Prescription Drugs

CLINICAL PHARMACOLOGY Hepatitis B Immune Globulin (Human) products provide passive immunization for individuals exposed to the hepatitis B virus as evidenced by a reduction in the attack rate of hepatitis B following use6-9. Clinical studies10,11 conducted prior to 1983 with hepatitis B immune globulins similar to Nabi-HB (hepatitis b vaccine recombinant) indicate the advantage of simultaneous administration of hepatitis B vaccine and Hepatitis B Immune Globulin (Human). The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) advises that the combination prophylaxis be provided in certain instances of exposure based upon the increased efficacy found with that regimen in neonates12. Cases of hepatitis B are rarely seen following exposure to HBV in persons with preexisting anti-HBs. However, no prospective studies have been performed on the efficacy of concurrent hepatitis B vaccine and Hepatitis B Immune Globulin (Human) administration following parenteral exposure, mucous membrane contact, or oral ingestion in adults. Infants born to HBsAg-positive mothers are at risk of being infected with HBV and becoming chronic carriers13. The risk is especially great if the mother is also HBeAg-positive14. Studies conducted with hepatitis B immune globulins similar to Nabi-HB (hepatitis b vaccine recombinant) indicated that for an infant with peri-natal 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 85-98% effective in preventing development of the HBV carrier state15-17. Regimens involving either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have a 70-90% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has 50% efficacy18. Since infants have close contact with primary caregivers 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 caregiver has acute HBV infection19. 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 B19. Pharmacokinetics Pharmacokinetics trials20 of Nabi-HB, Hepatitis B Immune Globulin (Human), given intramuscularly to 50 healthy volunteers demonstrated pharmacokinetic parameters similar to those reported by Scheiermann and Kuwert21. The half-life for Nabi-HB (hepatitis b vaccine recombinant) was 23.1 ± 5.5 days. The clearance rate was 0.35 ± 0.12 L/day and the volume of distribution was 11.2 ± 3.4 L. Maximum concentration of Nabi-HB (hepatitis b vaccine recombinant) was reached in 6.5 ±4.3 days. The maximum concentration of anti-HBs and the area under the time-concentration curve achieved by Nabi-HB (hepatitis b vaccine recombinant) were bio-equivalent to that of another licensed Hepatitis B Immune Globulin (Human) when compared in the same pharmacokinetics trial. Comparability of pharmacokinetics between Nabi-HB (hepatitis b vaccine recombinant) and a commercially available hepatitis B immunoglobulin indicate that similar efficacy of Nabi-HB (hepatitis b vaccine recombinant) should be inferred. REFERENCES 6. Grady GF, and Lee VA: Hepatitis B immune globulin - prevention of hepatitis from accidental exposure among medical personnel. N Engl J Med 1975; 293:1067-1070. 7. Seeff LB, et al.: Type B hepatitis after needle-stick exposure: Prevention with hepatitis B immune globulin. Ann Int Med 1978; 88:285-293. 8. Krugman S, and Giles JP: Viral hepatitis, type B (MS-2-strain). Further observations on natural history and prevention. N Engl J Med 1973; 288:755-760. 9. Hoofnagle JH, et al.: Passive - active immunity from hepatitis B immune globulin. Ann Int Med 1979; 91:813-818. 10. Beasley RP, et al.: Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo - controlled trial. Hepatology 1983; 3:135-141. 11. Szmuness W, et al.: Passive active immunisation against hepatitis B: Immunogenicity studies in adult Americans. Lancet 1981; 1:575-577. 12. Centers for Disease Control: Recommendations for protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1985; 34(22):313-335. 13. Shiraki Y, et al.: Hepatitis B surface antigen and chronic hepatitis in infants born to asymptomatic carrier mothers. Am J Dis Child 1977; 131:644-647. 14. Beasley RP, et al.: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105:94-98. 15. Wong VCW, et al.: Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin: Double-blind randomized placebo-controlled study. Lancet 1984; 1:921-926. 16. Poovorawan Y, et al.: Long term hepatitis B vaccine in infants born to hepatitis B e antigen positive mothers. Archives of Diseases in Childhood 1997; 77:F47-F51. 17. Stevens CE, et al.: Perinatal Hepatitis B virus transmission in the United States: Prevention by passive-active immunization. JAMA 1985; 253:1740-1745. 18. Jhaveri R, et al.: High titer multiple dose therapy with HBIG in newborn infants of HBsAg positive mothers. J Pediatr 1980; 97:305-308. 19. Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40(13):1-25. 20. Data on file, Nabi® Biopharmaceuticals

