ATC Class:J06BB04

VA Class:IM100

AHFS Class:

• Antitoxins and Immune Globulins 80:04

Generic Name(s):

• Hepatitis B Immune Globulin (Human)

• Hepatitis B Immune Globulin Intravenous (Human)

Hepatitis B immune globulin (HBIG) is a specific immune globulin (hyperimmune globulin).110 HBIG contains antibody to hepatitis B surface antigen (anti-HBs) prepared from plasma of donors with high titers of anti-HBs and is used to provide temporary passive immunity to hepatitis B virus (HBV).101,112,116,128,129,132

Hepatitis B immune globulin (HBIG) is used to provide passive immunity to hepatitis B virus (HBV) infection for prevention of perinatal HBV infection in neonates born to hepatitis B surface antigen-positive (HBsAg-positive) mothers,101,112,116,124,128,129,132 for postexposure prophylaxis in susceptible individuals exposed to HBV or HBsAg-positive materials (e.g., blood, plasma, serum),100,109,112,116,122,128,129,132 and for prevention of HBV recurrence in liver transplant recipients who are HBsAg-positive.132,135,136,137,138,139,140,141,142

A combined regimen that includes passive immunization with HBIG and active immunization with hepatitis B vaccine is used for prevention of perinatal HBV infection.112,116,128,129,132 (See Uses: Prevention of Perinatal Hepatitis B Virus [HBV] Infection.) Depending on the exposure circumstances, a combined regimen of passive immunization with HBIG and active immunization with hepatitis B vaccine also may be indicated for postexposure prophylaxis of HBV infection in individuals exposed to HBV or HBsAg-positive materials (e.g., health-care personnel, sexual or intimate contacts of individuals with acute or chronic HBV infection) since it provides both short- and long-term protection109,112 .116,128,129,132 (See Uses: Postexposure Prophylaxis of Hepatitis B Virus [HBV] Infection.)

HBIG is not indicated in the treatment of acute or chronic HBV infection.101

Risks of Exposure and Infection

HBV is transmitted by percutaneous or mucosal exposure to HBsAg-positive blood, serum, plasma, semen, or saliva from individuals who have acute HBV infection or individuals who are carriers of the virus.101,122,128,129,134,145 The principal sources of HBV are blood (plasma or serum) and serous fluids.122 Lower concentrations are found in saliva, semen, vaginal secretions, and wound exudates.134 Although saliva can be a vehicle of HBV transmission through bites, other types of exposure to saliva (e.g., kissing) are unlikely modes of transmission.134 Transmission of HBV does not appear to occur via tears, sweat, urine, feces, or droplet nuclei and the virus is not transmitted via the fecal-oral route.134

HBV can be transmitted perinatally from mother to infant at birth, usually as the result of blood exposures during labor and delivery.101,128,134,145 In utero transmission of HBV is rare.101 Without postexposure HBV prophylaxis in the neonate, the risk for perinatal transmission of the virus and chronic infection is 5-20% if the mother is HBsAg-positive and hepatitis B e antigen-negative (HBeAg-negative) and about 70-90% if the mother is positive for both HBsAg and HBeAg.101,128,134 Up to 90% of infants who become infected perinatally will become HBV carriers.101,134

In the US, the primary risk factors for HBV infection in adults and adolescents are unprotected sex with an infected partner, unprotected sex with more than one partner, men who have sex with men, history of other sexually transmitted diseases (STDs), and illicit injection drug use.129,134 The US Centers for Disease Control and Prevention (CDC) states that individuals considered at high risk of exposure to HBsAg-positive material include immigrants or refugees from areas of high HBV endemicity, residents in institutions for the developmentally disabled, users of illicit parenteral drugs, homosexually active men, hemodialysis patients, and household contacts of HBV carriers.134 Those considered at intermediate risk include male prisoners, health-care workers who have frequent blood contact, staff of institutions for the developmentally disabled, and heterosexuals with multiple partners.134

Presence of HBeAg indicates a high degree of infectivity of body fluids.134 Individuals exposed to body fluids that are positive for HBsAg, HBeAg, and HBV-specific DNA polymerase are more likely to develop HBV infection than individuals exposed to body fluids that are positive for HBsAg and anti-HBe but negative for HBeAg and DNA polymerase.134 The development of the HBV carrier state generally is associated with high serum titers of HBsAg and persistent, high serum titers of antibody to hepatitis B core antigen (anti-HBc); HBeAg also may be present.134

Acute HBV infection may be self-limited resulting in production of antibody to HBsAg (anti-HBs) and immunity against reinfection; however, it also may progress to chronic HBV infection (especially in infants or young children, immunocompromised individuals, patients with diabetes) or to fatal, fulminant hepatitis.101,128,129,134 The case fatality rate is 0.5-1.5% among those with acute HBV infection, and the highest fatality rates are in adults older than 60 years of age.128,129 Chronic HBV infection develops in 90% or more of infants infected perinatally, 25-50% of children infected at 1-5 years of age, and less than 5% of those infected at 5 years of age or older.101,128,129,134,145 Chronic infection is associated with persistent HBV replication in the liver and may result in liver cirrhosis, liver cancer, liver failure, and death.101,128,129,134,145 Data from 2006 indicate that approximately 800,000-1.4 million people in the US have chronic HBV infection.145

Prevention of Perinatal Hepatitis B Virus (HBV) Infection

A regimen that includes active immunization with hepatitis B vaccine and passive immunization with HBIG is used to prevent perinatal HBV infection in neonates born to HBsAg- positive women.101,112,116,124,128,129,132 This regimen is 85-95% effective in preventing acute and chronic HBV infection in infants born to women positive for both HBsAg and HBeAg.101,112,116,128,132

HBIG has been used alone for prevention of perinatal HBV infection in neonates born to HBsAg-positive women, but use of passive immunization alone no longer is recommended since a regimen that includes both HBIG and hepatitis B vaccine is more effective.112

The ACIP and AAP recommend routine serologic screening of all pregnant women during an early prenatal visit (e.g., first trimester) to determine their HBsAg status, even if they were tested previously or already have been vaccinated against HBV.101,124,128,129 Pregnant women who were not tested prenatally, those who engage in behaviors that put them at high risk for HBV (e.g., more than one sex partner in the previous 6 months, HBsAg-positive sex partner, evaluation or treatment for STDs, recent or current injection drug abuse), and those with clinical hepatitis should be tested for HBsAg status when admitted to the hospital for delivery.101,128

To prevent perinatal HBV infection, ACIP and AAP recommend that all neonates born to HBsAg-positive women receive a dose of HBIG and a dose of hepatitis B vaccine as soon as possible after birth (within 12 hours of birth), regardless of gestational age or birthweight.101,112,124,128

