Prescription Drugs

CLINICAL PHARMACOLOGY Hepatitis B Immune Globulin (Human) provides passive immunization for individuals exposed to the hepatitis B virus (HBV) as evidenced by a reduction in the attack rate of hepatitis B following its use.1-6 The administration of the usual recommended dose of this immune globulin generally results in a detectable level of circulating anti-HBs which persists for approximately 2 months or longer. The highest antibody (IgG) serum levels were seen in the following distribution of subjects studied: 7 DAY % OF SUBJECTS 3 38.9% 7 41.7% 14 11.1% 21 8.3% Mean values for half-life were between 17.5 and 25 days, with the shortest being 5.9 days and the longest 35 days. 7 Cases of type B hepatitis are rarely seen following exposure to HBV in persons with preexisting anti-HBs. No confirmed instance of transmission of hepatitis B has been associated with this product. In a clinical study in eight healthy human adults receiving another hyperimmune immune globulin product treated with solvent/detergent, Rabies Immune Globulin (Human), HyperRAB® S/D, prepared by the same manufacturing process, detectable passive antibody titers were observed in the serum of all subjects by 24 hours post injection and persisted through the 21 day study period. These results suggest that passive immunization with immune globulin products is not affected by the solvent/detergent treatment. REFERENCES 1. Grady GF, Lee VA: Hepatitis B immune globulin — prevention of hepatitis from accidental exposure among medical personnel. N Engl J Med 293(21):1067–70, 1975. 2. Seeff LB, Zimmerman HJ, Wright EC, et al: Efficacy of hepatitis B immune serum globulin after accidental exposure. Lancet 2(7942):939-41, 1975. 3. Krugman S, Giles JP: Viral hepatitis, type B (MS-2-strain). Further observations on natural history and prevention. N Engl J Med 288(15):755-60, 1973. 4. Current trends: Health status of Indochinese refugees: malaria and hepatitis B. MMWR 28(39):463-4; 469-70, 1979. 5. Jhaveri R, Rosenfeld W, Salazar JD, et al: High titer multiple dose therapy with HBIG in newborn infants of HBsAg positive mothers. J Pediatr 97(2):305–8, 1980. 6. Hoofnagle JH, Seeff LB, Bales ZB, et al: Passive-active immunity from hepatitis B immune globulin. Ann Intern Med 91(6):813-8, 1979. 7. Scheiermann N, Kuwert EK: Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Dev Biol Stand 54:347-55, 1983.

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 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.

CLINICAL PHARMACOLOGY Hepatitis B Immune Globulin (Human) provides passive immunization for individuals exposed to the hepatitis B virus (HBV) as evidenced by a reduction in the attack rate of hepatitis B following its use.1-6 The administration of the usual recommended dose of this immune globulin generally results in a detectable level of circulating anti-HBs which persists for approximately 2 months or longer. The highest antibody (IgG) serum levels were seen in the following distribution of subjects studied: 7 DAY % OF SUBJECTS 3 38.9% 7 41.7% 14 11.1% 21 8.3% Mean values for half-life were between 17.5 and 25 days, with the shortest being 5.9 days and the longest 35 days.7 Cases of type B hepatitis are rarely seen following exposure to HBV in persons with preexisting anti-HBs. No confirmed instance of transmission of hepatitis B has been associated with this product. In a clinical study in eight healthy human adults receiving another hyperimmune immune globulin product treated with solvent/detergent, Rabies Immune Globulin (Human), BayRab®, prepared by the same manufacturing process, detectable passive antibody titers were observed in the serum of all subjects by 24 hours post injection and persisted through the 21 day study period. These results suggest that passive immunization with immune globulin products is not affected by the solvent/detergent treatment. REFERENCES 1. Grady GF, Lee VA: Hepatitis B immune globulin — prevention of hepatitis from accidental exposure among medical personnel. N Engl J Med 293(21):1067–70, 1975. 2. Seeff LB, Zimmerman HJ, Wright EC, et al: Efficacy of hepatitis B immune serum globulin after accidental exposure. Lancet 2(7942):939-41, 1975. 3. Krugman S, Giles JP: Viral hepatitis, type B (MS-2-strain). Further observations on natural history and prevention. N Engl J Med 288(15):755-60, 1973. 4. Current trends: Health status of Indochinese refugees: malaria and hepatitis B. MMWR 28(39):463-4; 469-70, 1979. 5. Jhaveri R, Rosenfeld W, Salazar JD, et al: High titer multiple dose therapy with HBIG in newborn infants of HBsAg positive mothers. J Pediatr 97(2):305–8, 1980. 6. Hoofnagle JH, Seeff LB, Bales ZB, et al: Passive-active immunity from hepatitis B immune globulin. Ann Intern Med 91(6):813-8, 1979. 7. Scheiermann N, Kuwert EK: Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Dev Biol Stand 54:347-55, 1983.

HyperHEP B® S/D Hepatitis B Immune Globulin (Human) Injection Solvent/Detergent Treated DESCRIPTION Hepatitis B Immune Globulin (Human) — HyperHEP B® S/D treated with solvent/detergent is a colorless to pale yellow or pink sterile solution of hepatitis B hyperimmune immune globulin for intramuscular administration; it is preservative-free and latex-free. HyperHEP B S/D is prepared by cold ethanol fractionation from the plasma of donors with high titers of antibody to the hepatitis B surface antigen (anti-HBs). The immune globulin is isolated from solubilized Cohn Fraction II. The Fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. HyperHEP B S/D is formulated as a 15–18% protein solution at a pH of 6.4–7.2 in 0.21–0.32 M glycine. HyperHEP B S/D is then incubated in the final container for 21–28 days at 20–27°C. Each vial or syringe contains anti-HBs antibody equivalent to or exceeding the potency of anti-HBs in a U.S. referencea hepatitis B immune globulin (Center for Biologics Evaluation and Research, FDA). The U.S. reference has been tested against the World Health Organization standard Hepatitis B Immune Globulin and found to be equal to 220 international units (IU) per mL. The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for HyperHEP B S/D has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model Human Herpes viruses and other large enveloped DNA viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is achieved at two steps in the Cohn fractionation process leading to the collection of Cohn Fraction II: the precipitation and removal of Fraction III in the processing of Fraction II + IIIW suspension to Effluent III and the filtration step in the processing of Effluent III to Filtrate III. Significant inactivation of enveloped viruses is achieved at the time of treatment of solubilized Cohn Fraction II with TNBP/sodium cholate. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.22–25 Studies of the HyperHEP B S/D manufacturing process demonstrate that TSE clearance is achieved during the Pooled Plasma to Effluent III Fractionation Process (6.7 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. REFERENCES 22. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497-500. 23. Lee DC, Stenland CJ, Miller JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41(4):449-55. 24. Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84(1):77-89. 25. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.