CLINICAL PHARMACOLOGY Mechanism Of Action Infection with hepatitis B virus can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma. Antibody concentrations ≥ 10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.1 Seroconversion is defined as antibody titers ≥ 1 mIU/mL. Clinical Studies Efficacy In Neonates Protective efficacy with ENGERIX-B has been demonstrated in a clinical trial in neonates at high risk of hepatitis B infection.6,7 Fifty-eight neonates born of mothers who were both HBsAg- positive and hepatitis B “e” antigen (HBeAg)-positive were given ENGERIX-B (10 mcg/0.5 mL) at 0, 1, and 2 months, without concomitant hepatitis B immune globulin (HBIG). Two infants became chronic carriers in the 12-month follow-up period after initial inoculation. Assuming an expected carrier rate of 70%, the protective efficacy rate against the chronic carrier state during the first 12 months of life was 95%. Efficacy And Immunogenicity In Specific Populations Homosexual Men ENGERIX-B (20 mcg/1 mL) given at 0, 1, and 6 months was evaluated in homosexual men 16 to 59 years of age. Four of 244 subjects became infected with hepatitis B during the period prior to completion of the 3-dose immunization schedule. No additional subjects became infected during the 18-month follow-up period after completion of the immunization course. Adults with Chronic Hepatitis C In a clinical trial of 67 adults 25 to 67 years of age with chronic hepatitis C, ENGERIX-B (20 mcg/1 mL) was given at 0, 1, and 6 months. Of the subjects assessed at Month 7 (N = 31), 100% responded with seroprotective titers. The geometric mean antibody titer (GMT) was 1,260 mIU/mL (95% Confidence Interval [CI]: 709, 2,237). Adults on Hemodialysis Hemodialysis patients given hepatitis B vaccines respond with lower titers, which remain at protective levels for shorter durations than in normal subjects. In a clinical trial of 56 adults who had been on hemodialysis for a mean period of 56 months, ENGERIX-B (40 mcg/2 mL given as two 1-mL doses) was given at 0, 1, 2, and 6 months. Two months after the fourth dose, 67% (29/43) of patients had seroprotective antibody levels ( > 10 mIU/mL) and the GMT among seroconverters was 93 mIU/mL. Adults with Type 2 Diabetes Mellitus In a descriptive study, 674 adult subjects with type 2 diabetes (diagnosed within the preceding 5 years) or without type 2 diabetes were enrolled and stratified by age and body mass index (BMI). The per-protocol immunogenicity cohort included 378 diabetic subjects and 189 matched control subjects who received ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months. Among these subjects, the mean age was 54 years (range: 20 to 82 years); mean BMI was 32 kg/m (range: 17 to 64 kg/m ); 51% were male; 88% were white, 3% were American Indian or Alaskan Native, 3% were black, 2% were Asian, 4% were other racial groups; 2% were Hispanic or Latino. The overall seroprotection rates (1 month after the third dose) were 75% (95% CI: 71, 80) in patients with diabetes and 82% (95% CI: 76, 87) in control subjects. The seroprotection rates in those with diabetes aged 20 to 39 years, 40 to 49 years, 50 to 59 years, and at least 60 years were 89%, 81%, 83%, and 58%, respectively. The seroprotection rates in those without diabetes in these same age-groups were 100%, 86%, 82% and 70%, respectively. Subjects with diabetes and a BMI of at least 30 kg/m had a seroprotection rate of 72% compared with 80% in diabetic subjects with lower BMIs. In control subjects, seroprotection rates were 82% in those with a BMI of at least 30 kg/m² and 83% in those with lower BMIs. Immunogenicity In Neonates In clinical studies, neonates were given ENGERIX-B (10 mcg/0.5 mL) at 0, 1, and 6 months or at 0, 1, and 2 months of age. The immune response to vaccination was evaluated in sera obtained 1 month after the third dose of ENGERIX-B. Among infants administered ENGERIX-B at 0, 1, and 6 months, 100% of evaluable subjects (N = 52) seroconverted by Month 7. The GMT was 713 mIU/mL. Of these, 97% had seroprotective levels ( ≥ 10 mIU/mL). Among infants enrolled (N = 381) to receive ENGERIX-B at 0, 1, and 2 months of age, 96% had seroprotective levels ( ≥ 10 mIU/mL) by Month 4. The GMT among seroconverters (N = 311) (antibody titer ≥ 1 mIU/mL) was 210 mIU/mL. A subset of these children received a fourth dose of ENGERIX-B at 12 months of age. One month following this dose, seroconverters (N = 126) had a GMT of 2,941 mIU/mL. Immunogenicity In Children And Adults Persons 6 Months through 10 Years of Age In clinical trials, children (N = 242) 6 months through 10 years of age were given ENGERIX-B (10 mcg/0.5 mL) at 0, 1, and 6 months. One to 2 months after the third dose, the seroprotection rate was 98% and the GMT of seroconverters was 4,023 mIU/mL. Persons 5 through 16 Years of Age In a separate clinical trial including both children and adolescents 5 through 16 years of age, ENGERIX-B (10 mcg/0.5 mL) was administered at 0, 1, and 6 months (N = 181) or 0, 12, and 24 months (N = 161). Immediately before the third dose of vaccine, seroprotection was achieved in 92.3% of subjects vaccinated on the 0-, 1-, and 6-month schedule and 88.8% of subjects on the 0-, 12-, and 24-month schedule (GMT: 117.9 mIU/mL versus 162.1 mIU/mL, respectively, P = 0.18). One month following the third dose, seroprotection was achieved in 99.5% of children vaccinated on the 0-, 1-, and 6-month schedule compared with 98.1% of those on the 0-, 12-, and 24-month schedule. GMTs were higher (P = 0.02) for children receiving vaccine on the 0-, 1-, and 6-month schedule compared with those on the 0-, 12-, and 24-month schedule (5,687.4 mIU/mL versus 3,158.7 mIU/mL, respectively). Persons 11 through 19 Years of Age In clinical trials with healthy adolescent subjects 11 through 19 years of age, ENGERIX-B (10 mcg/0.5 mL) given at 0, 1, and 6 months produced a seroprotection rate of 97% at Month 8 (N = 119) with a GMT of 1,989 mIU/mL (N = 118, 95% CI: 1,318, 3,020). Immunization with ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months produced a seroprotection rate of 99% at Month 8 (N = 122) with a GMT of 7,672 mIU/mL (N = 122, 95% CI: 5,248, 10,965). Persons 16 through 65 Years of Age Clinical trials in healthy adult and adolescent subjects (16 through 65 years of age) have