HepaGam B

CLINICAL PHARMACOLOGY

Mechanism of Action

HBIGIV products provide passive immunization for individuals exposed to the hepatitis B virus, by binding to the surface antigen and reducing the rate of hepatitis B infection.13-16

Hepatitis B virus reinfection following liver transplantation is the consequence of exposure of the new liver graft to hepatitis B virus. Reinfection may occur immediately at the time of liver reperfusion due to circulating virus or later from virus retained in extrahepatic sites.

The mechanism whereby hepatitis B Immune globulin (HBIG) protects the transplanted liver against HBV reinfection is not well understood. HBIG may protect naive hepatocytes against infection through blockage of a putative HBV receptor.17 Alternatively, HBIG may neutralize circulating virions through immune precipitation and immune complex formation or may trigger an antibody-dependent cell-mediated cytotoxicity response resulting in target cell lysis.17-18 In addition, HBIG has been reported to bind to hepatocytes and interact with HBsAg within cells.19 Regardless of the mechanism, there is evidence of a dose-dependent response to HBIG treatment.5-8

Postexposure Prophylaxis.

Clinical studies conducted prior to 1983 with hepatitis B immune globulins similar to HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) demonstrated the advantage of simultaneous administration of hepatitis B vaccine and Hepatitis B Immune Globulin (Human), by the i.m. route. The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) advises that the combination prophylaxis be provided following certain instances of hepatitis B exposure.1-2 Recommendations on post-exposure prophylaxis are based on available efficacy data, primarily from studies in neonates.1-2 Cases of hepatitis B are rarely seen following exposure to HBV in persons with pre-existing anti-HBs antibodies.

Infants born to HBsAg-positive mothers are at risk of being infected with HBV and becoming chronic carriers.' The risk is especially great if the mother is also HBeAg-positive.1 For an infant with perinatal exposure to an HBsAg-positive and HBeAg-positive mother, a regimen combining one dose of Hepatitis B Immune Globulin (Human) at birth with the hepatitis B vaccine series started soon after birth has been shown to be 85-98% effective in preventing development of the HBV carrier state.1-2 Regimens involving either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have a 70-75% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has 50% efficacy.1-2

Since infants have close contact with primary caregivers and have a higher risk of becoming HBV carriers after acute HBV infection, prophylaxis of an infant less than 12 months of age with Hepatitis B Immune Globulin (Human) and Hepatitis B Vaccine is indicated if the mother or primary caregiver has acute HBV infection.1

Sexual partners of HBsAg-positive persons are at increased risk of acquiring HBV infection. A single dose of Hepatitis B immune Globulin (Human) is 75% effective if administered within two weeks of the last sexual exposure to a person with acute hepatitis B.12

HBV infection is a well-recognized risk to health-care personnel (HCP). The risk of HBV infection is primarily related to the degree of contact with blood in the work place and also to the hepatitis B e antigen (HBeAg) status of the source person. In studies of HCP who sustained injuries from needles contaminated with blood containing HBV, the risk of developing clinical hepatitis if the blood was hepatitis B surface antigen (HBsAg) and HBeAg-positive was 22%-31%; the risk of developing serologic evidence of HBV infection was 37%-62%. In comparison, the risk of developing clinical hepatitis from needles contaminated with HBsAg-positive, HBeAg-negative blood is 1 %-6%, and the risk of developing serological evidence of HBV infection is 23%-37%.20 The current recommendations of the Advisory Committee on Immunization Practices12, recommends postexposure prophylaxis with hepatitis B immune globulin and/or hepatitis B vaccine series for any susceptible, unvaccinated person who sustains an occupational blood or body fluid exposure.

The pharmacokinetic profile of HepaGam B (hepatitis b immune globulin (human)) has been evaluated in two clinical trials [see Clinical Studies].

The comparative bioavailability of HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) and another commercially available hepatitis B immunoglobulin product indicates that HepaGam B (hepatitis b immune globulin (human)) has similar efficacy.

Clinical Studies

Clinical Trials in Liver Transplant Patients

A clinical trial examining the effectiveness of HepaGam B (hepatitis b immune globulin (human)) in the prevention of hepatitis B recurrence following liver transplantation is currently ongoing. The study is a multi-center, open-labeled, superiority study involving HBsAg-positive/HBeAg-negative liver transplant patients. The study included two arms, an active treatment group of patients enrolled to receive the described dosing regimen of HepaGam B (hepatitis b immune globulin (human)) starting during transplant and continuing over the course of a year, and a retrospective untreated control group of historical patients with data gathered by chart review.

An interim report of this study evaluated the data from 30 liver transplant patients, 16 HepaGam B (hepatitis b immune globulin (human)) patients who have completed the study and 14 retrospective untreated control patients. The patients in both groups were HBsAg-positive/ HBeAg-negative liver transplant patients who met similar entry criteria, had similar medical history and had similar status at transplant based on MELD and/or ChildPugh-Turcotte scores.

In the active treatment group, HepaGam B (hepatitis b immune globulin (human)) doses of 35 mL started during transplant according to the regimen identified in Table 1 [see DOSING AND ADMINISTRATION]. As a result of the targeted potency of 550 lU/mL at the time of manufacture [see Dosage Forms and Strengths], the 35 mL doses of HepaGam B (hepatitis b immune globulin (human)) used in this study actually contained between 17,000 and 23,000 IU anti-HBs. These 35 mL doses consistently yielded anti-HBs trough levels > 500 IU/L (99% of all anti-HBs levels were > 500 IU/L; see Figure 1).

