then must be used immediately or discarded.341 Xembify^® 20% should not be frozen and should be discarded if it has been frozen.341

Only references cited for selected revisions after 1984 are available electronically.

103. Furusho K, Kamiya T, Nakano H et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet . 1984; 2:1055-8. [PubMed 6209513]

104. Newburger JW, Takahashi M, Burns JC et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med . 1986; 315:341-7. [PubMed 2426590]

105. American Academy of Pediatrics. Red Book: 2018-2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.

108. Arsura EL, Bick A, Brunner NG et al. High-dose intravenous immunoglobulin in the management of myasthenia gravis. Arch Intern Med . 1986; 146:1365-8. [PubMed 3718134]

109. Nakano H, Saito A, Ueda K et al. Clinical characteristics of myocardial infarction following Kawasaki disease: report of 11 cases. J Pediatr . 1986; 108:198-203. [PubMed 3944703]

110. Ippoliti G, Cosi V, Piccolo G et al. High-dose intravenous gammaglobulin for myasthenia gravis. Lancet . 1984; 2:809. [PubMed 6148545]

111. Lederman HM, Roifman CM, Lavi S et al. Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients. Am J Med . 1986; 81:443-6. [PubMed 3752145]

115. Centers for Disease Control and Prevention. CDC health information for international travel, 2018. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website. [Web]

116. Anon. Safety of therapeutic immune globulin preparations with respect to transmission of human T-lymphotropic virus type III/lymphadenopathy-associated virus infection. MMWR Morb Mortal Wkly Rep . 1986; 35:231-3. [PubMed 3007971]

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