shown that following a course of 3 doses of ENGERIX-B (20 mcg/1 mL) given at 0, 1, and 6 months, the seroprotection (antibody titers > 10 mIU/mL) rate for all individuals was 79% at Month 6 (5 months after second dose) and 96% at Month 7 (1 month after third dose); the GMT for seroconverters was 2,204 mIU/mL at Month 7 (N = 110). An alternate 3-dose schedule (20 mcg/1 mL given at 0, 1, and 2 months) designed for certain populations (e.g., individuals who have or might have been recently exposed to the virus and travelers to high-risk areas) was also evaluated. At Month 3 (1 month after third dose), 99% of all individuals were seroprotected and remained protected through Month 12. On the alternate schedule, a fourth dose of ENGERIX-B (20 mcg/1 mL) at 12 months produced a GMT of 9,163 mIU/mL at Month 13 (1 month after fourth dose) (N = 373). Persons 40 Years of Age and Older Among subjects 40 years of age and older given ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months, the seroprotection rate 1 month after the third dose was 88% and the GMT for seroconverters was 610 mIU/mL (N = 50). In adults older than 40 years of age, ENGERIX-B produced anti-HBsAg antibody titers that were lower than those in younger adults. Interchangeability With Other Hepatitis B Vaccines A controlled study (N = 48) demonstrated that completion of a course of immunization with 1 dose of ENGERIX-B (20 mcg/1 mL) at Month 6 following 2 doses of RECOMBIVAX HB® (10 mcg) at Months 0 and 1 produced a similar GMT (4,077 mIU/mL) to immunization with 3 doses of RECOMBIVAX HB (10 mcg) at Months 0, 1, and 6 (GMT: 2,654 mIU/mL). Thus, ENGERIX-B can be used to complete a vaccination course initiated with RECOMBIVAX HB.8 REFERENCES 5. Centers for Disease Control and Prevention. 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);1-25. 6. Andre FE, Safary A. Clinical experience with a yeast-derived hepatitis B vaccine. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York, NY: Alan R Liss, Inc.; 1988:1025-1030. 7. Poovorawan Y, Sanpavat S, Pongpunlert W, et al. Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers. JAMA. 1989;261(22):3278- 3281. 8. Bush LM, Moonsammy GI, Boscia JA. Evaluation of initiating a hepatitis B vaccination schedule with one vaccine and completing it with another. Vaccine. 1991;9(11):807-809.

Find Lowest Prices on Nabi-HB® Hepatitis B Immune Globulin (Human) Solvent/Detergent Treated and Filtered DESCRIPTION Hepatitis B Immune Globulin (Human), Nabi-HB (hepatitis b vaccine recombinant) , is a sterile solution of immunoglobulin (5 ± 1% protein) containing antibodies to hepatitis B surface antigen (anti-HBs). It is prepared from plasma donated by individuals with high titers of anti-HBs. The plasma is processed using a modified Cohn 6 / Oncley 9 cold-alcohol fractionation process1,2 with two added viral reduction steps described below. Nabi-HB (hepatitis b vaccine recombinant) is formulated in 0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate 80, at pH 6.2. The product is supplied as a nonturbid sterile liquid in single dose vials and appears as clear to opalescent. It contains no preservative and is intended for single use by the intramuscular route only. The manufacturing steps for Nabi-HB (hepatitis b vaccine recombinant) are designed to reduce the risk of transmission of viral disease. The solvent/detergent treatment step, using tri-n-butyl phosphate and Triton® X-100, is effective in inactivating known enveloped viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)3. Virus filtration, using a Planova® 35 nm Virus Filter, is effective in reducing some known enveloped and non-enveloped viruses4. The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in the following table: Table 1 : Log Reduction of Test Viruses5 Test Virus HIV BVD PRV EMC PPV Model Virus: HIV HCV HBV Hepatitis A PVB19 Envelope/Genome: yes/RNA yes/RNA yes/DNA no/RNA no/DNA Manufacturing Step Precipitation of Cohn Fraction III > 5.9 3.6 3.7 4.4 3.9 Cuno Filtration NT NT NT > 6.6 5.4 Solvent/Detergent > 4.2 > 6.9 > 6.4 NT NT Nanofiltration > 7.4 > 6.9 > 5.7 3.0 0.7 * Cumulative > 17.5 > 17.4 > 15.8 > 14.0 9.3 BVD = Bovine Viral Diarrhea Virus EMC = Encephalomyocarditis Virus HIV = Human Immunodeficiency Virus PVB19 = Parvovirus B19 PPV = Porcine Parvovirus PRV = Pseudorabies Virus NT = not tested * Value not included in cumulative clearance Product potency is expressed in international units (IU) by comparison to the World Health Organization (WHO) standard. Each milliliter (mL) of product contains greater than 312 IU anti-HBs. The potency of each milliliter of Nabi-HB (hepatitis b vaccine recombinant) exceeds the potency of anti-HBs in a U.S. reference hepatitis B immune globulin (FDA). The U.S. reference has been tested by Nabi® Biopharmaceuticals against the WHO standard and found to be equal to 208 IU/mL. REFERENCES 1. Cohn E.J., Strong W.L., Mulford D.J., Ashworth J.N., Melin M., Taylor H.L. Preparation and Properties of Serum and Plasma Proteins IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946, 68: 459-475. 2. Oncley J.L, Melin M, Richert D.A, Cameron J. W, Gross P.M. The separation of antibodies, isoagglutinins, prothrombin, plasminogen and b1-lipoproteins into sub-fractions of human plasma. J Am Chem Soc 1949, 71:541-550. 3. 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. 4. Burnouf T: Value of virus filtration as method for improving the safety of plasma products. Vox Sang 1996; 70:235-236. 5. Unpublished data on file, Viral Validation Study Reports, Nabi® Biopharmaceuticals.