Find Lowest Prices on HepaGam B™ [Hepatitis B Immune Globulin Intravenous (Human)], Sterile Solution for Intravenous or Intramuscular Injection Solvent/Detergent Treated and Filtered. >312 IU/mL DESCRIPTION HepaGam B, Hepatitis B Immune Globulin Intravenous (Human), is a solvent/detergent- treated sterile solution of purified gamma globulin containing anti-HBs. It is prepared from plasma donated by healthy, screened donors with high titers of anti-HBs that is purified by an anion- exchange column chromatography manufacturing method9,10. HepaGam B (hepatitis b immune globulin human) is formulated as a 5% (50 mg/mL) protein solution with 10% maltose and 0.03% polysorbate 80 at pH 5.6. It is available in 1 mL and 5 mL single dose vials. The product appears as a clear to opalescent liquid. It contains no preservatives and is intended for single use. HepaGam B (hepatitis b immune globulin human) may be administered intravenously or intramuscularly dependent upon indication [see INDICATIONS]. The source plasma used in the manufacture of this product was tested by FDA licensed Nucleic Acid testing (NAT) for HIV-1 and HCV and found to be negative. An investigational NAT for HBV was performed on all Source Plasma used, and found to be negative; however, the significance of a negative result has not been established. Plasma also has been tested by in-process NAT for hepatitis A virus (HAV) and parvovirus B19 (B19) via minipool testing and the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per mL. The manufacturing process contains two steps implemented specifically for virus clearance. The solvent and detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as hepatitis B, hepatitis C and HIV11. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses12. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses. The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in Table 5. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process's ability for viral clearance in general. Table 5 - Virus Reduction Values Obtained Through Validation Studies8 Enveloped Enveloped Non-Enveloped Genome RNA DNA RNA DNA Virus HIV-1 BVDV PRV HAV EMC MMV PPV Family retro flavi herpes picorna parvo Size (nm) 80-100 50-70 120-200 25-30 30 20-25 18-24 Anion Exchange Chromatography (partitioning) Not evaluated 2.3 n.e. 3.4 n.e. 20N Filtration (size exclusion) ≥ 4.7 ≥ 3.5 ≥ 5.6 a n.e. 4.8 n.e. 4.1 Solvent/Detergent (inactivation) ≥ 4.7 ≥ 7.3 ≥ 5.5 Not evaluated Total Reduction (log10) ≥ 9.4 ≥ 10.8 ≥ 11.1 2.3 4.8 3.4 4.1 Abbreviations: HIV-1: human immunodeficiency virus-1; relevant virus for human immunodeficiency virus-1 and model for HIV-2 BVDV: bovine viral diarrhea virus; model virus for hepatitis C virus (HCV) and West Nile virus (WNV) PRV: pseudorabies virus; model for large enveloped DNA viruses, including herpes HAV: human hepatitis A virus; relevant virus for HAV and model for small non-enveloped viruses in general EMC: encephalomyocarditis virus; model for HAV and for small non- enveloped viruses in general MMV: murine minute virus; model for human parvovirus B19 and for small non-enveloped viruses in general PPV: porcine parvovirus; model for human parvovirus B19 and for small non- enveloped viruses in general n.e.: not evaluated a The PRV was retained by the 0.1 µm pre-filter during the virus validation. Since manufacturing employs a 0.1 µm pre-filter before the 20N filter, the claim of ≥ 5.6 reduction is considered applicable. The product potency is expressed in international units (IU) by comparison to the World Health Organization (WHO) standard Hepatitis B Immune Globulin. Each vial contains greater than 312 IU/mL. The measured potency of each lot is stamped on the vial label [see Dosage Forms and Strengths]. REFERENCES 9. Bowman JM, et al. WinRho: Rh immune globulin prepared by ion exchange for intravenous use. Canadian Med Assoc J 1980; 123:1121-5. 10. Friesen AD, et al. Column ion-exchange preparation and characterization of an Rh immune globulin (WinRho) for intravenous use. Journal Appl Biochem 1981; 3:164- 75. 11. Horowitz B. Investigations into the application of tri(n-butyl)phosphate /detergent mixtures to blood derivatives. Morgenthaler J (ed): Virus Inactivation in Plasma Products, Curr Stud Hematol Blood Transfus 1989; 56:83-96. 12. Burnouf T. Value of virus filtration as method for improving the safety of plasma products. Vox Sang 1996; 70:235-6.

BayHep B® (hepatitis b immune globulin human) (Hepatitis B Immune Globulin (Human)) Solvent/Detergent Treated DESCRIPTION Hepatitis B Immune Globulin (Human) BayHep B® (hepatitis b immune globulin human) treated with solvent/detergent is a sterile solution of hepatitis B hyperimmune immune globulin for intramuscular administration; it contains no preservative. BayHep B (hepatitis b immune globulin human) is prepared by cold ethanol fractionation from the plasma of donors with high titers of antibody to the hepatitis B surface antigen (anti-HBs). The immune globulin is isolated from solubilized Cohn Fraction II. The Fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. BayHep B is formulated as a 15–18% protein solution at a pH of 6.4–7.2 in 0.21–0.32 M glycine. BayHep B (hepatitis b immune globulin human) is then incubated in the final container for 21–28 days at 20–27°C. Each vial contains anti-HBs antibody equivalent to or exceeding the potency of anti-HBs in a U.S. reference hepatitis B immune globulin (Center for Biologics Evaluation and Research, FDA). The U.S. reference has been tested against the World Health Organization standard Hepatitis B Immune Globulin and found to be equal to 217 international units (IU) per mL. The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for BayHep B (hepatitis b immune globulin human) has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model Hepatitis B virus and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is achieved at two steps in the Cohn fractionation process leading to the collection of Cohn Fraction II: the precipitation and removal of Fraction III in the processing of Fraction II + IIIW suspension to Effluent III and the filtration step in the processing of Effluent III to Filtrate III. Significant inactivation of enveloped viruses is achieved at the time of treatment of solubilized Cohn Fraction II with TNBP/sodium cholate.