Figure 1: Frequency Histogram of Trough anti-HBs Levels more than 30 days after Transplant

Frequency Histogram of Trough anti-HBs Levels more than 30 days after Transplant - illustration

Values below the target trough were only observed in the 2 patients with HBV recurrence who had anti-HBs levels <150 IU/L at the time of seroconversion.

For the efficacy endpoint of the proportion of patients with HBV recurrence (HBsAg positive and/or HBeAg positive after 4 weeks post-OLT), a significant treatment effect was observed. As summarized in Table 6, HBV recurrence was seen in 2/15 or 13% of HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) patients compared to 12/14 or 86% of retrospective untreated control patients (see Table 6). One of the 16 HepaGam B (hepatitis b immune globulin (human)) patients died 2 weeks post-transplant was excluded from all efficacy analyses, but was included for safety analyses. The death was not HBV or study drug related.

Table 6 - Interim Results of Study HB-005 for the Prevention of Hepatitis B Recurrence Following Liver Transplantation

  HepaGam B Retrospective Untreated Control P-value
(Fisher's Exact Test)
HBV Recurrence Proportion, % (95% confidence interval) 13.3
(1.7 -40.5)
85.7
(57.2 -98.2)
< 0.001

The conclusion that HepaGam B (hepatitis b immune globulin (human)) monotherapy post-OLT is effective at preventing HBV recurrence post-OLT is further supported by the secondary endpoints of time to recurrence, survival, anti-HBs levels and biochemical markers of liver inflammation. Time to recurrence for the HepaGam B (hepatitis b immune globulin (human)) treatment group was 358 days for two HBV recurrent patients. In comparison, the retrospective untreated control patients had a median time to recurrence of 88 days with a 95% confidence interval of 47 to 125 days. Survival calculations showed that 93% (14/15) of patients in the active treatment group survived for at least 1-year post-OLT compared to 43% (6/14) retrospective control patients. One patient in the active treatment group died 266 days post-OLT. The median time to death for the retrospective control patients was 339 days calculated using the product limit method. The endpoints for HBV recurrence were supported by an observed drop in anti-HBs levels and elevated liver function tests at the time of recurrence.

HepaGam B (hepatitis b immune globulin (human)) is recommended in patients who have no or low levels of viral replication at the time of liver transplantation. The clinical trial evaluating HepaGam B (hepatitis b immune globulin (human)) in liver transplant patients selected patients with no or low replication status only. HepaGam B (hepatitis b immune globulin (human)) therapy has not been evaluated in combination with antiviral therapy post-transplantation.

Comparative Bioavailability Studies

The pharmacokinetic profile of HepaGam B (hepatitis b immune globulin (human)) after intramuscular injection of 0.06 mL/kg in two 84-day pharmacokinetics studies8,70 volunteers were administered HepaGam B (hepatitis b immune globulin (human)) . The mean peak concentrations (Cmax) in both studies were comparable and occurred within 4-5 days of administration. Both studies demonstrated mean elimination half-lives (t½) following i.m. administration of 22 to 25 days. The mean clearance rate was 0.21 to 0.24 L/day and the volume of distribution was approximately 7.5 L. Thus, HepaGam B (hepatitis b immune globulin (human)) demonstrates pharmacokinetic parameters similar to those reported by Scheiermann and Kuwert.21

The maximum concentration of anti-HBs achieved by HepaGam B (hepatitis b immune globulin (human)) was consistent with that of two other licensed Hepatitis B Immune Globulin (Human) products when compared in the two pharmacokinetic trials.8 Comparability of pharmacokinetics between HepaGam B (hepatitis b immune globulin (human)) and a commercially available hepatitis B immune globulin product administered i.m. indicates that similar efficacy of HepaGam B (hepatitis b immune globulin (human)) should be inferred.

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. MMWR2005; 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.

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.

7. Committee for Proprietary Medicinal Products (CPMP). Core SPC for human plasma derived hepatitis-B immunoglobulin for intravenous use (CPMP/BPWG/4027/02). London, UK: The European Agency for the Evaluation of Medicinal Products. 2003.

8. Unpublished data on file.

12. Burnouf T. Value of virus filtration as method for improving the safety of plasma products. Vox Sang 1996; 70:235-6.

13. Grady GF, LeeVA. Hepatitis B immune globulin - prevention of hepatitis from accidental exposure among medical personnel. N Engl J Med 1975; 293:1067-70.

14.Seeff LB, et al. Type B hepatitis after needlestick exposure: Prevention with hepatitis B immune globulin. Ann Int Med 1978: 88: 285-93.

15. Krugman S, Giles JP. Viral hepatitis, type B (MS-2-strain). Further observations on natural history and prevention. N Engl J Med 1973; 288:755-60.

16. Hoofnagle JH, et al. Passive-active immunity from hepatitis B immune globulin. Ann Int Med 1979;91:813-8.

17.Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 2000: 32(6):1189-1195.

18. Sawyer RG, McGory RW, Gaffey MJ, McCullough CC, Shephard BL, Houlgrave CW et al. Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Ann Surg 1998; 227(6): 841-50.

19.Schilling R, Ijaz S, Davidoff M, Lee JY Locarnini S, Williams R, Naoumov NV. Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. J Virol 2003;77(16): 8882-92.

20.CDC. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR 2001; 50(RR-11): 1-42.

21 .Scheiermann N, Kuwert EK. Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Dev Biol Standard 1983; 54:347-55.

Last reviewed on RxList: 2/20/2009
This monograph has been modified to include the generic and brand name in many instances.

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