If maternal HBsAg status is unknown at birth, the neonate should receive the first dose of hepatitis B vaccine (within 12 hours of birth)101,124,127,128 and the mother's HBsAg status should be determined as quickly as possible; if positive, the infant should receive a dose of HBIG as soon as possible (no later than 7 days of age).101,124,128 For neonates weighing less than 2 kg, if the mother's HBsAg status cannot be determined within 12 hours of birth, a dose of HBIG should be given as soon as possible (within 12 hours of birth), and the birth vaccine dose should not be counted toward completion of the hepatitis B vaccine series; the usual 3-dose vaccine series should begin when the infant is 1 month of age.101,127,128

Postexposure Prophylaxis of Hepatitis B Virus (HBV) Infection

HBV postexposure prophylaxis is recommended in certain individuals exposed to HBV or HBsAg-positive materials (e.g., health-care personnel, sexual or intimate contacts of individuals with acute or chronic HBV infection).100,109,112,116,122,128,129,132 Depending on the exposure circumstances, a postexposure prophylaxis regimen may include combined passive immunization with HBIG and active immunization with hepatitis B vaccine to provide both short- and long-term protection.109,122,129 Although HBIG alone may effectively prevent HBV transmission, it typically is used as an adjunct to hepatitis B vaccine following occupational or nonoccupational exposures to HBV.129

Although a 2-dose regimen of HBIG alone (first dose at the time of exposure and second dose 1 month later) is reported to be about 75% effective in preventing HBV infection following percutaneous exposure,10,22,112,122 there is evidence that combined passive and active immunization is more effective than HBIG alone following perinatal HBV exposure.109,112,122,129 Therefore, although there are no prospective studies directly determining the efficacy of combined passive and active immunization in preventing HBV infection following percutaneous, permucosal, or peroral exposure to HBsAg-positive material,10,22,112,122 combined active and passive immunization is preferred for postexposure prophylaxis following an exposure to HBsAg-positive material.109,112,122,129 Combined passive and active immunization will provide both short-term protection and prolonged immunity to subsequent exposures and may increase efficacy in preventing HBV infection in such postexposure situations.132

The major determinant of postexposure prophylaxis effectiveness is early administration of the initial dose of hepatitis B vaccine with or without HBIG; postexposure prophylaxis is less effective depending on how long it has been since the exposure.144 Studies are limited regarding the maximum interval after exposure during which HBV postexposure prophylaxis is effective, but such prophylaxis is unlikely to be effective if initiated 7 days or longer after percutaneous (e.g., needlestick) exposures.144

HBV postexposure prophylaxis is not necessary in individuals who previously received primary immunization with hepatitis B vaccine and have serologic evidence of adequate levels of anti-HBs (10 mIU/mL or greater).122 In addition, HBV postexposure prophylaxis is not necessary in individuals previously infected with HBV since such individuals are immune to reinfection.122,134

The ACIP recommends that exposure to HBV infection and to body fluids that may be HBsAg-positive be evaluated individually according to the identity and HBsAg serologic status of the source and the hepatitis B vaccination status of the exposed individual.122 The US Public Health Service (USPHS), ACIP, and the Hospital Infection Control Practices Advisory Committee (HICPAC) recommend routine use of hepatitis B vaccine in certain individuals, including all health-care personnel who, because of their occupation and work environment, are at risk of exposure to blood, blood-contaminated body fluids, other body fluids, and/or needles that might be contaminated with HBsAg.122,125 Such health-care personnel should undergo serologic testing 1-2 months after completing the 3-dose vaccine series to confirm an anti-HBs response.122 (See Healthcare Personnel under Uses: Preexposure Vaccination in High-Risk Groups, in Hepatitis B Vaccine 80:12.) Nonresponders to vaccination who are HBsAg-negative should be considered susceptible to HBV infection and should be counseled regarding precautions to prevent HBV infection and the need for HBIG postexposure prophylaxis for any known or probable parenteral exposure to HBsAg-positive blood.122 An exposure-control plan should be established by health-care organizations that includes protocols for prompt reporting, evaluation, counseling, treatment, and follow-up of occupational exposures, as well as appropriate reporting of occupational exposure to blood-borne pathogens as required by standards established by the Occupational Safety and Health Administration.122 Working health-care personnel should always have convenient access to clinicians who can provide timely postexposure prophylaxis with HBIG and/or hepatitis B vaccine.122

Exposure to Materials with Known or Potential HBsAg-Positivity

Following percutaneous (e.g., needlestick, laceration) exposure to, direct mucous membrane contact (e.g., oral, ophthalmic) with, or ingestion of material containing HBV or a HBsAg-positive source of known identity or following a bite from a human carrier of HBsAg which penetrates the skin, the ACIP and USPHS state that immunization routinely should consist of combined passive immunization with HBIG and active immunization with hepatitis B vaccine for individuals incompletely or not previously vaccinated.112,122,128,129,132 HBIG should be administered as soon as possible, routinely within 24 hours but not later than 7 days after exposure,112,128,129 and hepatitis B vaccine should be administered in a recommended primary immunization regimen.109,122,129 (See Dosage and Administration: Dosage, in Hepatitis B Vaccine 80:12.)

For those not previously vaccinated, the first dose of hepatitis B vaccine is administered concurrently with HBIG (at a separate site) not later than 7 days after exposure; subsequent doses of the vaccine should be given according to the recommended schedule to complete primary immunization.112,122 For those incompletely vaccinated at the time of exposure, a dose of HBIG should be given immediately and the usual recommended regimen for primary immunization with the vaccine should be completed as previously scheduled.122

For individuals exposed to HBsAg-positive material and who previously completed primary immunization with the vaccine, the need for combined passive and active versus just passive or active immunization depends on the anti-HBs response of the individual.112,114,122 For those known to have exhibited an adequate anti-HBs response (i.e., an anti-HBs titer of 10 mIU/mL or greater), no treatment is necessary.114,122 For those whose response is not known, anti-HBs testing should be performed and the need for immunization based on this determination.122 No treatment is necessary when the antibody level is adequate; however, if an anti-HBs titer is determined to be less than 10 mIU/mL, the individual should receive a booster dose of hepatitis B vaccine and a single dose of HBIG administered concurrently but at separate sites. 112,114,122 For those known to be nonresponders to completed primary immunization with the vaccine, a single dose of HBIG and the initial dose of the 3-dose vaccine series should be given as soon as possible after exposure; alternately, 2 doses of HBIG should be given, one as soon as possible after exposure and the second 1 month later.112,122 This latter 2-dose HBIG regimen is preferred for those who have failed to respond to 2 complete 3-dose series of vaccine122 or refuse to receive hepatitis B vaccine.112

