Prevention of Hepatitis B recurrence following Liver Transplantation

HepaGam B™, Hepatitis B Immune Globulin Intravenous (Human), is indicated for the prevention of hepatitis B recurrence following liver transplantation, in HBsAg-positive liver transplant patients.

HepaGam B should be administered intravenously for this indication.

Postexposure Prophylaxis

HepaGam B is indicated for the treatment of acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg-positive persons and household exposure to persons with acute HBV infection in the following settings:

Acute Exposure to Blood Containing HBsAg

Following either parenteral exposure (needlestick, bite, sharps), direct mucous membrane contact (accidental splash), or oral ingestion (pipetting accident), involving HBsAg-positive materials such as blood, plasma or serum^1,2.

Perinatal Exposure of Infants Born to HBsAg- positive Mothers

Infants born to mothers positive for HBsAg with or without HBeAg¹.

Sexual Exposure to HBsAg-positive Persons

Sexual partners of HBsAg-positive persons^1,2.

Household Exposure to Persons with Acute HBV Infection

Infants less than 12 months old whose mother or primary caregiver is positive for HBsAg. Other household contacts with an identifiable blood exposure to the index patient.

HepaGam B is indicated for intramuscular use only for these post-exposure prophylaxis indications.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; if these are seen, vials should not be used. During preparation, do not shake vials; avoid foaming.

Any vial of HepaGam B that has been entered should be used promptly. Do not reuse or save for future use. This product contains no preservative; therefore, partially used vials should be discarded immediately.

Prevention of Hepatitis B recurrence following liver transplantation

For the prevention of hepatitis B recurrence following liver transplantation in HBsAg positive liver transplant patients, HepaGam B is administered intravenously according to a set dosing regimen designed to attain serum levels of antibodies to hepatitis B surface antigen (anti- HBs) greater than 500 IU/L³.

Based upon the HepaGam B clinical trial, patients should receive 20,000 IU/dose [see Clinical Trials in Liver Transplant Patients]. The volume of each 20,000 IU dose should be calculated from the measured potency of the particular lot of HepaGam B as stamped on the vial label.

The first dose should be administered concurrently with the grafting of the transplanted liver (the anhepatic phase) with subsequent dosing as recommended in Table 1.

Table 1 - HepaGam B Dosing Regimen

HepaGam B dose adjustments may be required in patients who fail to reach anti-HBs levels of 500 IU/L within the first week post-liver transplantation⁴. Patients who have surgical bleeding or abdominal fluid drainage ( > 500 mL) or patients who undergo plasmapheresis are particularly susceptible to extensive loss of circulated anti-HBs. In these cases, the dosing regimen should be increased to a half-dose (10,000 IU calculated from the measured potency as stamped on the vial label) intravenously every 6 hours until the target anti-HBs is reached.

Hepatitis B Immune Globulin (HBIG) products are most effective in patients with no or low levels of HBV replication at the time of transplantation⁵.

Regular monitoring of serum HBsAg and levels of anti-HBs antibody should be performed pre- infusion to track treatment response and allow for treatment adjustment.

HepaGam B should be prepared for intravenous administration under aseptic conditions. HepaGam B should be administered through a separate intravenous line using an intravenous administration set via infusion pump.

The rate of administration should be set at 2 mL per minute.

The rate of infusion should be decreased to 1 mL per minute or slower if the patient develops discomfort, infusion-related adverse events or there is concern about the speed of infusion.

Postexposure Prophlyaxis

For postexposure prophylaxis indications, HepaGam B must be administered intramuscularly only as directed below.

It is important to use a separate vial, sterile syringe, and needle for each individual patient, to prevent transmission of infectious agents from one person to another.

HepaGam B may be administered at the same time (but at a different site), or up to one month preceding hepatitis B vaccination without impairing the active immune response to Hepatitis B Vaccine^1,2.

Acute Exposure to Blood Containing HBsAg

Table 2 summarizes prophylaxis for percutaneous (needlestick, bite, sharps), ocular, or mucous membrane exposure to blood according to the source of exposure and vaccination status of the exposed person. For greatest effectiveness, passive prophylaxis with HepaGam B should be given as soon as possible after exposure, as its value after seven days following exposure is unclear^1,2. An injection of 0.06 mL/kg of body weight should be administered intramuscularly as soon as possible after exposure, and within 24 hours if possible. Consult the Hepatitis B Vaccine package insert for dosage information regarding the vaccine.

For persons who refuse Hepatitis B Vaccine or are known non-responders to vaccine, a second dose of HepaGam B should be given one month after the first dose².

