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CLINICAL PHARMACOLOGY Mechanism Of Action VAQTA has been shown to elicit antibodies to hepatitis A as measured by ELISA. Protection from hepatitis A disease has been shown to be related to the presence of antibody. However, the lowest titer needed to confer protection has not been determined. Clinical Studies Efficacy Of VAQTA: The Monroe Clinical Study The immunogenicity and protective efficacy of VAQTA were evaluated in a randomized, double-blind, placebo-controlled study involving 1037 susceptible healthy children and adolescents 2 through 16 years of age in a U.S. community with recurrent outbreaks of hepatitis A (The Monroe Efficacy Study). All of these children were Caucasian, and there were 51.5% male and 48.5% female. Each child received an intramuscular dose of VAQTA (25U) (N=519) or placebo (alum diluent) (N=518). Among those individuals who were initially seronegative (measured by a modification of the HAVAB radioimmunoassay [RIA]), seroconversion was achieved in > 99% of vaccine recipients within 4 weeks after vaccination. The onset of seroconversion following a single dose of VAQTA was shown to parallel the onset of protection against clinical hepatitis A disease. Because of the long incubation period of the disease (approximately 20 to 50 days, or longer in children), clinical efficacy was based on confirmed cases6 of hepatitis A occurring ≥ 50 days after vaccination in order to exclude any children incubating the infection before vaccination. In subjects who were initially seronegative, the protective efficacy of a single dose of VAQTA was observed to be 100% with 21 cases of clinically confirmed hepatitis A occurring in the placebo group and none in the vaccine group (p < 0.001). The number of clinically confirmed cases of hepatitis A ≥ 30 days after vaccination were also compared. In this analysis, 28 cases of clinically confirmed hepatitis A occurred in the placebo group while none occurred in the vaccine group ≥ 30 days after vaccination. In addition, it was observed in this trial that no cases of clinically confirmed hepatitis A occurred in the vaccine group after day 16.7 Following demonstration of protection with a single dose and termination of the study, a booster dose was administered to a subset of vaccinees 6, 12, or 18 months after the primary dose. No cases of clinically confirmed hepatitis A disease ≥ 50 days after vaccination have occurred in those vaccinees from The Monroe Efficacy Study monitored for up to 9 years. Other Clinical Studies The efficacy of VAQTA in other age groups was based upon immunogenicity measured 4 to 6 weeks following vaccination. VAQTA was found to be immunogenic in all age groups. Children — 12 through 23 Months of Age In a clinical trial, children 12 through 23 months of age were randomized to receive the first dose of VAQTA with or without M-M-R II and VARIVAX (N=617) and the second dose of VAQTA with or without Tripedia and optionally either oral poliovirus vaccine (no longer licensed in the US) or IPOL(N=555). The race distribution of study subjects who received at least one dose of VAQTA was as follows: 56.7% Caucasian; 17.5% Hispanic-American; 14.3% African-American; 7.0% Native American; 3.4% other; 0.8% Oriental; 0.2% Asian; and 0.2% Indian. The distribution of subjects by gender was 53.6% male and 46.4% female. In the analysis population, there were 471 initially seronegative children 12 through 23 months of age, who received the first dose of VAQTA with (N=237) or without (N=234) M-M-R II and VARIVAX of whom 96% (95% CI: 93.7%, 97.5%) seroconverted (defined as having an anti-HAV titer ≥ 10 mIU/mL) post dose 1 with an anti-HAV GMT of 48 mIU/mL (95% CI: 44.7, 51.6). There were 343 children in the analysis population who received the second dose of VAQTA with (N=168) or without (N=175) Tripedia and optional oral poliovirus vaccine or IPOL of whom 100% (95% CI: 99.3%, 100%) seroconverted post dose 2 with an anti-HAV GMT of 6920 mIU/mL (95% CI: 6136, 7801). Of children who received only VAQTA at both visits, 100% (n=97) seroconverted after the second dose of VAQTA. In a clinical trial involving 653 healthy children 12 to 15 months of age, 330 were randomized to receive VAQTA, ProQuad, and pneumococcal 7-valent conjugate vaccine concomitantly, and 323 were randomized to receive ProQuad and pneumococcal 7-valent conjugate vaccine concomitantly followed by VAQTA 6 weeks later. The race distribution of the study subjects was as follows: 60.3% Caucasian; 21.6% African-American; 9.5% Hispanic-American; 7.2% other; 1.1% Asian/Pacific; and 0.3% Native American. The distribution of subjects by gender was 50.7% male and 49.3% female. In the analysis population, the seropositivity rate for hepatitis A antibody (defined as the percent of subjects with an anti-HAV titer ≥ 10 mIU/mL) was 100% (n=182; 95% CI: 98.0%, 100%) post dose 2 with an anti-HAV GMT of 4977 mIU/mL (95% CI: 4068, 6089) when VAQTA was given with ProQuad and pneumococcal 7-valent conjugate vaccine and 99.4% (n=159, 95% CI: 96.5%, 100%) post dose 2 with an anti-HAV GMT of 6123 mIU/mL (95% CI: 4826, 7770) when VAQTA alone was given. These seropositivity rates were similar whether VAQTA was administered with or without ProQuad and pneumococcal 7-valent conjugate vaccine. In an open, multicenter, randomized study involving 617 children 15 months of age, 306 were randomized to receive VAQTA with or without PedvaxHIB and INFANRIX, and 311 were randomized to receive VAQTA with or without PedvaxHIB. The race distribution of the study subjects was as follows: 63.9% Caucasian; 17.5% Hispanic-American; 14.7% Black; 2.6% other; and 1.3% Asian. The distribution of subjects by gender was 54.0% male and 46.0% female. The seropositivity rate for hepatitis A antibody (defined as the percent of subjects with an anti-HAV titer ≥ 10 mIU/mL) 4 weeks post dose 2 was 100% (n=208, 95% CI: 98.2%, 100.0%) in those who received VAQTA concomitantly with PedvaxHIB and INFANRIX or concomitantly with PedvaxHIB. In those subjects who received VAQTA alone, the seropositivity rate for hepatitis A antibody was 100% (n=183, 95% CI: 98.0%, 100.0%), regardless of baseline hepatitis A serostatus. Overall, the anti-HAV GMT in the concomitant groups was 3616.5 mIU/mL (95% CI: 3084.5, 