INDICATIONS Recommendations on post-exposure prophylaxis are based on available efficacy data and on the likelihood of future HBV exposure for the person requiring treatment. In all exposures, a regimen combining Hepatitis B Immune Globulin (Human) with hepatitis B vaccine will provide both short- and long-term protection, will be less costly than the two-dose Hepatitis B Immune Globulin (Human) treatment alone, and is the treatment of choice.8 HyperHEP B S/D is indicated for post-exposure prophylaxis in the following situations: Acute Exposure To Blood Containing HBsAg After either parenteral exposure, e.g., by accidental “needlestick” or direct mucous membrane contact (accidental splash), or oral ingestion (pipetting accident) involving HBsAg-positive materials such as blood, plasma or serum. For inadvertent percutaneous exposure, a regimen of two doses of Hepatitis B Immune Globulin (Human), one given after exposure and one a month later, is about 75% effective in preventing hepatitis B in this setting. Perinatal Exposure Of Infants Born To HBsAg-positive Mothers Infants born to HBsAg-positive mothers are at risk of being infected with hepatitis B virus and becoming chronic carriers.5,8-10 This risk is especially great if the mother is HBeAg-positive.11-13 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 is 85%–95% effective in preventing development of the HBV carrier state.8,14 Regimens involving either multiple doses of  Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have 70%–90% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has only 50% efficacy.8,15 Sexual Exposure To An HBsAg-positive Person Sex partners of HBsAg-positive persons are at increased risk of acquiring HBV infection. For sexual exposure to a person with acute hepatitis B, a single dose of Hepatitis B Immune Globulin (Human) is 75% effective if administered within 2 weeks of last sexual exposure.8 Household Exposure To Persons With Acute HBV Infection Since infants have close contact with primary care-givers and they 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 care-giver has acute HBV infection.8 Administration of Hepatitis B Immune Globulin (Human) either preceding or concomitant with the commencement of active immunization with Hepatitis B Vaccine provides for more rapid achievement of protective levels of hepatitis B antibody, than when the vaccine alone is administered.16 Rapid achievement of protective levels of antibody to hepatitis B virus may be desirable in certain clinical situations, as in cases of accidental inoculations with contaminated medical instruments.16 Administration of Hepatitis B Immune Globulin (Human) either 1 month preceding or at the time of commencement of a program of active vaccination with Hepatitis B Vaccine has been shown not to interfere with the active immune response to the vaccine.16 DOSAGE AND ADMINISTRATION Acute Exposure To Blood Containing HBsAg15 Table 1 summarizes prophylaxis for percutaneous (needlestick or bite), ocular, or mucous-membrane exposure to blood according to the credit of exposure and vaccination status of the exposed person. For greatest effectiveness, passive prophylaxis with Hepatitis B Immune Globulin (Human) should be given as soon as possible after exposure (its value beyond 7 days of exposure is unclear). If Hepatitis B Immune Globulin (Human) is indicated (see Table 1), an injection of 0.06 mL/kg of body weight should be administered intramuscularly (see PRECAUTIONS) as soon as possible after exposure and within 24 hours, if possible. Consult Hepatitis B Vaccine package insert for dosage information regarding that product. Table 1:  (adapted from 20) Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure Source Exposed Person Unvaccinated Vaccinated HBsAg-Positive Hepatitis B Immune Globulin (Human)xl immediately* Initiate HB Vaccine Series† Test exposed person for anti-HBs. If inadequate antibody,‡ Hepatitis B Immune Globulin (Human) (xl) immediately plus HB Vaccine booster dose, or 2 doses of HBIG,* one as soon as possible after exposure and the second 1 month later. Known Source (High Risk) Initiate HB Vaccine Series Test credit for HBsAg. If positive, Hepatitis B Immune Globulin (Human)xl Test Source for HBsAg only if exposed is vaccine nonresponder; if credit is HBsAg-positive, give Hepatitis B Immune Globulin (Human)x1 immediately plus HB Vaccine booster dose, or 2 doses of HBIG* one as soon as possible after exposure and the second 1 month later. Low Risk HBsAg-Positive Initiate HB Vaccine series Nothing required. Unknown Source Initiate HB Vaccine series within 7 days of exposure Nothing required. * Hepatitis B Immune Globulin (Human), dose 0.06 mL / kg IM. † HB Vaccine dose 20 μg IM for adults; 10 μg IM for infants or children under 10 years of age. First dose within 1 week; second and third doses, 1 and 6 months later. ‡ Less than 10 sample ratio units (SRU) by radioimmunoassay (RIA), negative by enzyme immunoassay (EIA). For persons who refuse Hepatitis B Vaccine, a second dose of Hepatitis B Immune Globulin (Human) should be given 1 month after the first dose. Prophylaxis Of Infants Born To HBsAg And HBeAg Positive Mothers Efficacy of prophylactic Hepatitis B Immune Globulin (Human) in infants at risk depends on administering Hepatitis B Immune Globulin (Human) on the day of birth. It is therefore vital that HBsAg-positive mothers be identified before delivery. Hepatitis B Immune Globulin (Human) (0.5 mL) should be administered intramuscularly (IM) to the newborn infant after physiologic stabilization of the infant and preferably within 12 hours of birth. Hepatitis B Immune Globulin (Human) efficacy decreases markedly if treatment is delayed beyond 48 hours. Hepatitis B Vaccine should be administered IM in three doses of 0.5 mL of vaccine (10 μg) each. The first dose should be given within 7 days of birth and may be given concurrently with Hepatitis B Immune Globulin (Human) but at a separate site. The second and third doses of vaccine should be given 1 month and 6 months, respectively, after the first. If administration of the first dose of Hepatitis B Vaccine is delayed for as long as 3 months, then a 0.5 mL dose of Hepatitis B Immune Globulin (Human) should be repeated at 3 months. If Hepatitis B Vaccine is refused, the 0.5 mL dose of Hepatitis B Immune Globulin (Human) should be repeated at 3 and 6 months. Hepatitis B Immune Globulin (Human) administered at birth should not interfere with oral polio and diphtheria-tetanus-pertussis vaccines administered at 2 months of age.15 Sexual Exposure To An HBsAg-positive Person All susceptible persons whose sex partners have acute hepatitis B infection should receive a single dose of HBIG (0.06 mL/kg) and should begin the hepatitis B vaccine series if prophylaxis can be started within 14 days of the last sexual contact or if sexual contact with the infected person will continue (see Table 2 below). Administering the vaccine with HBIG may improve the efficacy of postexposure treatment. The vaccine has the added advantage of conferring long-lasting protection.8 Table 2: (adapted from21) Recommendations for Postexposure Prophylaxis for Sexual Exposure to Hepatitis B HBIG* Vaccine Dose Recommended timing Dose Recommended timing 0.06 mL/kg IM† Single dose within 14 days of last sexual contact 1.0 mL IMt First dose at time of HBIG* treatment¶ * HBIG = Hepatitis B Immune Globulin (Human) † IM = intramuscularly ¶ The first dose can be administered the same time as the HBIG dose but at a different site; subsequent doses should be administered as recommended for specific vaccine. Household Exposure To Persons With Acute HBV Infection Prophylactic treatment with a 0.5 mL dose of Hepatitis B Immune Globulin (Human) and hepatitis B vaccine is indicated for infants 12 months of age who have been exposed to a primary care-giver who has acute hepatitis B. Prophylaxis for other household contacts of persons with acute HBV infection is not indicated unless they have had 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.8 Hepatitis B Immune Globulin (Human) may be administered at the same time (but at a different site), or up to 1 month preceding Hepatitis B Vaccination without impairing the active immune response from Hepatitis B Vaccination.16 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administer intramuscularly. Do not inject intravenously. Hepatitis B Immune Globulin (Human) — HyperHEP B® S/D is supplied in a syringe with an attached UltraSafe® Needle Guard for your protection and convenience, as well as in vials. Please follow instructions below for proper use of syringe and UltraSafe® Needle Guard. Directions for Syringe Usage Remove the prefilled syringe from the package. Lift syringe by barrel, not by plunger. Twist the plunger rod clockwise until the threads are seated. With the rubber needle shield secured on the syringe tip, push the plunger rod forward a few millimeters to break any friction seal be tween the rubber stopper and the glass syringe barrel. Remove the needle shield and expel air bubbles. [Do not remove the rubber needle shield to prepare the product for administration until immediately prior to the anticipated injection time.] Proceed with hypodermic needle puncture. Aspirate prior to injection to confirm that the needle is not in a vein or artery. Inject the medication. Keeping your hands behind the needle, grasp the guard with free hand and slide forward toward needle until it is completely covered and guard clicks into place. If audible click is not heard, guard may not be completely activated. (See Diagrams A and B) Place entire prefilled glass syringe with guard activated into an approved sharps container for proper disposal. (See Diagram C) Figure A,B and C A number of factors could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use. HOW SUPPLIED HyperHEP B S/D is supplied in a 0.5 mL neonatal single dose syringe with attached needle, a 1 mL single dose syringe with attached needle and a 1 mL and a 5 mL single dose vial. HyperHEP B S/D is preservative-free and latex-free. NDC Number Size 13533-636-03 0.5 mL syringe 13533-636-02 1 mL syringe 13533-636-01 1 mL vial 13533-636-05 5 mL vial Storage Store at 2–8°C (36–46°F). Do not freeze. Do not use after expiration date. Caution U.S. federal law prohibits dispensing without prescription. REFERENCES 5. Jhaveri R, Rosenfeld W, Salazar JD, et al: High titer multiple dose therapy with HBIG in newborn infants of HBsAg positive mothers. J Pediatr 97(2):305–8, 1980. 6. Hoofnagle JH, Seeff LB, Bales ZB, et al: Passive-active immunity from hepatitis B immune globulin. Ann Intern Med 91(6):813-8, 1979. 7. Scheiermann N, Kuwert EK: Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Dev Biol Stand 54:347-55, 1983. 8. Recommendations of the Immunization Practices Advisory Committee (ACIP): Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination. Appendix A: Postexposure Prophylaxis for Hepatitis B. MMWR 40(RR-13):21-25, 1991. 9. Stevens CE, Beasley RP, Tsui J, et al: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 292(15):771-4, 1975. 10. Shiraki K, Yoshihara N, Kawana T, et al: Hepatitis B surface antigen and chronic hepatitis in infants born to asymptomatic carrier mothers. Am J Dis Child 131(6):644-7, 1977. 11. Recommendation of the Immunization Practices Advisory Committee (ACIP): Immune globulins for protection against viral hepatitis. MMWR 30(34):423-8; 433-5, 1981. 12. Okada K, Kamiyama I, Inomata M, et al: e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294(14):746-9, 1976. 13. Beasley RP, Trepo C, Stevens CE, et al: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 105(2):94-8, 1977. 14. Beasley RP, Hwang LY, Lee GCY, et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2(8359): 1099-102, 1983. 15. Recommendation of the Immunization Practices Advisory Committee (ACIP): Recommendations for protection against viral hepatitis. MMWR 34(22):313–35, 1985. 16. Szmuness W, Stevens CE, Olesko WR, et al: Passive-active immunisation against hepatitis B: immunogenicity studies in adult Americans. Lancet 1:575–77, 1981. Grifols Therapeutics Inc., Research Triangle Park, NC 27709 USA 08941117. Revised: Sep 2012