Table 2 - Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure^1,2

Prophylaxis of Infants Born to Mothers who are Positive for HBsAg with or without HBeAg

Table 3 contains the recommended schedule of Hepatitis B prophylaxis for infants born to mothers that are either known to be positive for HBsAg or have not been screened. Infants born to mothers known to be HBsAg-positive should receive 0.5 mL HepaGam B after physiologic stabilization of the infant and preferably within 12 hours of birth. The Hepatitis B Vaccine series should be initiated simultaneously, if not contraindicated, with the first dose of the vaccine given concurrently with the HepaGam B, but at a different site. Subsequent doses of the vaccine should be administered in accordance with the recommendations of the manufacturer. Women admitted for delivery, who were not screened for HBsAg during the prenatal period, should be tested. While test results are pending, the newborn infant should receive Hepatitis B Vaccine within 12 hours of birth (see manufacturers' recommendations for dose). If the mother is later found to be HBsAg-positive, the infant should receive 0.5 mL HepaGam B as soon as possible and within seven days of birth; however, the efficacy of HepaGam B administered after 48 hours of age is not known⁶. Testing for HBsAg and anti-HBs is recommended at 12-15 months of age. If HBsAg is not detectable and anti-HBs is present, the child has been protected1.

Table 3 - Recommended Schedule of Hepatitis B Immunoprophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus Infection¹

Sexual Exposure to HBsAg-positive Persons

All susceptible persons whose sexual partners have acute hepatitis B infection should receive a single dose of HepaGam B (0.06 mL/kg) and should begin the Hepatitis B Vaccine series, if not contraindicated, within 14 days of the last sexual contact or if sexual contact with the infected person will continue. Administering the vaccine with HepaGam B may improve the efficacy of post exposure treatment. The vaccine has the added advantage of conferring long-lasting protection^1,2.

Household Exposure to Persons with Acute HBV Infection

Prophylaxis of an infant less than 12 months of age with 0.5 mL HepaGam B and Hepatitis B Vaccine is indicated if the mother or primary caregiver has acute HBV infection. Prophylaxis of other household contacts of persons with acute HBV infection is not indicated unless they had an identifiable blood exposure to the index patient, such as by sharing toothbrushes or razors. Such exposures should be treated like sexual exposures. If the index patient becomes an HBV carrier, all household contacts should receive Hepatitis B Vaccine^1,2.

Dosage Forms And Strengths

HepaGam B, Hepatitis B Immune Globulin Intravenous (Human), is a sterile solution of purified gamma globulin (5% or 50 mg/mL) containing anti-HBs. Each vial contains greater than 312 IU/mL of anti-HBs and is supplied in a carton containing a 1.0 mL single use vial or a carton containing a 5.0 mL single use vial. The measured potency of each lot is stamped on the vial label.

To ensure that the label claim of > 312 IU/mL is maintained over the product shelf life, a higher potency of 550 IU/mL is targeted at the time of manufacture. As with other specific immune globulin products, this higher target potency is a manufacturing requirement to account for variability in the potency assay and changes in potency over time. The potency assay has a relative standard deviation (RSD) of approximately 10%. Based on statistical assessment of manufactured lots with a target potency of 550 IU/mL, the actual potency test result may vary from approximately 400 to 700 IU/mL (3x RSD). The measured potency is provided on the container label. Due to the inherent variability of the potency assay, dosing for the prevention of hepatitis B recurrence following liver transplantation should be calculated from the measured potency of the particular lot of HepaGam B as stamped on the vial label [see DOSAGE AND ADMINISTRATION].

NDC 60492-xxxx-1; a carton containing a 1.0 mL single dose vial ( > 312 IU/mL; measured potency of each lot is stamped on the vial label) and a package insert.

NDC 640492-xxxx-1; a carton containing a 5.0 mL single dose vial ( > 312 IU/mL; measured potency of each lot is stamped on the vial label) and a package insert.

Store at 36 to 46 °F (2 to 8 °C). Do not freeze. Do not use after expiration date. Use within 6 hours after the vial has been entered.

REFERENCES

1. CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: Immunization of infants, children, and adolescents. MMWR 2005; 54(RR-16): 1-32.

2. CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 2: Immunization of adults. MMWR 2006; 55(RR-16): 1-33.

3. Terrault NA, Zhou S, Combs C, Hahn JA, Lake JR, Roberts JP et al. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin. Hepatology 1996; 24(6):1327-33.

4. McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC et al. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation 1996; 61(9):1358-1364.

5. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329(25):1842-1847.

6. Beasley RP et al.: Efficacy of hepatitis B immune globulin for the prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo- controlled trial. Hepatology 1983; 3:135- 41.

FDA Rev date: 4/6/2007

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