Following exposure to a source of known identity but unknown HBsAg status, a decision regarding the need for HBsAg serologic testing and appropriate immunization must be made based on the likelihood that the source is HBsAg-positive or HBsAg-negative and on the hepatitis B vaccination status of the exposed individual. 122 Individuals considered at high risk of exposure to HBsAg-positive material are considered likely HBsAg-positive sources. If HBsAg testing of the source is positive, postexposure immunization is undertaken as described above for exposure to HBsAg-positive materials.122 If HBsAg testing of the source is negative, postexposure active immunization need only be undertaken in those incompletely or not previously vaccinated.122 Such previously unvaccinated individuals should receive the first dose of vaccine as soon as possible, preferably within 24 hours (with subsequent doses given according to the recommended schedule to complete primary immunization), and those incompletely vaccinated should simply complete the previously scheduled primary immunization regimen with the vaccine.122 Likewise, previously unvaccinated or incompletely vaccinated individuals exposed to an unknown source or one that is unavailable for testing should receive such active immunization with the vaccine.122 Individuals exposed to HBsAg-negative materials and who have completed primary immunization with the vaccine need not receive any further immunization at the time of such exposure, regardless of their response to such previous primary immunization.122 When the source of exposure is unavailable for testing or unknown in vaccinated individuals with a known anti-HBs response, those with an adequate response need receive no further immunization, but nonresponders exposed to a high-risk source can be immunized as described above for nonresponders exposed to HBsAg-positive materials.122 Vaccinees exposed to an unknown source or one that is unavailable for testing and in whom the anti-HBs response is unknown should undergo antibody testing and, if adequate, no further immunization is necessary but, if inadequate, a single booster dose of the vaccine should be given.122 (See Table 1.)

Sexual Assault Victims

ACIP and CDC recommend postexposure prophylaxis with hepatitis B vaccine with or without HBIG for victims of sexual assault (adult, adolescent, child) who are susceptible to HBV.109,129 Postexposure prophylaxis after a sexual assault is not necessary in those who previously received the complete hepatitis B vaccine series.109 If the victim is unvaccinated or incompletely vaccinated and the perpetrator is HBsAg-positive, the victim should receive a dose of HBIG within 14 days of the assault (preferably within 24 hours) and the hepatitis B vaccine series should be initiated or completed.109,129

Contacts of Individuals with Acute HBV Infection

Sexual or intimate contacts of individuals with acute HBV infection are at increased risk of acquiring HBV infection; therefore, postexposure prophylaxis is recommended in these contacts.109,112,132 The ACIP and CDC recommend that all susceptible individuals whose sexual or intimate contact has active HBV infection, contracts HBV, or is a chronic carrier receive postexposure prophylaxis with a single dose of HBIG and initiation of a primary immunization series of hepatitis B vaccine if such prophylaxis can be started within 14 days of the last such contact or if ongoing sexual or intimate contact with an infected individual is likely.109,112 This combined immunization strategy could potentially improve the efficacy of postexposure therapy compared with HBIG alone and can confer prolonged protection in this population.112 HBIG is most effective when administered as soon as possible after exposure (preferably within 24 hours) and may be ineffective if administered more than 14 days after a sexual exposure.109,112,122,128,129 Screening sexual or intimate contacts of individuals with acute HBV infection is recommended if it will not delay HBIG administration beyond 14 days after exposure.109

Data regarding the use of HBIG in children are mainly limited to its administration to neonates born to HBsAg-positive women.112,116,132 However, the AAP recommends that postexposure prophylaxis in children follow the ACIP guidelines for adults.101 In addition, because infants have a high risk of becoming chronic HBV carriers following acute infection, unvaccinated infants younger than 12 months of age who have close contact with a primary caregiver or family member with acute HBV infection should receive combined passive immunization with HBIG and active immunization with hepatitis B vaccine.101,112 If the infant has previously received a single dose of hepatitis B vaccine, the second vaccine dose should be administered if the interval is appropriate or, if it is too soon to give a vaccine dose, the infant should receive a dose of HBIG.101 HBIG is not required if, at the time of exposure, the infant has already received at least 2 doses of hepatitis B vaccine.101

Because of the potential risks from exposure to HBV infection and the potential for development of chronic infection in neonates, pregnancy is not considered a contraindication to the use of HBIG when clearly needed.122 (See Cautions: Pregnancy, Fertility, and Lactation.)

Household contacts of individuals with acute HBV infection, other than those described elsewhere as being at risk (e.g., infants, sexual or intimate contacts), generally do not require HBIG prophylaxis unless they have had identifiable blood exposure (e.g., sharing toothbrushes or razors) to the index patient.101,112,132 However, all household contacts of individuals with acute HBV infection should be encouraged to complete primary immunization with hepatitis B vaccine.101,112

Contacts of Individuals with Chronic HBV Infection

Sexual or needle-sharing partners and nonsexual household contacts of individuals with chronic HBV infection are at risk for HBV infection through percutaneous or mucosal exposures to blood or infectious body fluids (e.g., sharing a toothbrush or razor, contact with exudates from dermatologic lesions, contact with HBsAg-contaminated surfaces).129 Therefore, the ACIP recommends postexposure vaccination with hepatitis B vaccine for such individuals.129 A dose of HBIG also may be indicated for postexposure prophylaxis if the most recent sexual exposure to an HBsAg-positive individual occurred within the last 14 days.109

Individuals Wounded in Mass Casualty Settings

The CDC recommends that individuals wounded in bombings or other mass casualty settings who have not previously received hepatitis B vaccine or have an uncertain vaccination history receive postexposure vaccination with hepatitis B vaccine.144 (See Individuals Wounded in Mass Casualty Settings in Uses: Postexposure Prophylaxis, in Hepatitis B Vaccine 80:12.) In addition, the CDC recommends that responders and other personnel in mass casualty settings be managed using postexposure prophylaxis regimens recommended for occupational exposures to HBV.144 (See Table 1.)

Prevention of Hepatitis B Virus (HBV) Recurrence in Liver Transplant Recipients

HBIG is used to prevent HBV recurrence in liver transplant recipients who are HBsAg-positive.132,135,136,137,138,139,140,141,142

HBIG has been used alone132 or in conjunction with an antiviral agent active against HBV (e.g., lamivudine, adefovir) to suppress HBV replication and prevent recurrence of HBV infection in patients with chronic HBV infection undergoing liver transplantation.135,136,137,138,139,140,141,142 Optimum regimens for such prophylaxis (i.e., dosage, route, and duration of HBIG; specific antiviral for a combined regimen) have not been established.135,137,138,139,140,141,142

HepaGam B^® given by IV infusion is labeled by the Food and Drug Administration (FDA) for prevention of HBV recurrence in liver transplant recipients based on interim results of a clinical study in HBsAg-positive, HBeAg-negative transplant recipients who had only low or undetectable levels of HBV replication at the time of transplant.132 Although other HBIG preparations have been administered IM or IV for prevention of HBV recurrence in liver transplant recipients† and have been used alone or in conjunction with an antiviral active against HBV, safety and efficacy of these preparations have not been established for this use.135,136,137,138,139,140,141,142