4240.2). The anti-HAV GMT in the nonconcomitant groups was 4712.6 mIU/mL (95% CI: 3996.8, 5556.8). Comparable responses were observed in both the initially seronegative and seropositive subjects. In three combined clinical studies 1022 initially seronegative subjects received 2 doses of VAQTA alone or concomitantly with other vaccines. Of the seronegative subjects, 99.9% achieved an anti-HAV titer ≥ 10 mIU/mL (95% CI: 99.5%, 100%) and an anti-HAV GMT of 5392.1 mIU/mL (95% CI: 4996.5, 5819.0) 4 weeks following dose 2 of VAQTA. Children/Adolescents — 2 Years through 18 Years of Age Immunogenicity data were combined from eleven randomized clinical studies in children and adolescents 2 through 18 years of age who received VAQTA (25U/0.5 mL). These included administration of VAQTA in varying doses and regimens (N=404 received 25U/0.5 mL), the Monroe Efficacy Study (N=973), and comparison studies for process and formulation changes (N=1238). The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 84.8% Caucasian; 10.6% American Indian; 2.3% African-American; 1.5% Hispanic-American; 0.6% other; 0.2% Oriental. The distribution of subjects by gender was 51.2% male and 48.8% female. The proportions of subjects who seroconverted 4 weeks after the first and second doses administered 6 months apart were 97% (n=1230; 95% CI: 96%, 98%) and 100% (n=1057; 95% CI: 99.5%, 100%) of subjects with anti-HAV GMTs of 43 mIU/mL (95% CI: 40, 45) and 10,077 mIU/mL (95% CI: 9394, 10,810), respectively. Adults — 19 Years of Age and Older Immunogenicity data were combined from five randomized clinical studies in adults 19 years of age and older who received VAQTA (50U/1-mL). One single-blind study evaluated doses of VAQTA with varying amounts of viral antigen and/or alum content in healthy adults ≥ 170 pounds and ≥ 30 years of age (N=208 adults administered 50U/1-mL dose). One open-label study evaluated VAQTA given with immune globulin or alone (N=164 adults who received VAQTA alone). A third study was single-blind and evaluated 3 different lots of VAQTA (N=1112). The fourth study was single-blind and evaluated doses of VAQTA with varying amounts of viral antigen in healthy adults ≥ 170 pounds and ≥ 30 years of age (N=159 adults administered the 50U/1-mL dose). The fifth study was an open-label study to evaluate various regimens for time of administration of the booster dose of VAQTA (6, 12, and 18 months post dose 1, N=354). The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 93.2% Caucasian; 2.5% African-American; 2.1% Hispanic-American; 1.4% Oriental; 0.5% other; 0.3% American Indian. The distribution of subjects by gender was 44.8% male and 55.2% female. The proportion of subjects who seroconverted 4 weeks after the first and second doses administered 6 months apart was 95% (n=1411; 95% CI: 94%, 96%) and 99.9% (n=1244; 95% CI: 99.4%, 100%) with GMTs of 37 mIU/mL (95% CI: 35, 38) and 6013 mIU/mL (95% CI: 5592, 6467), respectively. Furthermore, at 2 weeks postvaccination, 69.2% (n=744; 95% CI: 65.7%, 72.5%) of adults seroconverted with an anti-HAV GMT of 16 mIU/mL after a single dose of VAQTA. Timing Of Booster Dose Administration Children/Adolescents — 2 through 18 Years of Age In the Monroe Efficacy Study, children were administered a second dose of VAQTA (25U/0.5 mL) 6, 12, or 18 months following the initial dose. For subjects who received both doses of VAQTA, the GMTs and proportions of subjects who seroconverted 4 weeks after the booster dose administered 6, 12, and 18 months after the first dose are presented in Table 9. Table 9 : Children/Adolescents from the Monroe Efficacy Study Seroconversion Rates (%) and Geometric Mean Titers (GMT) for Cohorts of Initially Seronegative Vaccinees at the Time of the Booster (25U) and 4 Weeks Later Months Following Initial 25U Dose Cohort* (n=960) 0 and 6 Months Cohort* (n=35) 0 and 12 Months Cohort* (n=39) 0 and 18 Months Seroconversion Rate GMT (mIU/mL) (95% CI) 6 97% 107 (98, 117) __ __ 7 100% 10433 (9681, 11243) __ __ 12 __ 91% 48 (33, 71) __ 13 __ 100% 12308 (9337, 16226) __ 18 __ __ 90% 50 (28, 89) 19 __ __ 100% 9591 (7613, 12082) * Blood samples were taken at prebooster and postbooster time points. Adults — 19 years of age and older Among the 5 randomized clinical studies in adults 19 years of age and older described in Section 14.2, there were additional data in which a booster dose of VAQTA (50U/1-mL) was administered 12 or 18 months after the first dose. For subjects in these studies who received both doses of VAQTA, the proportions who seroconverted 4 weeks after the booster dose administered 6, 12, and 18 months after the first dose were 100% of 1201 subjects, 98% of 91 subjects, and 100% of 84 subjects, respectively. GMTs in mIU/mL one month after the subjects received the booster dose at 6, 12, or 18 months after the primary dose were 5987 mIU/mL (95% CI: 5561, 6445), 4896 mIU/mL (95% CI: 3589, 6679), and 6043 mIU/mL (95% CI: 4687, 7793), respectively. Duration Of Immune Response In follow-up of subjects in The Monroe Efficacy Study, in children ( ≥ 2 years of age) and adolescents who received two doses (25U) of VAQTA, detectable levels of anti-HAV antibodies ( ≥ 10 mIU/mL) were present in 100% of subjects for at least 10 years postvaccination. In subjects who received VAQTA at 0 and 6 months, the GMT was 819 mIU/mL (n=175) at 2.5 to 3.5 years and 505 mIU/mL (n=174) at 5 to 6 years, and 574 mIU/mL (n=114) at 10 years postvaccination. In subjects who received VAQTA at 0 and 12 months, the GMT was 2224 mIU/mL (n=49) at 2.5 to 3.5 years, 1191 mIU/mL (n=47) at 5 to 6 years, and 1005 mIU/mL (n=36) at 10 years postvaccination. In subjects who received VAQTA at 0 and 18 months, the GMT was 2501 mIU/mL (n=53) at 2.5 to 3.5 years, 1614 mIU/mL (n=56) at 5 to 6 years, and 1507 mIU/mL (n=41) at 10 years postvaccination. In adults that were administered VAQTA at 0 and 6 months, the hepatitis A antibody response to date has been shown to persist at least 6 years. Detectable levels of anti-HAV antibodies ( ≥ 10 mIU/mL) were present in 100% (378/378) of subjects with a GMT of 1734 mIU/mL at 1 year, 99.2% (252/254) of subjects with a GMT of 687 mIU/mL at 2 to 3 years, 99.1% (219/221) of subjects with a GMT of 605 mIU/mL at 4 years, and 99.4% (170/171) of subjects with a GMT of 684 mIU/mL at 6 years