HEPAGAM B Solution for infusion Ref.[10823] Active ingredients: Human hepatitis B immunoglobulin

The pharmacokinetic profile of HepaGam B has been evaluated in two 84-day clinical trials in which 70 healthy subjects received an intramuscular injection of 0.06 milliliter per kilogram of HepaGam B. The mean peak concentrations (C_max) in both studies were comparable and occurred within 4-5 days of administration. Both studies demonstrated mean elimination half-lives (t_½) following IM administration of 22 to 25 days. The mean clearance rate was 0.21 to 0.24 liter per day and the volume of distribution was approximately 7.5 liter. Thus, HepaGam B demonstrates pharmacokinetic parameters similar to those reported by Scheiermann and Kuwert¹⁷.

The maximum concentration of anti-HBs achieved by HepaGam B was consistent with that of two other licensed comparator Hepatitis B Immune Globulin (Human) products⁶. Comparability of pharmacokinetics between HepaGam B and a commercially available hepatitis B immune globulin product administered IM indicates that comparable efficacy of HepaGam B should be inferred.

14.1 Clinical Trials in Liver Transplant Patients

A clinical trial examined the effectiveness of HepaGam B in the prevention of hepatitis B recurrence following liver transplantation. The study was 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 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.

There were 27 liver transplant patients who received HepaGam B 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 intravenous doses of 35 milliliters were initiated during transplant according to the regimen identified in Table 1 [see Dosage and Administration (2.1)]. As a result of the targeted potency of 550 IU per milliliter at the time of manufacture [see Dosage Forms and Strengths (3)], the 35 milliliter doses of HepaGam B used in this study actually contained between 17,000 and 23,000 IU anti-HBs. These 35 milliliter doses consistently yielded anti-HBs trough levels >500 IU per liter (99% of all anti-HBs levels were >500 IU per liter; see Figure 1). Patients received HepaGam B doses diluted with 50 mL of saline.

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

Values below the target trough were only observed in the 2 patients with HBV recurrence who had anti-HBs levels <150 IU per liter 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 5, HBV recurrence was seen in 2/24 or 8.3% of HepaGam B patients compared to 12/14 or 86% of retrospective untreated control patients (see Table 5). Two of the HepaGam B patients who died within 28 days post-transplant were excluded from all efficacy analyses, but included for safety analyses. The deaths were not HBV or study drug related.

Table 5. Results of Study HB-005 for the Prevention of Hepatitis B Recurrence Following Liver Transplantation:

The conclusion that HepaGam B 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, biochemical markers of liver inflammation, and liver biopsy. Time to recurrence for the HepaGam B 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 96% (23/24) of patients in the active treatment group survived for at least 1 year post-OLT compared to 43% (6/14) retrospective control patients. The endpoints for HBV recurrence were supported by an observed drop in anti-HBs levels, elevated liver function tests, and abnormal liver biopsy result at the time of recurrence.

HepaGam B 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 in liver transplant patients selected patients with no or low replication status only. HepaGam B therapy has not been evaluated in combination with antiviral therapy post-transplantation.