Administration

Hepatitis B immune globulin (HBIG) is administered by IM injection for prevention of perinatal hepatitis B virus (HBV) infection or for postexposure prophylaxis of HBV infection.112,116,132 HBIG is administered by IV infusion for prevention of HBV recurrence in liver transplant recipients132

Prior to administration, HBIG should be inspected visually for particulate matter and discoloration.112,116,132 HBIG should be administered undiluted and should not be mixed with any other drug or solution.116,132

IM Administration

HyperHEP B^®, Nabi-HB^®, and HepaGam B^® are administered by IM injection for prevention of perinatal HBV infection or for postexposure prophylaxis of HBV infection.112,116,132 HBIG should not be administered by IV infusion for these indications. 112,116,132

In adults and children, IM injections of HBIG preferably should be made into the deltoid muscle or anterolateral aspect of the thigh.110,112,116,128,129 In neonates and infants 12 months of age or younger, IM injections of HBIG preferably should be made into the anterolateral aspect of the thigh.110,128 In children 1-2 years of age, IM injections should preferably be administered into the anterolateral thigh; the deltoid muscle is an alternative if muscle mass is adequate.110,128 For children and adolescents 3-18 years of age and adults, the deltoid muscle is preferred, although the anterolateral thigh is an alternative.110,128,129

To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin using a needle length appropriate for the individual's age and body mass, the thickness of adipose tissue and muscle at the injection site, and the injection technique.110,128,129

Because of the risk of injury to the sciatic nerves, the upper, outer quadrant of the gluteal muscle should be used for IM injection of HBIG only if a large volume is indicated in an adult or if a large dose must be divided into multiple injection sites.112,116 If use of the gluteal area is considered necessary, use only the upper, outer quadrant and avoid the central gluteal region.112,116

Although some manufacturers recommend that aspiration (i.e., pulling back on the syringe plunger after needle insertion and before injection) should be performed to ensure that a blood vessel has not been entered,112 the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) state that this procedure is not required because large blood vessels are not present at recommended IM injection sites.101,110

HBIG may be given simultaneously with hepatitis B vaccine (using different syringes and different injection sites) when passive immunization is considered necessary in addition to active immunization with the vaccine (e.g., in neonates born to HBsAg-positive women, postexposure prophylaxis regimen in certain individuals exposed to HBV or HBsAg-positive materials).101,110,112,124,128,129,132

IV Administration

HepaGam B^® is given by IV infusion for prevention of HBV recurrence in liver transplant recipients.132 Other HBIG preparations also have been administered by IV infusion† for prevention of HBV recurrence in liver transplant recipients, but are not labeled by the US Food and Drug Administration (FDA) for this use.135,136,137,140,141,142

Vials of HepaGam B^® should not be shaken to avoid foaming.132

HepaGam B^® should be administered IV using a separate IV line and an IV infusion pump.132

Rate of Administration

HepaGam B^® should be administered by IV infusion at a rate of 2 mL/minute.132 If the patient develops discomfort or infusion-related adverse effects or if there is concern about the rate of infusion, the rate of administration should be decreased to 1 mL/minute or less.132

Dosage

Prevention of Perinatal HBV Infection

Neonates Born to HBsAg-positive Women

Neonates born to HBsAg- positive women, including those infected with human immunodeficiency virus (HIV), should receive combined passive immunization with HBIG and active immunization with hepatitis B vaccine to prevent perinatal HBV infection.101,124,127,128,132

The usual dose of HBIG in neonates born to HBsAg-positive women is 0.5 mL given IM within 12 hours of birth.101,112,116,124,127,128,132 These neonates also should receive a dose of monovalent hepatitis B vaccine within 12 hours of birth (using a different syringe and different injection site).101,112,116,124,127,128,132

If the first dose of hepatitis B vaccine is delayed for 3 months or longer, the manufacturer of HyperHEP B^® recommends that a second 0.5-mL dose of HBIG be given IM at 3 months of age.112 In addition, if hepatitis B vaccine is contraindicated or not available, this manufacturer recommends that second and third 0.5-mL doses of HBIG be given IM at 3 and 6 months of age, respectively.112

All infants born to HBsAg-positive women should undergo serologic testing at 9-18 months of age to document whether the combined regimen of active immunization with hepatitis B vaccines and passive immunization with HBIG prevented perinatal HBV infection.101,126,127 (See Uses: Pre- and Postvaccination Serologic Testing, in Hepatitis B Vaccine 80:12.)

Neonates Born the Women with Unknown HBsAg Status

Neonates born to women with unknown HBsAg status should receive active immunization with hepatitis B vaccine and, depending on the circumstances (e.g., HBsAg status of the mother), passive immunization with HBIG also may be indicated.100,101,124,127,128

All neonates born to women with unknown HBsAg status should receive a dose of monovalent hepatitis B vaccine within 12 hours of birth, and the HBsAg status of the mother should be determined as soon as possible.101,124,127,128 If the mother of a full-term neonate or preterm neonate weighing more than 2 kg at birth is subsequently found to be HBsAg-positive, these neonates should receive a 0.5-mL dose of HBIG as soon as possible (no later than 1 week of age).101,124,128,132 If the neonate was preterm and weighed less than 2 kg at birth, the neonate should receive a 0.5 mL dose of HBIG within 12 hours of birth if mother is found to be HBsAg-positive or if results are not available.101,127,128

Postexposure Prophylaxis of HBV Infection

The ACIP recommends that exposure to HBV infection or body fluids that might be HBsAg-positive should be evaluated individually according to the identity and HBsAg serologic status of the source and the hepatitis B vaccination status of the exposed individual to determine the need for postexposure prophylaxis.122 (See Uses: Postexposure Prophylaxis of Hepatitis B Virus [HBV] Infection.)

Known Source with HBsAg-positive Status

Following exposure to a HBsAg-positive source of known identity in an individual who has not previously received primary immunization with hepatitis B vaccine, the usual adult dose of HBIG is 0.06 mL/kg.109,112,116,132 A dose of hepatitis B vaccine should be administered concurrently (at a separate site) and the recommended primary immunization schedule for the vaccine should be completed; alternatively, the first dose of vaccine may be administered up to 7 days after percutaneous exposure.129 In individuals who have begun but not completed primary immunization with hepatitis B vaccine at the time of exposure, the usual dose of HBIG should be given immediately and the recommended primary immunization schedule for the vaccine completed as scheduled. Because immunoglobulins are most effective if given immediately after exposure, HBIG should be administered as soon as possible after exposure, preferably within 24 hours; the value of administering immunoglobulins later than 7 days after exposure is not known.122,132 Individuals who elect not to receive hepatitis B vaccine should receive the usual dose of HBIG as soon as possible (but within 24 hours after exposure) and a second dose of HBIG should be administered 1 month later.112,122,128,129,132

If the source is known to be HBsAg-positive and the exposed individual is unvaccinated or a known nonresponder to hepatitis B vaccine (anti-HBs is less than 10 mIU/mL), combined active immunization with hepatitis B vaccine and passive immunization with HBIG is indicated.122,129,132 (See Table 1 under Uses.)