postvaccination. The total duration of the protective effect of VAQTA in healthy vaccinees is unknown at present. Concomitant Administration Of VAQTA and Immune Globulin The concurrent use of VAQTA (50U) and immune globulin (IG, 0.06 mL/kg) was evaluated in an open-label, randomized clinical study involving 294 healthy adults 18 to 39 years of age. Adults were randomized to receive 2 doses of VAQTA 24 weeks apart (N=129), the first dose of VAQTA concomitant with a dose of IG followed by the second dose of VAQTA alone 24 weeks later (N=135), or IG alone (N=30). The race distribution of the study subjects who received at least one dose of VAQTA or IG in this study was as follows: 92.3% Caucasian; 4.0% Hispanic-American; 3.0% African-American; 0.3% Native American; 0.3% Asian/Pacific. The distribution of subjects by gender was 28.7% male and 71.3% female. Table 10 provides seroconversion rates and geometric mean titers (GMTs) at 4 and 24 weeks after the first dose in each treatment group and at one month after a booster dose of VAQTA (administered at 24 weeks) [see DRUG INTERACTIONS]. Table 10 : Seroconversion Rates (%) and Geometric Mean Titers (GMT) After Vaccination with VAQTA Plus IG, VAQTA Alone, and IG Alone Weeks VAQTA plus IG VAQTA IG Seroconversion Rate GMT (mIU/mL) (95% CI) 4 100% 96% 87% 42 (39, 45) 38 (33, 42) 19 (15, 23) (n=129) (n=135) (n=30) 24 92% 97%* 0% 83 (65, 105) 137* (112, 169) Undetectable† (n=125) (n=132) (n=28) 28 100% 100% N/A 4872 (3716, 6388) (n=114) 6498 (5111, 8261) (n=128) *The seroconversion rate and the GMT in the group receiving VAQTA alone were significantly higher than in the group receiving VAQTA plus IG (p=0.05, p < 0.001, respectively). †Undetectable is defined as < 10mIU/mL. N/A = Not Applicable. Interchangeability Of The Booster Dose A randomized, double-blind clinical study in 537 healthy adults, 18 to 83 years of age, evaluated the immune response to a booster dose of VAQTA and HAVRIX given at 6 or 12 months following an initial dose of HAVRIX. Subjects were randomized to receive VAQTA (50U) as a booster dose 6 months (N=232) or 12 months (N=124) following an initial dose of HAVRIX or HAVRIX (1440 EL. U) as a booster dose 6 months (N=118) or 12 months (N=63) following an initial dose of HAVRIX. The race distribution of the study subjects who received the booster dose of VAQTA or HAVRIX in this study was as follows: 87.2% Caucasian; 8.0% African-American; 1.9% Hispanic-American; 1.3% Oriental; 0.9% Asian; 0.4% Indian; 0.4% other. The distribution of subjects by gender was 44.9% male and 55.1% female. When VAQTA was given as a booster dose following HAVRIX, the vaccine produced an adequate immune response (see Table 11) [see DOSAGE AND ADMINISTRATION]. Table 11 : Seropositivity Rate, Booster Response Rate* and Geometric Mean Titer 4 Weeks Following a Booster Dose of VAQTA or HAVRIX Administered 6 to 12 Months After First Dose of HAVRIX† First Dose Booster Dose Seropositivity Rate Booster Response Rate* Geometric Mean Titer HAVRIX VAQTA 99.7% (n=313) 86.1% (n=310) 3272 (n=313) 1440 EL.U. 50 U HAVRIX HAVRIX 99.3% (n=151) 80.1% (n=151) 2423 (n=151) 1440 EL.U. 1440 EL.U. *Booster Response Rate is defined as greater than or equal to a tenfold rise from prebooster to postbooster titer and postbooster titer ≥ 100 mIU/mL. †Study conducted in adults 18 years of age and older. Immune Response To Concomitantly Administered Vaccines Clinical Studies of VAQTA with M-M-R II, VARIVAX, and Tripedia In the clinical trial in which children 12 months of age received the first dose of VAQTA concomitantly with M-M-R II and VARIVAX described in Section 14.2, rates of seroprotection to hepatitis A were similar between the two groups who received VAQTA with or without M-M-R II and VARIVAX. Measles, mumps, and rubella immune responses were tested in 241 subjects, 263 subjects, and 270 subjects, respectively. Seropositivity rates were 98.8% [95% CI: 96.4%, 99.7%] for measles, 99.6% [95% CI: 97.9%, 100%] for mumps, and 100% [95% CI: 98.6%, 100%] for rubella, which were similar to observed historical rates (seropositivity rates 99% for all three antigens, with lower bound of the 95% CI > 89%) following vaccination with a first dose of M-M-R II in this age group. Data from this study were insufficient to adequately assess the immune response to VARIVAX administered concomitantly with VAQTA. In this same study, the second dose of VAQTA at 18 months of age was given with or without Tripedia (DTaP). Seropositivity rates for diphtheria and tetanus were similar to those in historical controls. However, data from this study were insufficient to assess the pertussis response of DTaP when administered with VAQTA. Rates of seroprotection to hepatitis A were similar between the two groups who received VAQTA with or without M-M-R II and VARIVAX, and between the two groups who received VAQTA with or without DTaP. Clinical Studies of VAQTA with ProQuad and Prevnar In the clinical trial of concomitant use of VAQTA with ProQuad and pneumococcal 7-valent conjugate vaccine in children 12 to 15 months of age described in Section 14.2, the antibody GMTs for S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F 6 weeks after vaccination with pneumococcal 7-valent conjugate vaccine administered concomitantly with ProQuad and VAQTA were non-inferior as compared to GMTs observed in the group given pneumococcal 7-valent conjugate vaccine with ProQuad alone (the lower bounds of the 95% CI around the fold-difference for the 7 serotypes excluded 0.5). For the varicella component of ProQuad, in subjects with baseline antibody titers < 1.25 gpELISA units/mL, the proportion with a titer ≥ 5 gpELISA units/mL 6 weeks after their first dose of ProQuad was non-inferior (defined as -10 percentage point change) when ProQuad was administered with VAQTA and pneumococcal 7-valent conjugate vaccine as compared to the proportion with a titer ≥ 5 gpELISA units/mL when ProQuad was administered with pneumococcal 7-valent conjugate vaccine alone (difference in seroprotection rate -5.1% [95% CI: -9.3, -1.4%]). Hepatitis A responses were similar when compared between the two groups who received VAQTA with or without ProQuad and pneumococcal 7-valent conjugate vaccine. Seroconversion rates and antibody titers for varicella and