INDICATIONS 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 (hepatitis b immune globulin (human)) should be administered intravenously for this indication. Postexposure Prophylaxis HepaGam B (hepatitis b immune globulin (human)) 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 HBeAg.1 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 (hepatitis b immune globulin (human)) is indicated for intramuscular use only for these post-exposure prophylaxis indications. DOSAGE AND ADMINISTRATION 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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) clinical trial, patients should receive 20,000 lU/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™ (Hepatitis B Immune Globulin Intravenous [Human]) 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 (hepatitis b immune globulin (human)) Dosing Regimen Anhepatic Phase Week 1 Post-Operative Weeks 2-12 Post-Operative Month 4 Onwards First dose Daily from day 1-7 Every 2 weeks from day 14 Monthly * Each dose should contain 20,000 IU calculated from the measured potency as stamped on the vial label [see Dosage Forms and Strengths]. HepaGam B (hepatitis b immune globulin (human)) dose adjustments may be required in patients who fail to reach anti-HBs levels of 500 IU/L within the first week post-liver transplantation.4 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 transplantation.5 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 (hepatitis b immune globulin (human)) should be prepared for intravenous administration under aseptic conditions. HepaGam B (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) 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™ (Hepatitis B Immune Globulin Intravenous [Human]) should be given one month after the first dose.2 Table 2 - Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure1,2 Source Exposed Person Unvaccinated Vaccinated HBsAg-positive 1. Hepatitis B Immune Globulin Intravenous (Human) (HBIGIV) x 1 immediately* 2. Initiate HB vaccine series† 1. Test exposed person for anti-HBs 2. If inadequate antibody‡, Hepatitis B Immune Globulin Intravenous (Human) x1 immediately plus either HB vaccine booster dose, or a second dose of HBIGIV*, 1 month later* Known Source -High Risk for HBsAg-positive 1. Initiate HB vaccine series 2. Test source of HBsAg. If positive, Hepatitis B immune Globulin Intravenous (Human) (HBIGIV) x 1 1. Test source for HBsAg only if exposed is vaccine nonresponder; if source is HBsAg-positive, give Hepatitis B Immune Globulin Intravenous (Human) x 1 immediately plus eithei HB vaccine booster dose, or a second dose of HBIGIV*, 1 month later§ Known Source -Low Risk for HBsAg-positive Initiate HB vaccine series Nothing required Unknown Source Initiate HB vaccine series Nothing required *Hepatitis B Immune Globulin Intravenous (Human) dose of 0.06 mL/kg i.m. † See manufacturers' recommendation for appropriate dose. ‡ Less than 10 mlU/mL anti-HBs by radioimmunoassay, negative by enzyme immunoassay. § Two doses of Hepatitis B Immune Globulin Intravenous (Human) is preferred if no response after at least four doses of vaccine. 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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) , 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 (hepatitis b immune globulin (human)) as soon as possible and within seven days of birth; however, the efficacy of HepaGam B (hepatitis b immune globulin (human)) administered after 48 hours of age is not known.6 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 protected.1 Table 3 - Recommended Schedule of Hepatitis B Immune-prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus Infection1 Age of Infant Administer Infant born to mother known to be HBsAg-positive Infant born to mother not screened for HBsAg First Vaccination* Hepatitis B Immune Globulin Intravenous (Human)† Birth (within 12 hours) Birth (within 12 hours) Birth (within 12 hours) If mother is found to be HBsAg-positive, administer dose to infant as soon as possible, not later than 1 week after birth Second Vaccination* 1 month 1-2 months Third Vaccination* 6 months‡ 6 months‡ * See manufacturers' recommendations for appropriate dose, † 0.5 mL administered i.m. at a site different from that used for the vaccine, ‡ See ACIP recommendation.1 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™ (Hepatitis B Immune Globulin Intravenous [Human]) (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 (hepatitis b immune globulin (human)) 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 (hepatitis b immune globulin (human)) 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 HOW SUPPLIED Dosage Forms and Strength 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 lU/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 lU/mL is maintained over the product shelf life, a higher potency of 550 lU/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 lU/mL, the actual potency test result may vary from approximately 400 to 700 lU/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]. Storage and Handling HepaGam B (Hepatitis B Immune Globulin Intravenous [Human]) is supplied as: NDC Number: Contents: 60492-0052-1 60492-0052-2 a carton containing a 1.0 mL single dose vial (>312 lU/mL; measured potency of each lot is stamped on the vial label) and a package insert. NDC Number: Contents: 60492-0051-1 60492-0051-2 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. 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. Distributed by: Apotex Corp Weston, FL 33326. Manufactured by: Cangene Corporation Winnipeg, Canada R3T 5Y3. April 2007.