Known Source with HBsAg-negative Status

Administration of HBIG is unnecessary following exposure to an HBsAg-negative source in vaccinated individuals.122,132 However, hepatitis B vaccine is indicated in previously unvaccinated or incompletely vaccinated individuals following such exposures.122,132 (See Hepatitis B Vaccine 80:12.)

Known Source with Unknown HBsAg Status or Unknown Source

Following exposure to a source of known identity but unknown HBsAg status (i.e., not tested) or an unknown source, previously unvaccinated individuals should receive a complete series of primary immunization with hepatitis B vaccine, initiated within 7 days of exposure and completed according to the usual schedule.132 Incompletely vaccinated individuals should simply complete the previously scheduled primary vaccine series. Administration of HBIG is unnecessary in either incompletely or not previously vaccinated individuals.132 Previously vaccinated individuals whose response in the past was adequate need receive no further immunization at the time of exposure.122 Those who were nonresponders and now are exposed to a source that is likely to be HBsAg-positive can receive 0.06 mL/kg of HBIG immediately along with a booster dose of hepatitis B vaccine.122 Alternatively, such nonresponders can receive 2 doses (0.06 mL/kg each) of HBIG, one administered immediately and the second 1 month later; this regimen is preferred for those who have failed to respond to at least 4 doses of vaccine.122,132

Unvaccinated or Incompletely Vaccinated Sexual Assault Victims

Active immunization with hepatitis B vaccine is indicated and passive immunization with HBIG also may be indicated following a sexual assault.109,129

If the victim is unvaccinated or incompletely vaccinated and the perpetrator is HBsAg-positive, the victim should receive 0.06 mL/kg of HBIG within 14 days of the assault (preferably within 24 hours).109,129 In addition, primary immunization with hepatitis B vaccine should be initiated or completed in unvaccinated or incompletely vaccinated sexual assault victims.109,129

Contacts of Individuals with Acute HBV Infection

Active immunization with hepatitis B vaccine is indicated and passive immunization with HBIG also may be indicated following sexual or intimate exposure to individuals with acute HBV infection.109,129,132

Following sexual or intimate exposure to individuals with acute HBV infection, 0.06 mL/kg of HBIG should be given within 14 days of the last sexual or intimate exposure.109 In addition, primary immunization with hepatitis B vaccine should be initiated or completed in unvaccinated or incompletely vaccinated sexual assault victims.109,129

For unvaccinated or incompletely vaccinated infants younger than 12 months of age whose mother or other primary caregiver has acute HBV infection, a 0.5-mL dose of HBIG should be administered and primary immunization with hepatitis B vaccine should be initiated and completed.101,112,132 HBIG is unnecessary if the infant has already received 2 or more doses of hepatitis B vaccine.101

Prevention of HBV Recurrence in Liver Transplant Recipients (HepaGam B®)

For prevention of HBV recurrence following liver transplantation in HBsAg-positive liver transplant recipients, HepaGam B^® is administered by IV infusion in a dosage designed to provide anti-HBs serum levels greater then 500 international units/L.132

The manufacturer states that an initial IV dose of 20,000 international units of HepaGam B^® should be given concurrently with the grafting of the transplanted liver (anhepatic phase).132 Then, 20,000 international units should be given once daily on postoperative days 1-7, 20,000 international units should be given once every 2 weeks during postoperative weeks 2-12, and 20,000 international units should be given once monthly beginning at postoperative month 4.132

The treatment response should be tracked by monitoring serum HBsAg and anti-HBs antibody levels using a quantitative assay.132 The dosage of HepaGam B^® should be adjusted if anti-HBs levels do not increase to 500 international units/L or more within the first postoperative week.132 In such cases, dosage can be increased to 10,000 international units every 6 hours until the target anti-HBs level is reached.132 Individuals with surgical bleeding or abdominal fluid drainage (greater than 500 mL) and those undergoing plasmapheresis are particularly susceptible to extensive loss of circulating anti-HBs.132

Local Reactions

Following IM administration of hepatitis B immune globulin (HBIG), local pain, tenderness, swelling, and erythema may occur at the injection site.112,116,122

Systemic Effects

Following IM administration of HBIG, urticaria,112 angioedema,112 nausea,116,132 vomiting,116 myalgia,116 headache,116,132 flu or cold symptoms,132 lightheadedness/fainting,132 and malaise116 have been reported. Elevated serum alkaline phosphatase, AST (SGPT), and creatinine concentrations and ecchymosis, joint stiffness, and decreased leukocyte counts also have been reported.116

The most common adverse effects reported with IV immune globulins are chills, fever, headache, vomiting, allergic reactions, nausea, arthralgia, and moderate low back pain.132 In a clinical study evaluating IV administration of HBIG (HepaGam B^®) for prevention of hepatitis B recurrence in liver transplant patients, interim analysis indicated that the only adverse effects attributed to HBIG given by IV infusion were tremor and hypotension.132 Other adverse events reported in more than 10% of liver transplant patients in this study (including events assessed as unrelated to HBIG) include splenomegaly, presbyopia, aphthous stomatitis, diarrhea, dyspepsia, gingival hyperplasia, fatigue, peripheral edema, pyrexia, hepatobiliary disease, liver transplant rejection, infectious diarrhea, pneumonia, sepsis, hyperglycemia, back pain, amnesia, essential tremor, headache, agitation, nocturia, pleural effusion, pruritus, rash, hypertension, and hypotension.132

Precautions and Contraindications

HepaGam B^® and Nabi-HB^® are contraindicated in individuals with a history of anaphylactic or severe systemic reactions to parenteral human immune globulin.116,132 The manufacturer of HyperHEP B^® states that there are no known contraindications to use of this preparation of immune globulin, but the preparation should be used with caution in individuals who have exhibited previous systemic allergic reactions to immune globulin.112

Sensitivity Reactions

Although anaphylactic reactions have not been reported to date with HBIG, anaphylaxis has been reported rarely following administration of human immune globulins.112,116,132

Epinephrine should be readily available in case anaphylaxis occurs.116,132 If hypotension or a hypersensitivity reaction (e.g., anaphylaxis) occurs, HBIG should immediately be discontinued and appropriate therapy initiated as indicated.132