S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were similar between groups at 6 weeks postvaccination. Clinical Studies of VAQTA with INFANRIX and PedvaxHIB In the clinical trial of concomitant administration of VAQTA with INFANRIX and PedvaxHIB in children 15 months of age, described in Section 14.2, when the first dose of VAQTA was administered concomitantly with either INFANRIX and PedvaxHIB or PedvaxHIB, there was no interference in immune response to hepatitis A as measured by seropositivity rates after dose 2 of VAQTA compared to administration of both doses of VAQTA alone. When dose 1 of VAQTA was administered concomitantly with either PedvaxHIB and INFANRIX or PedvaxHIB, there was no interference in immune response to Haemophilus influenzae b (as measured by the proportion of subjects who attained an anti-polyribosylribitol phosphate antibody titer > 1.0 mcg/mL at 4 weeks after vaccination), compared to subjects receiving either PedvaxHIB and INFANRIX or PedvaxHIB. When VAQTA was administered concomitantly with INFANRIX and PedvaxHIB, there was no interference in immune responses at 4 weeks after vaccination to the pertussis antigens (PT, FHA, or pertactin, as measured by GMTs) and no interference in immune responses to diphtheria toxoid or tetanus toxoid (as measured by the proportion of subjects achieving an antibody titer > 0.1 IU/mL) compared to administration of INFANRIX and PedvaxHIB. Clinical Studies of VAQTA with Typhoid Vi Polysaccharide Vaccine and Yellow Fever Vaccine, Live Attenuated In the clinical trial of concomitant use of VAQTA with typhoid Vi polysaccharide and yellow fever vaccines in adults 18-54 years of age described in Section 6.1, the antibody response rates for typhoid Vi polysaccharide and yellow fever were adequate when typhoid Vi polysaccharide and yellow fever vaccines were administered concomitantly with (N=80) and nonconcomitantly without VAQTA (N=80). The seropositivity rate for hepatitis A when VAQTA, typhoid Vi polysaccharide, and yellow fever vaccines were administered concomitantly was generally similar to when VAQTA was given alone [see DRUG INTERACTIONS]. Data are insufficient to assess the immune response to VAQTA and poliovirus vaccine when administered concomitantly. REFERENCES 6 The clinical case definition included all of the following occurring at the same time: 1) one or more typical clinical signs or symptoms of hepatitis A (e.g., jaundice, malaise, fever ≥ 38.3°C); 2) elevation of hepatitis A IgM antibody (HAVAB-M); 3) elevation of alanine transferase (ALT) ≥ 2 times the upper limit of normal. 7 One vaccinee did not meet the pre-defined criteria for clinically confirmed hepatitis A but did have positive hepatitis A IgM and borderline liver enzyme (ALT) elevations on days 34, 50, and 58 after vaccination with mild clinical symptoms observed on days 49 and 50.

CLINICAL PHARMACOLOGY Mechanism Of Action The hepatitis A virus belongs to the picornavirus family. It is one of several hepatitis viruses that cause systemic disease with pathology in the liver. The incubation period for hepatitis A averages 28 days (range: 15 to 50 days).1 The course of hepatitis A infection is extremely variable, ranging from asymptomatic infection to icteric hepatitis and death. The presence of antibodies to HAV confers protection against hepatitis A infection. However, the lowest titer needed to confer protection has not been determined. Clinical Studies Pediatric Effectiveness Studies Protective efficacy with HAVRIX has been demonstrated in a double-blind, randomized controlled study in school children (age 1 to 16 years) in Thailand who were at high risk of HAV infection. A total of 40,119 children were randomized to be vaccinated with either HAVRIX 360 EL.U. or ENGERIX-B 10 mcg at 0, 1, and 12 months. Of these, 19,037 children received 2 doses of HAVRIX (0 and 1 months) and 19,120 children received 2 doses of control vaccine, ENGERIX-B (0 and 1 months). A total of 38,157 children entered surveillance at day 138 and were observed for an additional 8 months. Using the protocol-defined endpoint ( ≥ 2 days absence from school, ALT level > 45 U/mL, and a positive result in the HAVAB-M test), 32 cases of clinical hepatitis A occurred in the control group. In the HAVRIX group, 2 cases were identified. These 2 cases were mild in terms of both biochemical and clinical indices of hepatitis A disease. Thus the calculated efficacy rate for prevention of clinical hepatitis A was 94% (95% Confidence Interval [CI]: 74, 98). In outbreak investigations occurring in the trial, 26 clinical cases of hepatitis A (of a total of 34 occurring in the trial) occurred. No cases occurred in vaccinees who received HAVRIX. Using additional virological and serological analyses post hoc, the efficacy of HAVRIX was confirmed. Up to 3 additional cases of mild clinical illness may have occurred in vaccinees. Using available testing, these illnesses could neither be proven nor disproven to have been caused by HAV. By including these as cases, the calculated efficacy rate for prevention of clinical hepatitis A would be 84% (95% CI: 60, 94). Immunogenicity In Children And Adolescents Immune Response to HAVRIX 720 EL.U./0.5 mL at 11 to 25 Months of Age (Study HAV 210) In this prospective, open-label, multicenter study, 1,084 children were administered study vaccine in one of 5 groups: Children 11 to 13 months of age who received HAVRIX on a 0- and 6-month schedule; Children 15 to 18 months of age who received HAVRIX on a 0- and 6-month schedule; Children 15 to 18 months of age who received HAVRIX coadministered with INFANRIX and Haemophilus b (Hib) conjugate vaccine (no longer US-licensed) at month 0 and HAVRIX at month 6; Children 15 to 18 months of age who received INFANRIX coadministered with Hib conjugate vaccine at month 0 and HAVRIX at months 1 and 7; Children 23 to 25 months of age who received HAVRIX on a 0- and 6-month schedule. Among subjects in all groups, 52% were male; 61% of subjects were white, 9% were black, 3% were Asian, and 27% were other racial/ethnic groups. The anti-hepatitis A antibody vaccine responses and GMTs, calculated on responders for groups 1, 2, and 5 are presented in Table 2. Vaccine response rates were similar among the 3 age groups that received HAVRIX. One month after the second dose of HAVRIX, the