INDICATIONS Recommendations on post-exposure prophylaxis are based on available efficacy data and on the likelihood of future HBV exposure for the person requiring treatment. In all exposures, a regimen combining Hepatitis B Immune Globulin (Human) with hepatitis B vaccine will provide both short- and long-term protection, will be less costly than the two-dose Hepatitis B Immune Globulin (Human) treatment alone, and is the treatment of choice.8 BayHep B (hepatitis b immune globulin (human)) is indicated for post-exposure prophylaxis in the following situations: Acute Exposure to Blood Containing HBsAg After either parenteral exposure, e.g., by accidental “needlestick” or direct mucous membrane contact (accidental splash), or oral ingestion (pipetting accident) involving HBsAg-positive materials such as blood, plasma or serum. For inadvertent percutaneous exposure, a regimen of two doses of Hepatitis B Immune Globulin (Human), one given after exposure and one a month later, is about 75% effective in preventing hepatitis B in this setting. Perinatal Exposure of Infants Born to HBsAg-positive Mothers Infants born to HBsAg-positive mothers are at risk of being infected with hepatitis B virus and becoming chronic carriers.5,8-10 This risk is especially great if the mother is HBeAg-positive.11-13 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 is 85%–95% effective in preventing development of the HBV carrier state.8,14 Regimens involving either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have 70%–90% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has only 50% efficacy.8,15 Sexual Exposure to an HBsAg-positive Person Sex partners of HBsAg-positive persons are at increased risk of acquiring HBV infection. For sexual exposure to a person with acute hepatitis B, a single dose of Hepatitis B Immune Globulin (Human) is 75% effective if administered within 2 weeks of last sexual exposure.8 Household Exposure to Persons with Acute HBV Infection Since infants have close contact with primary care-givers and they 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 care-giver has acute HBV infection.8 Administration of Hepatitis B Immune Globulin (Human) either preceding or concomitant with the commencement of active immunization with Hepatitis B Vaccine provides for more rapid achievement of protective levels of hepatitis B antibody, than when the vaccine alone is administered.16 Rapid achievement of protective levels of antibody to hepatitis B virus may be desirable in certain clinical situations, as in cases of accidental inoculations with contaminated medical instruments.16 Administration of Hepatitis B Immune Globulin (Human) either 1 month preceding or at the time of commencement of a program of active vaccination with Hepatitis B Vaccine has been shown not to interfere with the active immune response to the vaccine.16 DOSAGE AND ADMINISTRATION Acute Exposure to Blood Containing HBsAg15 Table 1 summarizes prophylaxis for percutaneous (needlestick or bite), 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 Hepatitis B Immune Globulin (Human) should be given as soon as possible after exposure (its value beyond 7 days of exposure is unclear). If Hepatitis B Immune Globulin (Human) is indicated (see Table 1), an injection of 0.06 mL/kg of body weight should be administered intramuscularly (see PRECAUTIONS) as soon as possible after exposure and within 24 hours, if possible. Consult Hepatitis B Vaccine package insert for dosage information regarding that product. Table 1 : (adapted from 20) Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure Exposed Person Source Unvaccinated Vaccinated HBsAg-Positive Hepatitis B Immune Globulin (Human) X 1 immediately* Initiate HB Vaccine Series† Test exposed person for anti-HBs. If inadequate antibody,‡ Hepatitis B Immune Globulin (Human) (X1) immediately plus HB Vaccine booster dose, or 2 doses of HBIG,* one as soon as possible after exposure and the second 1 month later. Known Source (High Risk) Initiate HB Vaccine Series Test source for HBsAg. If positive, Hepatitis B Immune Globulin (Human) X 1 Test Source for HBsAg only if exposed is vaccine nonresponder; if source is HBsAg-positive, give Hepatitis B Immune Globulin (Human) X 1 immediately plus HB Vaccine booster dose, or 2 doses of HBIG*, one as soon as possible after exposure and the second 1 month later. Low Risk HBsAg-Positive Initiate HB Vaccine series Nothing required. Unknown Source Initiate HB Vaccine series within 7 days of exposure Nothing required. * Hepatitis B Immune Globulin (Human), dose 0.06 mL / kg IM. † HB Vaccine dose 20 μg IM for adults; 10 μg IM for infants or children under 10 years of age. First dose within 1 week; second and third doses, 1 and 6 months later. ‡ Less than 10 sample ratio units (SRU) by radioimmunoassay (RIA), negative by enzyme immunoassay (EIA). For persons who refuse Hepatitis B Vaccine, a second dose of Hepatitis B Immune Globulin (Human) should be given 1 month after the first dose. Prophylaxis of Infants Born to HBsAg and HBeAg Positive Mothers Efficacy of prophylactic Hepatitis B Immune Globulin (Human) in infants at risk depends on administering Hepatitis B Immune Globulin (Human) on the day of birth. It is therefore vital that HBsAg-positive mothers be identified before delivery. Hepatitis B Immune Globulin (Human) (0.5 mL) should be administered intramuscularly (IM) to the newborn infant after physiologic stabilization of the infant and preferably within 12 hours of birth. Hepatitis B Immune Globulin (Human) efficacy decreases markedly if treatment is delayed beyond 48 hours. Hepatitis B Vaccine should be administered IM in three doses of 0.5 mL of vaccine (10 μg) each. The first dose should be given within 7 days of birth and may be given concurrently with Hepatitis B Immune Globulin (Human) but at a separate site. The second and third doses of vaccine should be given 1 month and 6 months, respectively, after the first. If administration of the first dose of Hepatitis B Vaccine is delayed for as long as 3 months, then a 0.5 mL dose of Hepatitis B Immune Globulin (Human) should be repeated at 3 months. If Hepatitis B Vaccine is refused, the 0.5 mL dose of Hepatitis B Immune Globulin (Human) should be repeated at 3 and 6 months. Hepatitis B Immune Globulin (Human) administered at birth should not interfere with oral polio and diphtheria-tetanuspertussis vaccines administered at 2 months of age.15 Sexual Exposure to an HBsAg-positive Person All susceptible persons whose sex partners have acute hepatitis B infection should receive a single dose of HBIG (0.06 mL/kg) and should begin the hepatitis B vaccine series if prophylaxis can be started within 14 days of the last sexual contact or if sexual contact with the infected person will continue (see Table 2 below). Administering the vaccine with HBIG may improve the efficacy of postexposure treatment. The vaccine has the added advantage of conferring long-lasting protection.8 Table 2 : (adapted from 21) Recommendations for Postexposure Prophylaxis for Sexual Exposure to Hepatitis B HBIG* Vaccine Dose Recommended timing Dose Recommended timing 0.06 mL/kg IM† Single dose within 14 days of last sexual contact 1.0 mL IM† First dose at time of HBIG* treatment¶ * HBIG = Hepatitis B Immune Globulin (Human) † IM = intramuscularly ¶ The first dose can be administered the same time as the HBIG dose but at a different site; subsequent doses should be administered as recommended for specific vaccine. Household Exposure to Persons with Acute HBV Infection Prophylactic treatment with a 0.5 mL dose of Hepatitis B Immune Globulin (Human) and hepatitis B vaccine is indicated for infants < 12 months of age who have been exposed to a primary care-giver who has acute hepatitis B. Prophylaxis for other household contacts of persons with acute HBV infection is not indicated unless they have had 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.8 Hepatitis B Immune Globulin (Human) may be administered at the same time (but at a different site), or up to 1 month preceding Hepatitis B Vaccination without impairing the active immune response from Hepatitis B Vaccination.16 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administer intramuscularly. Do not inject intravenously. Hepatitis B Immune Globulin (Human) — BayHep B® (hepatitis b immune globulin (human)) is supplied with a syringe and an attached UltraSafe® Needle Guard for your protection and convenience. Please follow instructions below for proper use of syringe and UltraSafe® Needle Guard. Directions for Syringe Usage Remove the prefilled syringe from the package. Lift syringe by barrel, not by plunger. Twist the plunger rod clockwise until the threads are seated. With the rubber needle shield secured on the syringe tip, push the plunger rod forward a few millimeters to break any friction seal between the rubber stopper and the glass syringe barrel. Remove the needle shield and expel air bubbles. [Do not remove the rubber needle shield to prepare the product for administration until immediately prior to the anticipated injection time.] Proceed with hypodermic needle puncture. Aspirate prior to injection to confirm that the needle is not in a vein or artery. Inject the medication. Keeping your hands behind the needle, grasp the guard with free hand and slide forward toward needle until it is completely covered and guard clicks into place. If audible click is not heard, guard may not be completely activated. (See Diagrams A and B) Place entire prefilled glass syringe with guard activated into an approved sharps container for proper disposal. (See Diagram C) A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use. HOW SUPPLIED BayHep B (hepatitis b immune globulin (human)) is supplied in a 0.5 mL neonatal single dose syringe with attached needle, a 1 mL single dose syringe with attached needle and a 1 mL and a 5 mL single dose vial. NDC Number Size 0026-0636-03 0.5 mL syringe 0026-0636-02 1 mL syringe 0026-0636-01 1 mL vial 0026-0636-05 5 mL vial Storage Store at 2–8°C (36–46°F). Do not freeze. Do not use after expiration date. Caution U.S. federal law prohibits dispensing without prescription. REFERENCES 8. Recommendations of the Immunization Practices Advisory Committee (ACIP): Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination. Appendix A: Postexposure Prophylaxis for Hepatitis B. MMWR 40(RR-13):21-25, 1991. 9. Stevens CE, Beasley RP, Tsui J, et al: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 292(15):771-4, 1975. 10. Shiraki K, Yoshihara N, Kawana T, et al: Hepatitis B surface antigen and chronic hepatitis in infants born to asymptomatic carrier mothers. Am J Dis Child 131(6):644-7, 1977. 11. Recommendation of the Immunization Practices Advisory Committee (ACIP): Immune globulins for protection against viral hepatitis. MMWR 30(34):423-8; 433-5, 1981. 12. Okada K, Kamiyama I, Inomata M, et al: e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294(14):746-9, 1976. 13. Beasley RP, Trepo C, Stevens CE, et al: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 105(2):94-8, 1977. 14. Beasley RP, Hwang LY, Lee GCY, et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2(8359): 1099-102, 1983. 15. Recommendation of the Immunization Practices Advisory Committee (ACIP): Recommendations for protection against viral hepatitis. MMWR 34(22):313–35, 1985. 16. Szmuness W, Stevens CE, Olesko WR, et al: Passive-active immunisation against hepatitis B: immunogenicity studies in adult Americans. Lancet 1:575–77, 1981. 20. Recommendations of the Immunization Practices Advisory Committee (ACIP): Update on Adult Immunization. Table 9. Recommendations for postexposure prophylaxis for percutaneous or permucosal exposure to hepatitis B, United States. MMWR 40(RR-12):70, 1991. 21. Recommendations of the Immunization Practices Advisory Committee (ACIP): Update on Adult Immunization. Table 10. Recommendations for postexposure prophylaxis for perinatal and sexual exposure to hepatitis B, United States. MMWR 40(RR-12):71, 1991. Bayer Corporation, Pharmaceutical Division, Elkhart, IN 46515 USA. Rev. March 2004.