ENGERIX-B [Hepatitis B Vaccine (Recombinant)] Vaccine DESCRIPTION ENGERIX-B [Hepatitis B Vaccine (Recombinant)] is a sterile suspension of noninfectious hepatitis B virus surface antigen (HBsAg) for intramuscular administration. It contains purified surface antigen of the virus obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus. The HBsAg expressed in the cells is purified by several physicochemical steps and formulated as a suspension of the antigen adsorbed on aluminum hydroxide. The procedures used to manufacture ENGERIX-B result in a product that contains no more than 5% yeast protein. Each 0.5-mL pediatric/adolescent dose contains 10 mcg of HBsAg adsorbed on 0.25 mg aluminum as aluminum hydroxide. Each 1-mL adult dose contains 20 mcg of HBsAg adsorbed on 0.5 mg aluminum as aluminum hydroxide. ENGERIX-B contains the following excipients: Sodium chloride (9 mg/mL) and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/mL; sodium dihydrogen phosphate dihydrate, 71 mg/mL). ENGERIX-B is available in vials and prefilled syringes. The tip caps of the prefilled syringes may contain natural rubber latex; the plungers are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex. ENGERIX-B is formulated without preservatives.

INDICATIONS Nabi-HB, Hepatitis B Immune Globulin (Human), is indicated for 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. Perinatal Exposure of Infants Born to HBsAg-positive Mothers Infants born to mothers positive for HBsAg with or without HBeAg12. Sexual Exposure to HBsAg-positive Persons Sexual partners of HBsAg-positive persons. 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. Nabi-HB (hepatitis b vaccine recombinant) is indicated for intramuscular use only. DOSAGE AND ADMINISTRATION This product is for intramuscular use only. The use of this product by the intravenous route is not indicated. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. It is important to use a separate vial, sterile syringe, and needle for each individual patient, in order to prevent transmission of infectious agents from one person to another. Any vial of Nabi-HB, 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. 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 vaccine11. 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 Hepatitis B Immune Globulin (Human) should be given as soon as possible after exposure, as its value after seven days following exposure is unclear12. 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 Hepatitis B Immune Globulin (Human) should be given one month after the first dose12. Table 2 : Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure12 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&Daffer;, Hepatitis B Immune Globulin (Human) X 1 immediately plus either HB vaccine booster dose or second dose of Hepatitis B Immune Globulin (Human) one month later§ Known Source - High Risk for HBsAg-positive 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 either HB vaccine booster dose or second dose of Hepatitis B Immune Globulin (Human) one 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 (Human) dose of 0.06 mL/kg IM. † See manufacturers' recommendation for appropriate dose. ‡ Less than 10 mIU/mL anti-HBs by radioimmunoassay, negative by enzyme immunoassay. § Two doses of Hepatitis B Immune Globulin (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 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 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 Hepatitis B Immune Globulin (Human) as soon as possible and within seven days of birth; however, the efficacy of Hepatitis B Immune Globulin (Human) administered after 48 hours of age is not known10,19. 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 protected12. Table 3 : Recommended Schedule of Hepatitis B Immunoprophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus Infection 19 Age of Infant Administer Infant Born to mother known to be HBsAg-positive Infant born to mother not screened for HBsAg First Vaccination* Birth (within 12 hours) Birth (within 12 hours) Hepatitis B Immune Globulin (Human)† 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 IM at a site different from that used for the vaccine. ‡See ACIP recommendation. Sexual Exposure to HBsAg-positive Persons All susceptible persons whose sexual partners have acute hepatitis B infection should receive a single dose of Hepatitis B Immune Globulin (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 Hepatitis B Immune Globulin (Human) may improve the efficacy of post exposure treatment. The vaccine has the added advantage of conferring long-lasting protection19. Household Exposure to Persons with Acute HBV Infection Prophylaxis of an infant less than 12 months of age with 0.5 mL 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 vaccine19. HOW SUPPLIED Nabi-HB, Hepatitis B Immune Globulin (Human), is supplied as: NDC Number Contents 59730-4202-1 a carton containing a 1 mL dose in a single-use vial ( > 312 IU) and 59730-4204-1 package insert 59730-4203-1 a carton containing a 5 mL dose in a single-use vial ( > 1560 IU) and 59730-4205-1 package insert Storage Refrigerate between 2 to 8 °C (36 to 46 °F). Do not freeze. Do not use after expiration date. Use within 6 hours after the vial has been entered. REFERENCES 10.Beasley RP, et al.: Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo - controlled trial. Hepatology 1983; 3:135-141. 11.Szmuness W, et al.: Passive active immunisation against hepatitis B: Immunogenicity studies in adult Americans. Lancet 1981; 1:575-577. 12.Centers for Disease Control: Recommendations for protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1985; 34(22):313-335. 19.Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40(13):1-25. Manufactured by: Nabi® Biopharmaceuticals Boca Raton, FL 33487. June 2003.