GMT in each of the younger age groups (11 to 13 and 15 to 18 months of age) was shown to be similar to that achieved in the 23 to 25 months of age group. Table 2: Anti-Hepatitis A Immune Response Following 2 Doses of HAVRIX 720 EL.U./0.5 mL Administered 6 Months Apart in Children Given the First Dose of HAVRIX at 11 to 13 Months of Age, 15 to 18 Months of Age, or 23 to 25 Months of Age Age group N Vaccine Response GMT (mIU/mL) % 95% CI 11-13 months (Group 1) 218 99 97, 100 1,461a 15-18 months (Group 2) 200 100 98, 100 1,635a 23-25 months (Group 5) 211 100 98, 100 1,911 Vaccine response = Seroconversion (anti-HAV ≥ 15 mlU/mL [lower limit of antibody measurement by assay]) in children initially seronegative or at least the maintenance of the pre-vaccination anti-HAV concentration in initially seropositive children. CI = Confidence Interval; GMT = Geometric mean antibody titer. a Calculated on vaccine responders one month post-dose 2. GMTs in children 11 to 13 months of age and 15 to 18 months of age were non-inferior (similar) to the GMT in children 23 to 25 months of age (i.e., the lower limit of the two-sided 95% CI on the GMT ratio for Group 1/Group 5 and for Group 2/Group 5 were both ≥ 0.5). In 3 additional clinical studies (HAV 232, HAV 220, and HAV 231), children received either 2 doses of HAVRIX alone or the first dose of HAVRIX concomitantly administered with other routinely recommended US-licensed vaccines followed by a second dose of HAVRIX. After the second dose of HAVRIX, there was no evidence for interference with the anti-HAV response in the children who received concomitantly administered vaccines compared to those who received HAVRIX alone. [See ADVERSE REACTIONS and Clinical Studies.] Immune Response to HAVRIX 360 EL.U. Among Individuals 2 to 18 Years of Age In 6 clinical studies, 762 subjects 2 to 18 years of age received 2 doses of HAVRIX (360 EL.U.) given 1 month apart (GMT ranged from 197 to 660 mIU/mL). Ninety-nine percent of subjects seroconverted following 2 doses. When a third dose of HAVRIX 360 EL.U. was administered 6 months following the initial dose, all subjects were seropositive (anti-HAV ≥ 20 mIU/mL) 1 month following the third dose, with GMTs rising to a range of 3,388 to 4,643 mIU/mL. In 1 study in which children were followed for an additional 6 months, all subjects remained seropositive. Immune Response to HAVRIX 720 EL.U./0.5 mL Among Individuals 2 to 19 Years of Age In 4 clinical studies, 314 children and adolescents ranging from 2 to 19 years of age were immunized with 2 doses of HAVRIX 720 EL.U./0.5 mL given 6 months apart. One month after the first dose, seroconversion (anti-HAV ≥ 20 mIU/mL [lower limit of antibody measurement by assay]) ranged from 96.8% to 100%, with GMTs of 194 mIU/mL to 305 mIU/mL. In studies in which sera were obtained 2 weeks following the initial dose, seroconversion ranged from 91.6% to 96.1%. One month following the booster dose at month 6, all subjects were seropositive, with GMTs ranging from 2,495 mIU/mL to 3,644 mIU/mL. In an additional study in which the booster dose was delayed until 1 year following the initial dose, 95.2% of the subjects were seropositive just prior to administration of the booster dose. One month later, all subjects were seropositive, with a GMT of 2,657 mIU/mL. Immunogenicity In Adults More than 400 healthy adults 18 to 50 years of age in 3 clinical studies were given a single 1440 EL.U. dose of HAVRIX. All subjects were seronegative for hepatitis A antibodies at baseline. Specific humoral antibodies against HAV were elicited in more than 96% of subjects when measured 1 month after vaccination. By day 15, 80% to 98% of vaccinees had already seroconverted (anti-HAV ≥ 20 mIU/mL [lower limit of antibody measurement by assay]). GMTs of seroconverters ranged from 264 to 339 mIU/mL at day 15 and increased to a range of 335 to 637 mIU/mL by 1 month following vaccination. The GMTs obtained following a single dose of HAVRIX are at least several times higher than that expected following receipt of immune globulin. In a clinical study using 2.5 to 5 times the standard dose of immune globulin (standard dose = 0.02 to 0.06 mL/kg), the GMT in recipients was 146 mIU/mL at 5 days post-administration, 77 mIU/mL at month 1, and 63 mIU/mL at month 2. In 2 clinical trials in which a booster dose of 1440 EL.U. was given 6 months following the initial dose, 100% of vaccinees (n = 269) were seropositive 1 month after the booster dose, with GMTs ranging from 3,318 mIU/mL to 5,925 mIU/mL. The titers obtained from this additional dose approximate those observed several years after natural infection. In a subset of vaccinees (n = 89), a single dose of HAVRIX 1440 EL.U. elicited specific anti-HAV neutralizing antibodies in more than 94% of vaccinees when measured 1 month after vaccination. These neutralizing antibodies persisted until month 6. One hundred percent of vaccinees had neutralizing antibodies when measured 1 month after a booster dose given at month 6. Immunogenicity of HAVRIX was studied in subjects with chronic liver disease of various etiologies. 189 healthy adults and 220 adults with either chronic hepatitis B (n = 46), chronic hepatitis C (n = 104), or moderate chronic liver disease of other etiology (n = 70) were vaccinated with HAVRIX 1440 EL.U. on a 0- and 6-month schedule. The last group consisted of alcoholic cirrhosis (n = 17), autoimmune hepatitis (n = 10), chronic hepatitis/cryptogenic cirrhosis (n = 9), hemochromatosis (n = 2), primary biliary cirrhosis (n = 15), primary sclerosing cholangitis (n = 4), and unspecified (n = 13). At each time point, geometric mean antibody titers (GMTs) were lower for subjects with chronic liver disease than for healthy subjects. At month 7, the GMTs ranged from 478 mIU/mL (chronic hepatitis C) to 1,245 mIU/mL (healthy). One month after the first dose, seroconversion rates in adults with chronic liver disease were lower than in healthy adults. However, 1 month after the booster dose at month 6, seroconversion rates were similar in all groups; rates ranged from 94.7% to 98.1%. The relevance of these data to the duration of protection afforded by HAVRIX is unknown. In subjects with chronic liver disease, local injection site reactions with HAVRIX were similar among all 4 groups, and no serious