Selective IgA Deficiency

HBIG should be used with caution in individuals with specific IgA deficiency since these individuals may have serum antibodies to IgA or may develop such antibodies and anaphylaxis could result following administration of blood products containing IgA.116,132

HepaGam B^® contains less than 40 mcg/mL and Nabi-HB^® contains less than 100 mcg/mL of IgA.116,132 If these preparations are used, the potential benefits should be weighed against the potential for a hypersensitivity reaction.116,132

Individuals with Bleeding Disorders

HBIG should be administered IM with caution in patients with thrombocytopenia or bleeding disorders since bleeding may occur following IM injections (probably because of injury from injection).110,112,116,132 HBIG should be administered IM in these patients only if the expected benefits outweigh the potential risks.116,132

The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that IM injections can be used in individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the injection can be administered with reasonable safety.110 In these cases, a fine needle (23 gauge) should be used to administer the dose and firm pressure applied to the injection site (without rubbing) for at least 2 minutes.110 If the patient is receiving antihemophilia therapy, the IM dose should be administered shortly after a scheduled dose of such therapy.110 The patient and/or their family should be advised about the risk of hematoma from IM injections.110

Risk of Transmissible Agents in Plasma-derived Preparations

Because HBIG is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and human immunodeficiency virus (HIV) infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).112,116,117,132 The manufacturing process for HBIG includes a chemical (solvent/detergent) treatment procedure and filtration procedures that reduce the viral infectious potential of the preparations.112,116,132 Solvent/detergent inactivation processes apparently can inactivate lipid-enveloped viruses (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV] type 1 and type 2 [HIV-1 and HIV-2]) but are less effective against viruses that do not have a lipid envelope (e.g., hepatitis A virus [HAV], parvovirus B-19).116,132 Certain filtering procedures are effective in reducing levels of some enveloped and non-enveloped viruses.132

Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and/or filtration procedures have reduced, but not completely eliminated, risk of pathogen transmission with plasma-derived preparations.104,112,116,132 Because no purification method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations and because new blood-borne viruses or other disease agents may emerge which may not be inactivated by the manufacturing process or the chemical (solvent/detergent) treatment procedures currently used, HBIG should be administered only when a benefit is expected.112,116,132 Any infection believed to have been transmitted by HBIG should be reported to the manufacturer.112,116,132

Epidemiologic and laboratory evidence to date indicate that preparations of HBIG do not have a discernible risk of transmitting HIV infection.104 In addition to the screening of all donor units for antibody to HIV and rejection of all repeatedly reactive units, the manufacturing process of HBIG includes purification steps that provide an extremely high margin of safety in removal of HIV infectivity.104,112,116,128 Although some HBIG produced in 1982-1985 may have contained antibody to HIV,104,105,106 all HBIG produced since April 1985 should be free of the antibody.104

For further information on precautions related to transmissible agents in plasma-derived preparations, see Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications, in Antihemophilic Factor (Human) 20:12.16.

Individuals with Altered Immunocompetence

HBIG may be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.110,130

Recommendations regarding the use of HBIG in HIV-infected individuals or use in neonates born to HIV-infected women are the same as those for individuals who are not infected with HIV.110,126,127,130

Infusion Reactions

HyperHEP B^® administered by IV infusion may be associated with certain adverse effects related to the rate of infusion.132 Therefore, the recommended infusion rate (2 mL/minute) should not be exceeded.132 In addition, the patient should be monitored closely during and immediately following the infusion.132

Pediatric Precautions

HepaGam B^® is labeled by the US Food and Drug Administration (FDA) for use in neonates and children.132

Although the manufacturers of HyperHEP B^® and Nabi-HB^® state that safety and efficacy of these preparations have not been established in infants and children,112,116 safety and efficacy of similar HBIG preparations have been demonstrated in infants and children.116

HBIG is used in conjunction with hepatitis B vaccine for prevention of perinatal HBV infection in neonates born to HBsAg-positive mothers and for postexposure prophylaxis in unvaccinated children younger than 12 months of age whose mother or primary caregiver has acute HBV infection.101,112,132 (See Uses.)

Geriatric Precautions

The manufacturer of Nabi-HB^® states that clinical studies of HBIG did not include sufficient numbers of adults 65 years of age and older to determine whether geriatric adults respond differently than younger individuals.116 Other reported clinical experience has not identified differences in responses between geriatric and younger individuals.116

Pregnancy, Fertility, and Lactation

Pregnancy

Because of the potential risks to the neonate from exposure to HBV infection, pregnancy and lactation are not considered a contraindications to the use of HBIG when clearly needed.122 Animal reproduction studies have not been performed with HBIG and it is not known whether HBIG can cause fetal harm when administered to pregnant women.112,116,132 The manufacturers state that HBIG should be given to pregnant women only when clearly needed.112,116,132 The ACIP states there are no known risks associated with use of immune globulins for passive immunization in pregnant women.110

Fertility

It is not known if HBIG affects fertility.112,116,132

Lactation

Information on the distribution of HBIG into milk is not available;116,132 it is not known if transmission of HBIG to a nursing infant presents any unusual risk. HBIG should be administered with caution to nursing women.116,132

Immunosuppressive Agents

Recommendations for use of immune globulins, including hepatitis B immune globulin (HBIG), in patients receiving immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation) are the same as those for patients not receiving such agents.130

Inactivated Vaccines and Toxoids

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) state that immune globulins (including HBIG) are not expected to have a clinically important effect on the immune response to inactivated vaccines and toxoids.101,110 Therefore, inactivated vaccines, recombinant vaccines, polysaccharide vaccines, or toxoids may be administered simultaneously with (using different syringes and injection sites) or at any interval before or after administration of HBIG.101,110

Neonates born to hepatitis B surface antigen-positive (HBsAg-positive) women who receive combined passive immunization with HBIG and active immunization with hepatitis B vaccine at birth can receive immunization with other age-appropriate vaccines (e.g., diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed [DTaP], poliovirus vaccine inactivated [IPV], haemophilus b [Hib] conjugate vaccine) according to the usual childhood immunization schedule.110

Hepatitis B Vaccine

Passively acquired antibody to hepatitis B surface antigen (anti-HBs), which is present in HBIG, does not appear to interfere with the active immune response to hepatitis B vaccine.112 When combined active immunization with hepatitis B vaccine and passive immunization with HBIG is indicated, the first dose of vaccine should be administered simultaneously with HBIG (using different syringes and injection sites).122,128,129

The manufacturer of HepaGam B^® states that this preparation may be administered concurrently with (at a different site) or up to 1 month preceding hepatitis B vaccine without impairing the active immune response to the vaccine.132

Influenza Vaccine

HBIG is not expected to interfere with the immune response to parenteral trivalent influenza virus vaccine inactivated (TIV); therefore, the parenteral vaccine may be given simultaneously with HBIG (using different syringes and injection sites) or at any time before or after HBIG.110