PATIENT INFORMATION Patients should be informed that HepaGam B™ (hepatitis b immune globulin (human)) (Hepatitis B Immune Globulin Intravenous [Human]) is prepared from human plasma. Products made from human plasma may contain infectious agents such as viruses that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals known to have severe, potentially life-threatening reaction to human globulin should not receive HepaGam B (hepatitis b immune globulin (human)) or any other immune globulin products. Individuals who are deficient in IgA may have the potential for developing IgA antibodies and have severe potentially life threatening allergic reactions. In case of allergic or anaphylactic reaction, the infusion should be stopped immediately. In case of shock, the current medical standards for treatment of shock should be observed. The maltose contained in HepaGam B (hepatitis b immune globulin (human)) can interfere with some types of blood glucose monitoring systems. Only testing systems that are glucose-specific should be used in patients receiving HepaGam B (hepatitis b immune globulin (human)) . This inference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Consequences of an overdose are not known. Although no data are available, clinical experience reported with other intravenously administered human immune globulin preparations suggests that doses above 1 g immune globulin/kg body weight are tolerated. For intramuscular administration of HepaGam B (hepatitis b immune globulin (human)) , the only manifestations of overdose would be pain and tenderness at the injection site. CONTRAINDICATIONS Individuals known to have anaphylactic or severe systematic reactions associated with the parenteral administration of human globulin preparations should not receive HepaGam B (hepatitis b immune globulin (human)) , (Hepatitis B Immune Globulin Intravenous [Human]), or any other human immune globulin. HepaGam B (hepatitis b immune globulin (human)) contains less than 40 micro-grams/mL of IgA. Individuals who are deficient in IgA may have the potential to develop IgA antibodies and have an anaphylactoid reaction. The physician must weigh the potential benefit of treatment with HepaGam B (hepatitis b immune globulin (human)) against the potential for hypersensitivity reactions. For postexposure prophylaxis indications, HepaGam B (hepatitis b immune globulin (human)) must be administered intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, HepaGam B (hepatitis b immune globulin (human)) should be given only if the expected benefits outweigh the potential risks.