adverse events attributed to the vaccine were reported in subjects with chronic liver disease. Duration Of Immunity The duration of immunity following a complete schedule of immunization with HAVRIX has not been established. Immune Response To Concomitantly Administered Vaccines In 3 clinical studies HAVRIX was administered concomitantly with other routinely recommended US-licensed vaccines: Study HAV 232: Diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (INFANRIX, DTaP) and Haemophilus b (Hib) conjugate vaccine (tetanus toxoid conjugate) (manufactured by sanofi pasteur SA); Study HAV 220: Pneumococcal 7-valent conjugate vaccine (PCV-7) (manufactured by Pfizer), and Study HAV 231: MMR and varicella vaccines. [See ADVERSE REACTIONS] Concomitant Administration With DTaP and Hib Conjugate Vaccine (Study HAV 232) In this US multicenter study, 468 subjects, children 15 months of age were randomized to receive: Group 1) HAVRIX coadministered with INFANRIX and Hib conjugate vaccine (n = 127); Group 2) INFANRIX and Hib conjugate vaccine alone followed by a first dose of HAVRIX one month later (n = 132); or Group 3) HAVRIX alone (n = 135). All subjects received a second dose of HAVRIX alone 6 to 9 months following the first dose. Among subjects in all groups combined, 53% were male; 64% of subjects were white, 12% were black, 6% were Hispanic, and 18% were other racial/ethnic groups. There was no evidence for reduced antibody response to diphtheria and tetanus toxoids (percentage of subjects with antibody levels ≥ 0.1 mIU/mL to each antigen), pertussis antigens (percentage of subjects with seroresponse, antibody concentrations ≥ 5 EL.U./mL in seronegative subjects or post-vaccination antibody concentration ≥ 2 times the pre-vaccination antibody concentration in seropositive subjects, and GMTs), or Hib (percentage of subjects with antibody levels ≥ 1 mcg/mL to polyribosyl-ribitol phosphate, PRP) when HAVRIX was administered concomitantly with INFANRIX and Hib conjugate vaccine (Group 1) relative to INFANRIX and Hib conjugate vaccine administered together (Group 2). Concomitant Administration With Pneumococcal 7-Valent Conjugate Vaccine (Study HAV 220) In this US multicenter study, 433 children 15 months of age were randomized to receive: Group 1) HAVRIX coadministered with PCV-7 vaccine (n = 137); Group 2) HAVRIX administered alone (n = 147); or Group 3) PCV-7 vaccine administered alone (n = 149) followed by a first dose of HAVRIX one month later. All subjects received a second dose of HAVRIX 6 to 9 months after the first dose. Among subjects in all groups combined, 53% were female; 61% of subjects were white, 16% were Hispanic, 15% were black, and 8% were other racial/ethnic groups. There was no evidence for reduced antibody response to PCV-7 (GMC to each serotype) when HAVRIX was administered concomitantly with PCV-7 vaccine (Group 1) relative to PCV- 7 administered alone (Group 3). Concomitant Administration With MMR and Varicella Vaccines (Study HAV 231) In a US multicenter study, there was no evidence for interference in the immune response to MMR and varicella vaccines (the percentage of subjects with pre-specified seroconversion/seroresponse levels) administered at 15 months of age concomitantly with HAVRIX relative to the response when MMR and varicella vaccines are administered without HAVRIX. [See ADVERSE REACTIONS] REFERENCES 1. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 2006;55(RR-7):1-23.

Find Lowest Prices on VAQTA® (Hepatitis A Vaccine, Inactivated) Intramuscular Injection DESCRIPTION VAQTA is an inactivated whole virus vaccine derived from hepatitis A virus grown in cell culture in human MRC-5 diploid fibroblasts. It contains inactivated virus of a strain which was originally derived by further serial passage of a proven attenuated strain. The virus is grown, harvested, purified by a combination of physical and high performance liquid chromatographic techniques developed at the Merck Research Laboratories, formalin inactivated, and then adsorbed onto amorphous aluminum hydroxyphosphate sulfate. VAQTA is a sterile suspension for intramuscular injection. One milliliter of the vaccine contains approximately 50U of hepatitis A virus antigen, which is purified and formulated without a preservative. Within the limits of current assay variability, the 50U dose of VAQTA contains less than 0.1 mcg of non-viral protein, less than 4 x 10–6 mcg of DNA, less than 10–4 mcg of bovine albumin, and less than 0.8 mcg of formaldehyde. Other process chemical residuals are less than 10 parts per billion (ppb), including neomycin. Each 0.5-mL pediatric dose contains 25U of hepatitis A virus antigen and adsorbed onto approximately 0.225 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride. Each 1-mL adult dose contains 50U of hepatitis A virus antigen and adsorbed onto approximately 0.45 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 70 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

Find Lowest Prices on HAVRIX (Hepatitis A Vaccine) Injection DESCRIPTION HAVRIX (Hepatitis A Vaccine) is a sterile suspension of inactivated virus for intramuscular administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. After removal of the cell culture medium, the cells are lysed to form a suspension. This suspension is purified through ultrafiltration and gel permeation chromatography procedures. Treatment of this lysate with formalin ensures viral inactivation. Viral antigen activity is referenced to a standard using an enzyme linked immunosorbent assay (ELISA), and is therefore expressed in terms of ELISA Units (EL.U.). Each 1-mL adult dose of vaccine contains 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide. Each 0.5-mL pediatric dose of vaccine contains 720 EL.U. of viral antigen, adsorbed onto 0.25 mg of aluminum as aluminum hydroxide. HAVRIX contains the following excipients: Amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/mL). From the manufacturing process, HAVRIX also contains residual MRC-5 cellular proteins (not more than 5 mcg/mL), formalin (not more than 0.1 mg/mL), and neomycin sulfate (not more than 40 ng/mL), an aminoglycoside antibiotic included in the cell growth media. HAVRIX is formulated without preservatives. HAVRIX 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.