INDICATIONS ENGERIX-B® is indicated for immunization against infection caused by all known subtypes of hepatitis B virus. DOSAGE AND ADMINISTRATION For intramuscular administration. See below for subcutaneous administration in persons at risk of hemorrhage. Preparation For Administration Shake well before use. With thorough agitation, ENGERIX-B is a homogeneous, turbid white suspension. Do not administer if it appears otherwise. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. For the prefilled syringes, attach a sterile needle and administer intramuscularly. For the vials, use a sterile needle and sterile syringe to withdraw the vaccine dose and administer intramuscularly. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. Use a separate sterile needle and syringe for each individual. Administration ENGERIX-B should be administered by intramuscular injection. The preferred administration site is the anterolateral aspect of the thigh for infants younger than 1 year and the deltoid muscle in older children (whose deltoid is large enough for an intramuscular injection) and adults. ENGERIX-B should not be administered in the gluteal region; such injections may result in suboptimal response. ENGERIX-B may be administered subcutaneously to persons at risk of hemorrhage (e.g., hemophiliacs). However, hepatitis B vaccines administered subcutaneously are known to result in a lower antibody response. Additionally, when other aluminum-adsorbed vaccines have been administered subcutaneously, an increased incidence of local reactions including subcutaneous nodules has been observed. Therefore, subcutaneous administration should be used only in persons who are at risk of hemorrhage with intramuscular injections. Do not administer this product intravenously or intradermally. Recommended Dose And Schedule Persons from Birth through 19 Years of Age Primary immunization for infants (born of hepatitis B surface antigen [HBsAg]-negative or HBsAg-positive mothers), children (birth through 10 years of age), and adolescents (11 through 19 years of age) consists of a series of 3 doses (0.5 mL each) given on a 0-, 1-, and 6-month schedule. Persons 20 Years of Age and Older Primary immunization for persons 20 years of age and older consists of a series of 3 doses (1 mL each) given on a 0-, 1-, and 6-month schedule. Adults on Hemodialysis Primary immunization consists of a series of 4 doses (2 mL each) given as a single 2-mL dose or two 1-mL doses on a 0-, 1-, 2-, and 6-month schedule. In hemodialysis patients, antibody response is lower than in healthy persons and protection may persist only as long as antibody levels remain above 10 mIU/mL. Therefore, the need for booster doses should be assessed by annual antibody testing. A 2-mL booster dose (as a single 2-mL dose or two 1-mL doses) should be given when antibody levels decline below 10 mIU/mL.1 [See Clinical Studies] Table 1: Recommended Dosage and Administration Schedules Group Dosea Schedules Infants born of: HBsAg-negative mothers 0.5 mL 0, 1, 6 months HBsAg-positive mothersb 0.5 mL 0, 1, 6 months Children: Birth through 10 years of age 0.5 mL 0, 1, 6 months Adolescents: 11 through 19 years of age 0.5 mL 0, 1, 6 months Adults: 20 years of age and older 1 mL 0, 1, 6 months Adults on hemodialysis 2 mLc 0, 1, 2, 6 months HBsAg = Hepatitis B surface antigen. a 0.5 mL (10 mcg); 1 mL (20 mcg). b Infants born to HBsAg-positive mothers should receive vaccine and hepatitis B immune globulin (HBIG) within 12 hours after birth [see section below on Known or Presumed Exposure to Hepatitis B Virus]. c Given as a single 2-mL dose or as two 1-mL doses. Alternate Dosing Schedules There are alternate dosing and administration schedules which may be used for specific populations (e.g., neonates born of hepatitis B-infected mothers, persons who have or might have been recently exposed to the virus, and travelers to high-risk areas) (Table 2). For some of these alternate schedules, an additional dose at 12 months is recommended for prolonged maintenance of protective titers. Table 2: Alternate Dosage and Administration Schedules Group Dosea Schedules Infants born of: HBsAg-positive mothersb 0.5 mL 0, 1, 2, 12 months Children: Birth through 10 years of age 0.5 mL 0, 1, 2, 12 months 5 through 10 years of age 0.5 mL 0, 12, 24 monthsc Adolescents: 11 through 16 years of age 0.5 mL 0, 12, 24 monthsc 11 through 19 years of age 1 mL 0, 1, 6 months 11 through 19 years of age 1 mL 0, 1, 2, 12 months Adults: 20 years of age and older 1 mL 0, 1, 2, 12 months HBsAg = Hepatitis B surface antigen. a 0.5 mL (10 mcg); 1 mL (20 mcg). b Infants born to HBsAg-positive mothers should receive vaccine and hepatitis B immune globulin (HBIG) within 12 hours after birth [seesection below on Known or Presumed Exposure to Hepatitis B Virus]. c For children and adolescents for whom an extended administration schedule is acceptable based on risk of exposure. Booster Vaccinations Whenever administration of a booster dose is appropriate, the dose of