Typhoid Vaccine

Because parenteral typhoid Vi polysaccharide vaccine (Typhim Vi^®) is an inactivated vaccine, HBIG is not expected to interfere with the immune response to the vaccine; therefore, the parenteral vaccine may be given simultaneously with HBIG (using different syringes and injection sites) or at any time before or after HBIG.101,110

Live Vaccines

Antibodies present in immune globulins, including HBIG, may interfere with the immune response to certain live virus vaccines, including measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, rotavirus vaccine live oral, and varicella virus vaccine live, and these vaccines should not be administered simultaneously with or for specified intervals before or after administration of HBIG.101,110,128,131,132,143

There is no evidence that immune globulin preparations interfere with the immune response to yellow fever virus vaccine live, typhoid vaccine live oral (Vivotif^®), influenza virus vaccine live intranasal (LAIV; Flumist^®), or poliovirus vaccine live oral (OPV; no longer commercially available in the US), and these live vaccines may be administered simultaneously with or at any time before or after administration of HBIG.101,110,143

Measles, Mumps, Rubella, and Varicella Vaccines

Antibodies contained in HBIG may interfere with the immune response to measles virus vaccine live and rubella virus vaccine live.101,110,128,132 The duration of possible interference between immune globulin preparations and live viral vaccines appears to depend on the dosage of the immune globulin and there is evidence that high doses of certain immune globulin preparations can inhibit the immune response to measles virus vaccine live and rubella virus vaccine live for more than 3 months.110 Although specific information regarding the effect of immune globulin preparations on the immune response to mumps virus vaccine live and varicella virus vaccine live are not available, there is potential for similar interference since immune globulin preparations contain antibodies to these viruses.101,110,128,132

Measles, mumps, and rubella virus vaccine live (MMR) or varicella virus vaccine live should not be administered simultaneously with or within 3 months before or after HBIG.101,110,128,132 If a dose of a vaccine containing live measles, mumps, rubella, or varicella virus is deemed necessary (e.g., because of imminent exposure to the disease) and is administered simultaneously with (at a separate site) or within 6 months after HBIG administration, the ACIP and AAFP recommend that a repeat dose of the vaccine be given at least 3 months after the HBIG dose, unless serologic testing is feasible and indicates an adequate immune response to the vaccine.101,110 In addition, the fact that revaccination may be necessary in individuals who receive HBIG shortly after a live virus vaccine also should be considered.110 In general, vaccine virus replication and stimulation of immunity occur within 7-14 days after administration of a live virus vaccine.110 Therefore, if HBIG must be administered within 14 days after receipt of a vaccine containing live measles, mumps, rubella, or varicella virus, revaccination is necessary at least 3 months after administration of HBIG, unless there is serologic evidence of an adequate immune response to the vaccine.101,110,132

Rotavirus Vaccine

Safety and efficacy data are not available regarding the use of rotavirus vaccine live oral in infants who have received an immune globulin within 42 days.131 Therefore, if possible, the dose of rotavirus vaccine should be deferred until 42 days (6 weeks) after the immune globulin; alternatively, if the 42-day deferral would result in the first dose of rotavirus vaccine being scheduled at 13 weeks of age or older, a shorter interval may be used.110

Laboratory Test Interferences

Immunohematology Tests

The manufacturer states that antibodies present in HepaGam B^® may interfere with some serologic tests.132 Administration of immune globulins similar to HepaGam B^® result in transitory increases of passively transferred antibodies in patient blood and may result in misleading positive results in serologic tests (e.g. direct antiglobulin [Coombs'] test).132

Tests for anti-HBs

Antibodies specific to hepatitis B surface antigen (HBsAg) (anti-HBs) are present in serum for 2-6 months following a dose of hepatitis B immune globulin (HBIG) and may result in positive tests for anti-HBs that reflect passively-acquired antibody rather than an immune response to hepatitis B vaccine.109,122,128,129

In neonates who receive a combined regimen of HBIG and hepatitis B vaccine for prevention of perinatal hepatitis B virus (HBV) infection (i.e., neonates born to HBsAg-positive mothers), postvaccination testing for anti-HBs to confirm an immunologic response to the vaccine should not be performed until the child is 9 months of age or older to avoid detecting passively-acquired antibody from HBIG.128

If a combined regimen of HBIG and hepatitis B vaccine is used for postexposure prophylaxis following exposure to HBV or HBsAg-positive materials, postvaccination testing for anti-HBs should not be performed until 3-4 months after the HBIG dose.122

Tests for Glucose

HepaGam B^® contains maltose,132 which may interfere with blood glucose monitoring systems based on glucose dehydrogenase pyrroloquinequinone (GDH-PQQ) and cause falsely elevated blood glucose results.132,133 This may result in inappropriate insulin administration and life-threatening hypoglycemia or may mask true hypoglycemia.132,133 Only glucose-specific test methods not affected by maltose (e.g., glucose dehydrogenase nicotine adenine dinucleotide [GDH-NAD], glucose oxidase, glucose hexokinase) should be used in patients receiving HepaGam B^®.132,133

Product information for the blood glucose testing meter and test strips should be reviewed to determine if the testing system is appropriate for patients receiving HepaGam B^®;132,133 If any uncertainty exists, the manufacturer of the glucose testing system should be contacted to determine whether the system will provide accurate blood glucose determinations in patients receiving HepaGam B^®.132,133

Acute Toxicity

Data are not available regarding overdosage of hepatitis B immune globulin (HBIG).112,116,132 The manufacturers state that clinical experience with other IM immunoglobulin preparations suggests that the only manifestations of overdosage would be pain and tenderness at the injection site.112,116,132

Pharmacology

Hepatitis B immune globulin (HBIG) is used to provide temporary passive immunity to hepatitis B virus (HBV) infection in the postexposure prophylaxis of individuals exposed to HBV or hepatitis B surface antigen-positive (HBsAg-positive) materials (e.g., blood, plasma, serum).109,112,116,128,129 Antibody to HBsAg (anti-HBs) present in HBIG combines with HBsAg and neutralizes circulating HBV so that its infective or pathogenic properties are inhibited.112,116,128,129

HBIG administered to HBsAg-positive individuals undergoing liver transplantation may protect the new liver from HBV reinfection.132 Reinfection in such individuals may occur immediately at the time of liver reperfusion because of circulating HBV or may occur at a later time because of HBV retained in extrahepatic sites.132 The mechanism by which HBIG protects the transplanted liver against HBV reinfection has not been fully determined.132 HBIG may protect naive hepatocytes against infection by blocking an HBV receptor.132 Alternatively, HBIG may neutralize circulating HBV through immune precipitation and immune complex formation or may trigger an antibody-dependent cell-mediated cytotoxicity response resulting in target cell lysis.132 There is evidence that HBIG binds to hepatocytes and interacts with HBsAg within cells.132