OVERDOSE Although no data are available, clinical experience with other immunoglobulin preparations suggests that the only manifestations would be pain and tenderness at the injection site. CONTRAINDICATIONS None known.

SIDE EFFECTS Local pain and tenderness at the injection site, urticaria and angioedema may occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations.19 DRUG INTERACTIONS ALTHOUGH administration of Hepatitis B Immune Globulin (Human) did not interfere with measles vaccination,18 it is not known whether Hepatitis B Immune Globulin (Human) may interfere with other live virus vaccines. Therefore, use of such vaccines should be deferred until approximately 3 months after Hepatitis B Immune Globulin (Human) administration. Hepatitis B Vaccine may be administered at the same time, but at a different injection site, without interfering with the immune response.16 No interactions with other products are known. REFERENCES 19. Ellis EF, Henney CS: Adverse reactions following administration of human gamma globulin. J Allerg 43(1):45-54, 1969.

SIDE EFFECTS Overall Adverse Reaction Profile The most common expected adverse drug reactions for intravenous immune globulins like HepaGam B (hepatitis b immune globulin (human)) are chills, fever, headaches, vomiting, allergic reactions, nausea, arthralgia and moderate low back pain.7-8 In a clinical trial in liver transplant patients, 2 adverse drug reactions of tremor and hypotension were reported in 2 of 14 patients who received intravenous infusions of HepaGam B.8 In studies with healthy volunteers, only 1 adverse drug reaction of nausea was reported in the 70 adult subjects who received an intramuscular administration of HepaGam B (hepatitis b immune globulin (human)) .8 Although no anaphylactic reactions have been reported following HepaGam B (hepatitis b immune globulin (human)) administration, anaphylactic reactions have been reported following the administration of other immune globulin products on rare occasions [see WARNINGS AND PRECAUTIONS]. Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hepatitis B-Related Liver Transplantation In an ongoing clinical trial, only 2 adverse drug reactions occurred following the 313 (<1%) HepaGam B (hepatitis b immune globulin (human)) infusions in 14 liver transplant patients. A listing of all adverse events (including those assessed as unrelated to study drug) occurring in >10% of patients are summarized in Table 4 below. These adverse events were reported in an interim analysis from a one-year Phase 3 clinical trial examining HepaGam B (hepatitis b immune globulin (human)) for the prevention of hepatitis B recurrence following liver transplantation. This study utilized the recommended dosing regimen outlined in Table 1 [See DOSAGE AND ADMINISTRATION]. The 2 attributed adverse drug reactions of tremor and hypotension were reported in 2 patients. All reactions were associated with a single HepaGam B (hepatitis b immune globulin (human)) infusion during the first week post-transplant. All reactions resolved on the same day and did not recur with subsequent HepaGam B (hepatitis b immune globulin (human)) infusions. Table 4 - Adverse Events (AEs) Occurring in >10% of Liver Transplant Patients Adverse Event by system organ class Number of AEs (in number of patients) N=14 Blood and lymphatic systems disorder - Splenomegaly 8(6) Eye disorders - Presbyopia 2(2) Gastrointestinal disorders -Aphthous stomatitis 3(3) - Diarrhoea 10(8) - Dyspepsia 5(5) - Gingival Hyperplasia 3(3) General disorders - Fatigue 6(6) - Oedema peripheral 3(2) - Pyrexia 3(3) Hepatobiliary disorders - Hepatobiliary disease 3(3) Immune system disorders - Liver transplant rejection 7(5) Infections and infestations - Diarrhea Infectious 2(2) - Pneumonia 2(2) - Sepsis 3(2) Metabolism and nutrition disorders - Hyperglycaemia 4(4) Musculoskeletal - Back pain 2(2) Nervous system disorders - Amnesia 2(2) - Essential Tremor 6(2) - Headache 15(9) Psychiatric disorders - Agitation 2(2) Renal and urinary disorders - Nocturia 2(2) Respiratory thoracic and mediastinal - Pleural effusion 3(3) Skin and subcutaneous tissue disorders - Pruritus 3(3) - Rash 2(2) Vascular disorders - Hypertension 8(7) - Hypotension 2(2) Healthy Volunteer Studies Seventy healthy male and female volunteers received a single dose of HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) intramuscularly in clinical trials.8 Seventeen (17) subjects reported 30 adverse events following administration of HepaGam B (hepatitis b immune globulin (human)) . The most frequently reported adverse events included 4 subjects (6%) who experienced headache. 7 subjects (10%) who had cold symptoms or flu and 2 subjects (3%) who experienced lightheadeness/ fainted. The majority of events were reported as mild and were not related to study drug. One adverse event, an episode of nausea, was considered to be drug related. There were no serious adverse events reported. A similar number of subjects in the comparator groups reported adverse events. Postmarketing Experience As of April 2007, there have been no postmarketing adverse events reported for HepaGam B (hepatitis b immune globulin (human)) administered i.m. DRUG INTERACTIONS Live Attenuated Virus Vaccines Immune globulin administration may impair the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella.1,2,7 Vaccination with live virus vaccines should be deferred until approximately three months after administration of HepaGam B, Hepatitis B Immune Globulin Intravenous (Human). Persons who received HepaGam B (hepatitis b immune globulin (human)) less than 14 days after live virus vaccination should be revaccinated 3 months after the administration of the immune globulin, unless serologic test results indicate that antibodies were produced.1-2 There are no available data on drug interactions of HepaGam B (hepatitis b immune globulin (human)) with other medications. Drug-Laboratory Interactions: Serological Testing Antibodies present in HepaGam B (hepatitis b immune globulin (human)) may interfere with some serological tests. After administration of immune globulins like HepaGam B (hepatitis b immune globulin (human)) , a transitory increase of passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing (e.g. Coombs' test). Drug-Laboratory Interactions: Blood Glucose Testing HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) contains maltose which can interfere with certain types of blood glucose monitoring systems, [see WARNINGS AND PRECAUTIONS] Only testing systems that are glucose-specific should be used in patients receiving HepaGam B. This interference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products. 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. 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.