ENGERIX-B is 0.5 mL for children 10 years of age and younger and 1 mL for persons 11 years of age and older. Studies have demonstrated a substantial increase in antibody titers after booster vaccination with ENGERIX-B. See above for information on booster vaccination for adults on hemodialysis. Known Or Presumed Exposure To Hepatitis B Virus Persons with known or presumed exposure to the hepatitis B virus (e.g., neonates born of infected mothers, persons who experienced percutaneous or permucosal exposure to the virus) should be given hepatitis B immune globulin (HBIG) in addition to ENGERIX-B in accordance with Advisory Committee on Immunization Practices recommendations and with the package insert for HBIG. ENGERIX-B can be given on either dosing schedule (0, 1, and 6 months or 0,2, and 12 months). HOW SUPPLIED Dosage Forms And Strengths ENGERIX-B is a sterile suspension available in the following presentations: 0.5-mL (10 mcg) single-dose vials and prefilled TIP-LOK® syringes 1-mL (20 mcg) single-dose vials and prefilled TIP-LOK syringes [See DESCRIPTION, and Storage and Handling] Storage And Handling ENGERIX-B is available in single-dose vials and prefilled disposable TIP-LOK syringes (packaged without needles) (Preservative-Free Formulation): 10-mcg/0.5 mL Pediatric/Adolescent Dose NDC 58160-820-01 Vial in Package of 10: NDC 58160-820-11 NDC 58160-820-43 Syringe in Package of 10: NDC 58160-820-52 20-mcg/mL Adult Dose NDC 58160-821-01 Vial in Package of 10: NDC 58160-821-11 NDC 58160-821-05 Syringe in Package of 1: NDC 58160-821-34 NDC 58160-821-43 Syringe in Package of 10: NDC 58160-821-52 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze; discard if product has been frozen. Do not dilute to administer. REFERENCES 1. Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W, Wolfe C, Humiston S, Nelson R, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 6th ed. Atlanta, GA: Public Health Foundation; 2000:207-229. Manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium. Distributed by GlaxoSmithKline Research Triangle Park, NC 27709

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

OVERDOSE Although no data are available, clinical experience reported with other human immune globulins suggests that the only manifestations of overdose with Nabi-HB, Hepatitis B Immune Globulin (Human), would be pain and tenderness at the injection site. CONTRAINDICATIONS Individuals known to have had an anaphylactic or severe systemic reaction to human globulin should not receive Nabi-HB, Hepatitis B Immune Globulin (Human), or any other human immune globulin. Nabi-HB (hepatitis b vaccine recombinant) contains less than 100 micrograms per mL IgA. Individuals who are deficient in IgA may have the potential to develop IgA antibodies and have an anaphylac-toid reaction. The physician must weigh the potential benefit of treatment with Nabi-HB (hepatitis b vaccine recombinant) against the potential for hypersensitivity reactions.

OVERDOSE No information provided. CONTRAINDICATIONS Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B-containing vaccine, or to any component of ENGERIX-B, including yeast, is a contraindication to administration of ENGERIX-B [see DESCRIPTION].

SIDE EFFECTS Fifty male and female volunteers received Nabi-HB, Hepatitis B Immune Globulin (Human), intramuscularly in pharmacokinetics trials20. The number of patients with reactions related to the administration of Nabi-HB (hepatitis b vaccine recombinant) included local reactions such as erythema 6 (12%) and ache 2 (4%) at the injection site, as well as systemic reactions such as headache 7 (14%), myal-gia 5 (10%), malaise 3 (6%), nausea 2 (4%), and vomiting 1 (2%). The majority (92%) of reactions were reported as mild. The following adverse events were reported in the phar-macokinetics trials and were considered probably related to Nabi-HB (hepatitis b vaccine recombinant) : elevated alkaline phos-phatase 2 (4%), ecchymosis 1 (2%), joint stiffness 1 (2%), elevated AST 1 (2%), decreased WBC 1 (2%), and elevated creatinine 1 (2%). All adverse events were mild in intensity. There were no serious adverse events. No anaphylactic reactions with Nabi-HB (hepatitis b vaccine recombinant) have been reported. However, these reactions, although rare, have been reported following the injection of human immune globulins23. DRUG INTERACTIONS Vaccination with live virus vaccines should be deferred until approximately three months after administration of Nabi-HB, Hepatitis B Immune Globulin (Human). It may be necessary to revaccinate persons who received Nabi-HB (hepatitis b vaccine recombinant) shortly after live virus vaccination. There are no available data on concomitant use of Nabi-HB (hepatitis b vaccine recombinant) and other drugs; therefore, Nabi-HB (hepatitis b vaccine recombinant) should not be mixed with other drugs. REFERENCES 20. Data on file, Nabi® Biopharmaceuticals 23. Ellis EF, Henney CS: Adverse reactions following administration of human gamma globulin. J Allerg 1969; 43:45-54.