Hepatitis B Virus and Infection

HBV is a DNA virus from the family Hepadnaviridae128,134,145 consisting of antigenically distinct surface and core components.129,134 The presence of HBsAg in serum indicates active HBV infection (either acute or chronic).134,145 HBsAg also may be found in other body fluids and tissues.134 (See Uses: Risks of Exposure and Infection, in Hepatitis B Vaccine 80:12.) The HBV viral core consists of DNA, DNA polymerase, hepatitis B core antigen (HBcAg), and hepatitis B e antigen (HBeAg).129,134 The presence of HBeAg and HBV DNA in serum generally indicates high levels of viral replication and suggests that the serum is highly infectious.101,128,129,134,145

The incubation period from exposure to HBV to onset of symptoms of HBV infection is 6 weeks to 6 months (average: 90-150 days).128,134,145 Serologic markers of HBV infection (i.e., HBsAg, HBeAg, antibody to hepatitis B core antigen [anti-HBc], antibody to hepatitis B e antigen [anti-HBe], anti-HBs) are used to define the clinical status of those exposed to HBV infection or virus.101,128,129,134,145 HBsAg appears in the serum about 30 days (range 6-60 days) after exposure and indicates an ongoing HBV infection.128,129,134,145 HBsAg persists during an acute infection and usually disappears as the acute infection resolves; however, the presence of HBsAg in the serum for 6 months or longer generally indicates chronic infection.101,128,129,134,145 Anti-HBs develops during convalescence after an acute HBV infection (usually within 3-4 months).101,128,129,134 The presence of anti-HBs indicates recovery from and immunity to further HBV infection.101,128,129,134

Acute HBV infection may be self-limited resulting in production of anti-HBs and immunity against reinfection; however, it also may progress to chronic HBV infection (especially in infants or young children, immunocompromised individuals, patients with diabetes) or to fatal, fulminant hepatitis.101,128,129,134,145 The case fatality rate is 0.5-1.5% among those with acute HBV infection and the highest fatality rates are in adults older than 60 years of age.128,129 Chronic HBV infection develops in 90% or more of infants infected perinatally, 25-50% of children infected at 1-5 years of age, and less than 5% of those infected at 5 years of age or older.101,128,129,134,145 Chronic infection is associated with continuing viral replication in the liver and persistent viremia and may result in liver cirrhosis, liver cancer, liver failure, and death.101,128,129,134,145 Data from 2006 indicate that approximately 800,000-1.4 million people in the US have chronic HBV infection.145 HBV is transmitted by percutaneous or mucosal exposure to HBsAg-positive blood, serum, plasma, semen, or saliva101,122,128,129,134,145 and can be transmitted perinatally from mother to infant at birth, usually from blood exposures during labor and delivery.101,128,134,145

Response to HBIG

Once HBV infection becomes clinically apparent and/or serologic testing indicates the presence of HBsAg, it does not appear that the virus can be neutralized by HBIG, although HBIG may modify or ameliorate the infection.

A single HBIG dose provides passive immunity against HBV for about 3-6 months.109,128,129 In some patients, postexposure administration of HBIG may delay the development of HBV infection. Since the virus may be established in the individual at the time of HBIG administration, clinical symptoms of the disease may appear as passively acquired anti-HBs decreases. Alternatively, delay in development of infection may result from a second exposure to the virus several months after HBIG administration when circulating levels of passively acquired anti-HBs have decreased.

When HBIG is administered concomitantly with hepatitis B vaccine at separate sites, it does not appear to suppress the active immune to the vaccine.122,128,129 (See Hepatitis B Vaccine under Drug Interactions: Inactivated Vaccines and Toxoids.)

Pharmacokinetics

Absorption

Hepatitis B immune globulin (HBIG) is slowly absorbed following IM administration. Following IM administration of HBIG, serum concentrations of anti-HBs usually peak within 3-7 days112,116,132 and persist for about 2-6 months.112,128,129 In a study using HepaGam B^®, mean peak concentrations occurred 4-5 days after an IM dose of 0.06 mL/kg.132

Distribution

Although specific information is not available, it is likely that HBIG crosses the placenta since other immunoglobulins cross the placenta. Virtually all transplacental passage of immunoglobulins occurs during the last 4 weeks of pregnancy.

Information on the distribution of HBIG into milk is not available;132 HBIG may be distributed into milk since immunoglobulins (e.g., IgA, IgM, IgG) are present in the colostrum.

The volume of distribution of HepaGam B^® or Nabi-HB^® is approximately 7.5 L or11.2 L, respectively.116,132

Elimination

Following IM administration, the mean half-life of HepaGam B^®, HyperHEP B^®, or Nabi-HB^® is 22-25 days, 17.5-25 days, or 23 days, respectively.112,116,132

The clearance rate of HepaGam B^® or Nabi-HB^® is 0.21-0.24 L/day or 0.35 L/day, respectively.116

Chemistry and Stability

Chemistry

Hepatitis B immune globulin (HBIG) is a sterile solution prepared from plasma of healthy individuals with high titers of antibody to hepatitis B surface antigen (anti-HBs) and whose plasma does not show serologic evidence of hepatitis B surface antigen (HBsAg).112,116,128,129,132

Commercially available HBIG meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration112 and contains an anti-HBs titer equivalent to or greater than that contained in a US reference HBIG.112,116 Plasma donors and plasma used in the preparation of HBIG have been screened and tested for certain viruses and shown to be negative.112,116,132 In addition, the manufacturing process used for HBIG includes purification steps and a chemical (solvent/detergent) inactivation process that reduce the risk for transmission of bloodborne viruses.112,116,132 However, these steps may not completely eliminate the risk of pathogen transmission with plasma-derived preparations.112,116,132 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications.)

HBIG is commercially available as HepaGam B^®,132 HyperHEP B^® S/D,112 and Nabi-HB^®.116 HepaGam B^® occurs as a clear to opalescent liquid, contains 5% protein with 10% maltose and 0.03% polysorbate 80, and has a pH of 5.6.132 HyperHEP B^® S/D contains 15-18% protein stabilized in 0.21-0.32 M glycine, and has a pH of 6.4-7.2.112 Nabi-HB^® contains 4-6% protein in 0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate; has a pH of 6.2; and occurs as a clear to opalescent, nonturbid liquid.116

HepaGam B^®, HyperHEP B^® S/D, and Nabi-HB^® do not contain thimerosal or any other preservatives.112,116,132

Stability

HyperHEP B^®, Nabi-HB^®, and HepaGam B^® should be refrigerated at 2-8°C; freezing should be avoided.112,116,132

Single-dose vials of HBIG should be used within 6 hours after the vial has been entered, and any unused portion should be discarded.116,128,132

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