SIDE EFFECTS Local pain and tenderness at the injection site, urticaria and angioedema may occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations.19 DRUG INTERACTIONS Although administration of Hepatitis B Immune Globulin (Human) did not interfere with measles vaccination,18 it is not known whether Hepatitis B Immune Globulin (Human) may interfere with other live virus vaccines. Therefore, use of such vaccines should be deferred until approximately 3 months after Hepatitis B Immune Globulin (Human) administration. Hepatitis B Vaccine may be administered at the same time, but at a different injection site, without interfering with the immune response.16 No interactions with other products are known. REFERENCES 18. Beasley RP, Hwang LY: Measles vaccination not interfered with by hepatitis B immune globulin. Lancet 1:161, 1982. 19. Ellis EF, Henney CS: Adverse reactions following administration of human gamma globulin. J Allerg 43(1):45-54, 1969.

WARNINGS HyperHEP B S/D is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob Disease (CJD) agent that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. HyperHEP B S/D should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immune globulin preparations. Epinephrine should be available. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, Hepatitis B Immune Globulin (Human) should be given only if the expected benefits outweigh the risks. PRECAUTIONS General HyperHEP B S/D should not be administered intravenously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Intramuscular injections are preferably administered in the deltoid muscle of the upper arm or lateral thigh muscle. The gluteal region should not be used as an injection site because of the risk of injury to the sciatic nerve.17 An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. Laboratory Tests None required. Pregnancy Category C Animal reproduction studies have not been conducted with HyperHEP B S/D. It is also not known whether HyperHEP B S/D can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HyperHEP B S/D should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. REFERENCES 16. Szmuness W, Stevens CE, Olesko WR, et al: Passive-active immunisation against hepatitis B: immunogenicity studies in adult Americans. Lancet 1:575–77, 1981. 18. Beasley RP, Hwang LY: Measles vaccination not interfered with by hepatitis B immune globulin. Lancet 1:161, 1982.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General HepaGam B is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically, the Creutzfeldt-Jakob disease agent. The risk that such products can transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. The HepaGam B (hepatitis b immune globulin (human)) manufacturing process includes a solvent/detergent treatment step (using tri-n-butyl phosphate and Triton X-100) that is effective in inactivating known enveloped viruses such as HBV, HCV, and HIV. HepaGam B (hepatitis b immune globulin (human)) is filtered using a Planova 20N Virus Filter that is effective in reducing the levels of some enveloped and non-enveloped viruses. These two processes are designed to increase product safety. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician to have been transmitted by this product should be reported by the physician or other healthcare provider to Cangene Corporation at 1-877-CANGENE (226-4363). The physician should discuss the risks and benefits of this product with the patient. Anaphylactic Precautions Although allergic reactions have not been reported following HepaGam B administration [see ADVERSE REACTIONS], the product should be administered only in a setting where appropriate equipment and personnel trained in the management of acute anaphylaxis are available. If hypotension or anaphylaxis occurs, the administration of HepaGam B (hepatitis b immune globulin (human)) should be discontinued immediately and supportive care given as needed. Interference with Blood Glucose Testing The maltose contained in HepaGam B (hepatitis b immune globulin (human)) can interfere with some types of blood glucose monitoring systems, i.e., those based on the glucose dehydrogenase pyrroloquinequinone (GDH-PQQ) method. This can result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated results. Monitoring: Serum anti-HBs Antibody Levels Liver transplant patients should be monitored regularly for serum anti-HBs antibody levels using a quantitative assay [See DOSAGE AND ADMINISTRATION]. Infusion Reactions Certain adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under DOSAGE AND ADMINISTRATION must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period and immediately following an infusion. Coagulation Disorders For postexposure prophylaxis indications, HepaGam B™ (Hepatitis B Immune Globulin Intravenous [Human]) must be administered intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, HepaGam B (hepatitis b immune globulin (human)) should be given only if the expected benefits outweigh the potential risks. Nonclinical Toxicology Nonclinical pharmacology studies have not been performed with Hepatitis B Immune Globulin Intravenous (Human) as there is broad experience in humans with intravenous and intramuscular administration of immune globulin products. Since the product is of human origin, immunogenicity is expected when administered to animals. Toxicology studies have not been performed with Hepatitis B Immune Globulin Intravenous (Human) because the product has been formulated with ingredients that are know to be non-toxic at the levels at which they are present in the final product. Use in Specific Populations Pregnancy Category C Animal reproduction studies have not been conducted with HepaGam B (hepatitis b immune globulin (human)) . It is also not known whether HepaGam B (hepatitis b immune globulin (human)) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. HepaGam B (hepatitis b immune globulin (human)) should be given to a pregnant woman only if clearly indicated. Nursing Mothers It is not known whether HepaGam B is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HepaGam B (hepatitis b immune globulin (human)) is administered to a nursing mother.

WARNINGS BayHep B (hepatitis b immune globulin (human)) is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bayer Corporation [1-800-288-8371]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. BayHep B (hepatitis b immune globulin (human)) should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immune globulin preparations. Epinephrine should be available. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, Hepatitis B Immune Globulin (Human) should be given only if the expected benefits outweigh the risks. PRECAUTIONS General BayHep B (hepatitis b immune globulin (human)) should not be administered intravenously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Intramuscular injections are preferably administered in the anterolateral aspects of the upper thigh and the deltoid muscle of the upper arm. The gluteal region should not be used routinely as an injection site because of the risk of injury to the sciatic nerve. An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. If the gluteal region is used when very large volumes are to be injected or multiple doses are necessary, the central region MUST be avoided; only the upper, outer quadrant should be used.17 Laboratory Tests None required. Pregnancy Category C Animal reproduction studies have not been conducted with BayHep B (hepatitis b immune globulin (human)) . It is also not known whether BayHep B (hepatitis b immune globulin (human)) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BayHep B (hepatitis b immune globulin (human)) should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established.