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The most common solicited adverse events were injection site soreness (22%) and fatigue (14%). In 36 clinical studies, a total of 13,495 doses of ENGERIX-B were administered to 5,071 healthy adults and children who were initially seronegative for hepatitis B markers, and healthy neonates. All subjects were monitored for 4 days post-administration. Frequency of adverse events tended to decrease with successive doses of ENGERIX-B. Using a symptom checklist, the most frequently reported adverse events were injection site soreness (22%) and fatigue (14%). Other events are listed below. Parent or guardian completed forms for children and neonates. Neonatal checklist did not include headache, fatigue, or dizziness. Incidence 1% to 10% of Injections Nervous System Disorders: Dizziness, headache. General Disorders and Administration Site Conditions: Fever ( > 37.5°C), injection site erythema, injection site induration, injection site swelling. Incidence < 1% of Injections Infections and Infestations: Upper respiratory tract illnesses. Blood and Lymphatic System Disorders: Lymphadenopathy. Metabolism and Nutrition Disorders: Anorexia. Psychiatric Disorders: Agitation, insomnia. Nervous System Disorders: Somnolence, tingling. Vascular Disorders: Flushing, hypotension. Gastrointestinal Disorders: Abdominal pain/cramps, constipation, diarrhea, nausea, vomiting. Skin and Subcutaneous Tissue Disorders: Erythema, petechiae, pruritus, rash, sweating, urticaria. Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, myalgia, pain/stiffness in arm, shoulder, or neck. General Disorders and Administration Site Conditions: Chills, influenza-like symptoms, injection site ecchymosis, injection site pain, injection site pruritus, irritability, malaise, weakness. In a clinical trial, 416 adults with type 2 diabetes and 258 control subjects without type 2 diabetes who were seronegative for hepatitis B markers received at least one dose of ENGERIX-B. Subjects were monitored for solicited adverse events for 4 days following each vaccination. The most frequently reported solicited adverse events in the entire study population were injection site pain (reported in 39% of diabetic subjects and 45% of control subjects) and fatigue (reported in 29% of diabetic subjects and 27% of control subjects). Serious adverse events were monitored through 30 days following the last vaccination. Serious adverse events (SAEs) occurred in 3.8% of diabetic subjects and 1.6% of controls. No SAEs were deemed related to ENGERIX-B. Postmarketing Experience In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for ENGERIX-B since market introduction (1990) are listed below. This list includes serious adverse events or events that have a suspected causal connection to components of ENGERIX-B. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Infections and Infestations Herpes zoster, meningitis. Blood and Lymphatic System Disorders Thrombocytopenia. Immune System Disorders Allergic reaction, anaphylactoid reaction, anaphylaxis. An apparent hypersensitivity syndrome (serum sickness-like) of delayed onset has been reported days to weeks after vaccination, including: arthralgia/arthritis (usually transient), fever, and dermatologic reactions such as urticaria, erythema multiforme, ecchymoses, and erythema nodosum. Nervous System Disorders Encephalitis, encephalopathy, migraine, multiple sclerosis, neuritis, neuropathy including hypoesthesia, paresthesia, Guillain-Barre syndrome and Bell's palsy, optic neuritis, paralysis, paresis, seizures, syncope, transverse myelitis. Eye Disorders Conjunctivitis, keratitis, visual disturbances. Ear and Labyrinth Disorders Earache, tinnitus, vertigo. Cardiac Disorders Palpitations, tachycardia. Vascular Disorders Vasculitis. Respiratory, Thoracic, and Mediastinal Disorders Apnea, bronchospasm including asthma-like symptoms. Gastrointestinal Disorders Dyspepsia. Skin and Subcutaneous Tissue Disorders Alopecia, angioedema, eczema, erythema multiforme including Stevens-Johnson syndrome, erythema nodosum, lichen planus, purpura. Musculoskeletal and Connective Tissue Disorders Arthritis, muscular weakness. General Disorders and Administration Site Conditions Injection site reaction. Investigations Abnormal liver function tests. DRUG INTERACTIONS Concomitant Administration With Vaccines And Immune Globulin ENGERIX-B may be administered concomitantly with immune globulin. When concomitant administration of other vaccines or immune globulin is required, they should be given with different syringes and at different injection sites. Do not mix ENGERIX-B with any other vaccine or product in the same syringe or vial. Interference With Laboratory Tests Hepatitis B surface antigen (HBsAg) derived from hepatitis B vaccines has been transiently detected in blood samples following vaccination. Serum HBsAg detection may not have diagnostic value within 28 days after receipt of a hepatitis B vaccine, including ENGERIX-B.

WARNINGS In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, Nabi-HB, Hepatitis B Immune Globulin (Human), should be given only if the expected benefits outweigh the potential risks. Nabi-HB is made from human plasma. Products made from human plasma may contain infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) 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 viral infections, and by inactivating and/or reducing certain viruses. The Nabi-HB (hepatitis b vaccine recombinant) 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. Nabi-HB (hepatitis b vaccine recombinant) is filtered using a Planova® 35 nm 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 possibly to have been transmitted by this product should be reported by the physician or other health care provider to Nabi® Biopharmaceuticals at 1-800-458-4244. The physician should discuss the risks and benefits of this product with the patient. PRECAUTIONS General Nabi-HB, Hepatitis B Immune Globulin (Human), must be administered only intramuscularly for post-exposure prophylaxis. The preferred sites for intramuscular injections are the anterolateral aspect of the upper thigh and the deltoid muscle. If the buttock is used due to the volume to be injected, the central region should be avoided; only the upper, outer quadrant should be used, and the needle should be directed anterior (i.e., not inferior or perpendicular to the skin) to minimize the possibility of involvement with the sciatic nerve22. The 50 healthy volunteers who received Nabi-HB (hepatitis b vaccine recombinant) in pharmacokinetic studies were followed for 84 days for possible development of anti-HCV antibodies. No subject seroconverted. Pregnancy Category C Animal reproduction studies have not been conducted with Nabi-HB (hepatitis b vaccine recombinant) . It is also not known whether Nabi-HB (hepatitis b vaccine recombinant) can cause fetal harm when administered to a pregnant woman or can affect a woman's ability to conceive. Nabi-HB (hepatitis b vaccine recombinant) should be given to a pregnant woman only if clearly indicated. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nabi-HB (hepatitis b vaccine recombinant) is administered to a nursing mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established for Nabi-HB (hepatitis b vaccine recombinant) . However, the safety and effectiveness of similar hepatitis B immune globulins have been demonstrated in infants and children12. Geriatric Use Clinical studies of Nabi-HB (hepatitis b vaccine recombinant) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. REFERENCES 12. Centers for Disease Control: Recommendations for protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1985; 34(22):313-335. 22. Centers for Disease Control: General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1994; 43:1-38.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Latex The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. Syncope Syncope (fainting) can occur in association with administration of injectable vaccines, including ENGERIX-B. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. Infants Weighing Less than 2,000 g At Birth Hepatitis B vaccine should be deferred for infants with a birth weight < 2,000 g if the mother is documented to be HBsAg negative at the time of the infant's birth. Vaccination can commence at chronological age 1 month or hospital discharge. Infants born weighing < 2,000 g to HBsAg- positive mothers should receive vaccine and hepatitis B immune globulin (HBIG) within 12 hours after birth. Infants born weighing < 2,000 g to mothers of unknown HBsAg status should receive vaccine and HBIG within 12 hours after birth if the mother's HBsAg status cannot be determined within the first 12 hours of life. The birth dose in infants born weighing < 2,000 g should not be counted as the first dose in the vaccine series and it should be followed with a full 3-dose standard regimen (total of 4 doses).2 [See DOSAGE AND ADMINISTRATION.] Apnea In Premature Infants Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including ENGERIX-B, to infants born prematurely should be based on consideration of the infant's medical status, and the potential benefits and possible risks of vaccination. For ENGERIX-B, this assessment should include consideration of the mother's hepatitis B antigen status and the high probability of maternal transmission of hepatitis B virus to infants born of mothers who are HBsAg positive if vaccination is delayed. Preventing And Managing Allergic Vaccine Reactions Prior to immunization, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur. [See CONTRAINDICATIONS] Moderate Or Severe Acute Illness To avoid diagnostic confusion between manifestations of an acute illness and possible vaccine adverse effects, vaccination with ENGERIX-B should be postponed in persons with moderate or severe acute febrile illness unless they are at immediate risk of hepatitis B infection (e.g., infants born of HBsAg-positive mothers). Altered Immunocompetence Immunocompromised persons may have a diminished immune response to ENGERIX-B, including individuals receiving immunosuppressant therapy. Multiple Sclerosis Results from 2 clinical studies indicate that there is no association between hepatitis B vaccination and the development of multiple sclerosis3, and that vaccination with hepatitis B vaccine does not appear to increase the short-term risk of relapse in multiple sclerosis.4 Limitations Of Vaccine Effectiveness Hepatitis B has a long incubation period. ENGERIX-B may not prevent hepatitis B infection in individuals who had an unrecognized hepatitis B infection at the time of vaccine administration. Additionally, it may not prevent infection in individuals who do not achieve protective antibody titers. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility ENGERIX-B has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with ENGERIX-B. It is also not known whether ENGERIX-B can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ENGERIX-B should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether ENGERIX-B is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ENGERIX-B is administered to a nursing woman. Pediatric Use Safety and effectiveness of ENGERIX-B have been established in all pediatric age groups. Maternally transferred antibodies do not interfere with the active immune response to the vaccine. [See ADVERSE REACTIONS, Clinical Studies] The timing of the first dose in infants weighing less than 2,000 g at birth depends on the HBsAg status of the mother. [See WARNINGS AND PRECAUTIONS] Geriatric Use Clinical studies of ENGERIX-B used for licensure did not include sufficient numbers of subjects years of age and older to determine whether they respond differently from younger subjects. However, in later studies it has been shown that a diminished antibody response and seroprotective levels can be expected in persons older than 60 years of age.5 [See Clinical Studies] REFERENCES 2. Centers for Disease Control and Prevention. A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: Immunization of Infants, Children, and Adolescents, MMWR 2005;54(RR-16);1-23. 3.. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. NEngl JMed. 2001;344(5):327-332. 4. Confavreux C, Suissa S, Saddier P, et al. Vaccination and the risk of relapse in multiple sclerosis. N Engl J Med. 2001-344(5):319-326. 5. Centers for Disease Control and Prevention. 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);1-25.