INDICATIONS VAQTA® [Hepatitis A Vaccine, Inactivated] is indicated for the prevention of disease caused by hepatitis A virus (HAV) in persons 12 months of age and older. The primary dose should be given at least 2 weeks prior to expected exposure to HAV. DOSAGE AND ADMINISTRATION FOR INTRAMUSCULAR ADMINISTRATION ONLY. Dosage And Schedule Children/Adolescents (12 Months Through 18 Years Of Age) The vaccination schedule consists of a primary 0.5-mL dose administered intramuscularly, and a 0.5-mL booster dose administered intramuscularly 6 to 18 months later. Adults ( ≥ 19 Years Of Age) The vaccination schedule consists of a primary 1-mL dose administered intramuscularly, and a 1-mL booster dose administered intramuscularly 6 to 18 months later. Booster Immunization Following Another Manufacturer's Hepatitis A Vaccine A booster dose of VAQTA may be given at 6 to 12 months following a primary dose of HAVRIX [see Clinical Studies]. Preparation And Administration Shake the single-dose vial or single-dose prefilled syringe well to obtain a slightly opaque, white suspension before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the suspension does not appear homogenous or if extraneous particulate matter remains or discoloration is observed. For single-dose vials, withdraw and administer entire dose of VAQTA intramuscularly using a sterile needle and syringe. For single-dose prefilled syringes, securely attach a needle by twisting in a clockwise direction and administer dose of VAQTA intramuscularly. For adults, adolescents, and children older than 2 years of age, the deltoid muscle is the preferred site for intramuscular injection. For children 12 through 23 months of age, the anterolateral area of the thigh is the preferred site for intramuscular injection. HOW SUPPLIED Dosage Forms And Strengths Suspension for injection available in four presentations: 0.5-mL pediatric dose in single-dose vials and prefilled syringes 1-mL adult dose in single-dose vials and prefilled syringes  [See DESCRIPTION for listing of vaccine components and Storage and Handling] Storage And Handling VAQTA is available in single-dose vials and prefilled Luer Lock syringes. Pediatric/Adolescent Formulations 25U/0.5 mL in single-dose vials and prefilled Luer Lock syringes. NDC 0006-4831-41 – box of ten 0.5-mL single dose vials. NDC 0006-4095-09 – carton of six 0.5-mL prefilled single-dose Luer Lock syringes with tip caps. Adult Formulations 50U/1-mL in single-dose vials and prefilled Luer Lock syringes. NDC 0006-4841-00 – 1-mL single dose vial. NDC 0006-4841-41 – box of ten 1-mL single dose vials. NDC 0006-4096-09 – carton of six 1-mL prefilled single-dose Luer Lock syringes with tip caps. Store vaccine at 2-8°C (36-46°F). DO NOT FREEZE since freezing destroys potency. Manuf. and Dist. by : Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

INDICATIONS HAVRIX® is indicated for active immunization against disease caused by hepatitis A virus (HAV). HAVRIX is approved for use in persons 12 months of age and older. Primary immunization should be administered at least 2 weeks prior to expected exposure to HAV. DOSAGE AND ADMINISTRATION Preparation For Administration Shake well before use. With thorough agitation, HAVRIX 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 HAVRIX should be administered by intramuscular injection only. HAVRIX should not be administered in the gluteal region; such injections may result in suboptimal response. Do not administer this product intravenously, intradermally, or subcutaneously. Recommended Dose And Schedule Children and Adolescents Primary immunization for children and adolescents (12 months through 18 years of age) consists of a single 0.5-mL dose and a 0.5-mL booster dose administered anytime between 6 and 12 months later. The preferred sites for intramuscular injections are the anterolateral aspect of the thigh in young children or the deltoid muscle of the upper arm in older children. Adults Primary immunization for adults consists of a single 1-mL dose and a 1-mL booster dose administered anytime between 6 and 12 months later. In adults, the injection should be given in the deltoid region. HOW SUPPLIED Dosage Forms And Strengths Suspension for injection available in the following presentations: 0.5-mL single-dose vials and prefilled TIP-LOK® syringes. 1-mL single-dose vials and prefilled TIP-LOK syringes. Storage And Handling HAVRIX is available in single-dose vials and prefilled disposable TIP-LOK syringes (packaged without needles) (Preservative Free Formulation): 720 EL.U./0.5 mL NDC 58160-825-01 Vial in Package of 10: NDC 58160-825-11 NDC 58160-825-43 Syringe in Package of 10: NDC 58160-825-52 1440 EL.U./mL NDC 58160-826-01 Vial in Package of 10: NDC 58160-826-11 NDC 58160-826-05 Syringe in Package of 1: NDC 58160-826-34 NDC 58160-826-43 Syringe in Package of 10: NDC 58160-826-52 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Do not dilute to administer. Manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium, US License No. 1617. Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer VAQTA to individuals with a history of immediate and/or severe allergic or hypersensitivity reactions (e.g., anaphylaxis) after a previous dose of any hepatitis A vaccine, or to individuals who have had an anaphylactic reaction to any component of VAQTA, including neomycin [see DESCRIPTION].

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

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 safety of VAQTA has been evaluated in over 10,000 subjects 1 year to 85 years of age. Subjects were given one or two doses of the vaccine. The second (booster dose) was given 6 months or more after the first dose. The most common local adverse reactions and systemic adverse events ( ≥ 15%) reported in different clinical trials across different age groups when VAQTA was administered alone or concomitantly were: Children — 12 through 23 months of age: injection-site pain/tenderness (37.0%), injection-site erythema (21.2%), fever (16.4% when administered alone, and 27.0% when administered concomitantly). Children/Adolescents — 2 through 18 years of age: injection-site pain (18.7%) Adults — 19 years of age and older: injection-site pain, tenderness, or soreness (67.0%), injection-site warmth (18.2%) and headache (16.1%) Allergic Reactions Local and/or systemic allergic reactions that occurred in < 1% of over 10,000 children/adolescents or adults in clinical trials regardless of causality included: injection-site pruritus and/or rash; bronchial constriction; asthma; wheezing; edema/swelling; rash; generalized erythema; urticaria; pruritus; eye irritation/itching; dermatitis [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Children — 12 through 23 Months of Age Across five clinical trials, 4374 children 12 to 23 months of age received one or two 25U doses of VAQTA, including 3885 children who received 2 doses of VAQTA and 1250 children who received VAQTA concomitantly with one or more other vaccines, including Measles, Mumps, and Rubella Virus Vaccine, Live (M-M-R II1), Varicella Vaccine, Live (VARIVAX1), Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine, Adsorbed (Tripedia or INFANRIX), Measles, Mumps, Rubella, and Varicella Vaccine, Live (ProQuad), Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 , Prevnar), or Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate, PedvaxHIB). Overall, the race distribution of study subjects was as follows: 64.7% Caucasian; 15.7% Hispanic-American; 12.3% Black; 4.8% other; 1.4% Asian; and 1.1% Native American. The distribution of subjects by gender was 51.8% male and 48.2% female. In an open-label clinical trial, 653 children 12 to 23 months of age were randomized to receive a first dose of VAQTA with ProQuad and Prevnar concomitantly (N=330) or a first dose of ProQuad and pneumococcal 7-valent conjugate vaccine concomitantly, followed by a first dose of VAQTA 6 weeks later (N=323). Approximately 6 months later, subjects received either the second doses of ProQuad and VAQTA concomitantly or the second doses of ProQuad and VAQTA separately. The race distribution of the study subjects was as follows: 60.3% Caucasian; 21.6% African-American; 9.5% Hispanic-American; 7.2% other; 1.1% Asian; and 0.3% Native American. The distribution of subjects by gender was 50.7% male and 49.3% female. Table 1 presents rates of solicited local reactions at the VAQTA injection site and rates of elevated temperatures ( ≥ 100.4°F and ≥ 102.2°F) that occurred within 5 days following each dose of VAQTA and elevated temperatures > 98.6°F for a total of 14 days after vaccination; occurrences of these events were recorded daily on diary cards. Table 2 presents rates of unsolicited systemic adverse events that occurred within 14 days at ≥ 5% in any group following each dose of VAQTA. Table 1 : Incidences of Solicited Local Adverse Reactions at the VAQTA Injection Site and Elevated Temperatures Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PREVNAR* Adverse reaction: Days 1-5 unless noted Dose 1 Dose 2 VAQTA alone VAQTA + ProQuad + Prevnar concomitantly VAQTA alone VAQTA + ProQuad concomitantly Injection site adverse reactions N=274 N=311 N=251 N=263 Injection site erythema 11.7% 9.6% 12.7% 9.5% Injection site pain/tenderness 15.3% 20.9% 20.3% 17.5% Injection site swelling 9.5% 6.8% 7.6% 6.1% Temperature > 98.6°F or feverish (Days 1-14) 12.4% 35.7% 10.8% 10.3% N=243 N=285 N=221 N=237 Temperature ≥ 100.4°F 10.3% 16.8% 10% 4.2% Temperature ≥ 102.2 °F 2.1% 3.5% 2.3% 2.5% *Pneumococcal 7-valent Conjugate Vaccine N=number of subjects for whom data are available. Table 2 : Incidences of Unsolicited Systemic Adverse Events ≥ 5% in Any Group Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PREVNAR* Adverse Event: Days 1-14 Dose 1 Dose 2 VAQTA alone VAQTA + ProQuad + PREVNAR concomitantly VAQTA alone VAQTA + ProQuad concomitantly N=274 N=311 N=251 N=263 General Disorders and Administration Site Conditions Irritability 3.6% 6.1% 2.8% 2.7% Infections and Infestations Upper respiratory tract infection 3.3% 6.1% 4.8% 5.7% Skin and Subcutaneous Tissue Disorders Dermatitis diaper 1.1% 6.1% 2.4% 3.4% *Pneumococcal 7-valent Conjugate Vaccine In Stage I of an open, multicenter, randomized study, children 15 months of age were randomized to receive the first dose of VAQTA alone (N=151) or concomitantly with PedvaxHIB and INFANRIX (N=155); another group of children 15 months of age were randomized to receive the first dose of VAQTA alone (N=152) or concomitantly with PedvaxHIB (N=159). All groups received the second dose of VAQTA alone at least 6 months following the first dose. The race distribution of Stage I study subjects was: 63.9% Caucasian; 17.5% Hispanic-American; 14.7% Black; 2.6% other; and 1.3% Asian. The distribution of subjects by gender was 54.0% male and 46.0% female. In Stage II of this study, an additional 654 children 12-17 months of age received the first dose of VAQTA alone followed by the second dose of VAQTA 6 months later. The race distribution of Stage II of the study subjects was: 66.1% Caucasian; 10.6% Hispanic-American; 16.8% Black; 4.7% other; and 1.5% Asian. The distribution of subjects by gender was 51.2% male and 48.8% female. Table 3 presents rates of solicited local reactions at the VAQTA injection-site and rates of elevated temperatures ( ≥ 100.4°F and ≥ 102.2°F) that occurred within 5 days following each dose of VAQTA and elevated temperatures > 98.6°F for a total of 14 days following each dose of VAQTA. Occurrences of these events were recorded daily on diary cards. Table 4 presents rates of unsolicited systemic adverse events that occurred within 14 days at ≥ 5% following each dose of VAQTA. Table 3 : Incidences of Solicited Local Adverse Reactions at the VAQTA Injection Site and Elevated Temperatures Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly with PedvaxHIB With or Without INFANRIX (Stage I) and those Receiving VAQTA Alone at Both Doses (Stage II) Adverse Reaction: Days 1-5 unless noted Stage I Stage II Dose 1 Dose 2 Dose 1 Dose 2 VAQTA alone VAQTA + PedvaxHIB and Infanrix or VAQTA + PedvaxHIB concomitantly VAQTA alone VAQTA alone VAQTA alone Injection site adverse reactions N=256 N=302 N=503 N=647 N=599 Injection site erythema 18.0% 19.9% 21.5% 11.7% 16.2% Injection site pain/tenderness 21.9% 36.4% 27.4% 20.1% 22.9% Injection site swelling 10.2% 14.2% 10.1% 7.1% 7.0% Temperature > 98.6°F or feverish (Days 1-14) 10.2% 17.2% 10.7% 10.0% 8.2% N=234 N=290 N=473 N=631 N=591 Temperature ≥ 100.4°F 9.0% 16.9% 9.1% 9.4% 8.6% Temperature ≥ 102.2 °F 3.8% 3.1% 3.2% 2.9% 2.4% N= number of subjects for whom data is available Table 4 : Incidences of Unsolicited Systemic Adverse Events ≥ 5% in Any Group Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly with PedvaxHIB With or Without INFANRIX (Stage I) and those Receiving VAQTA Alone at Both Doses (Stage II) Adverse Event: Days 1-14 Stage I Stage II Dose 1 Dose 2 Dose 1 Dose 2 VAQTA alone VAQTA + PedvaxHIB and Infanrix or VAQTA + PedvaxHIB concomitantly VAQTA alone VAQTA alone VAQTA alone N=256 N=302 N=503 N=647 N=599 Gastrointestinal Disorders Diarrhea 3.9% 8.3% 3.8% 4.6% 3.8% Teething 3.1% 2.3% 1.4% 5.7% 4.3% General Disorders and Administration Site Conditions Irritability 6.3% 9.6% 4.0% 8.8% 6.5% Infections and Infestations Upper respiratory tract infection 2.3% 3.3% 3.0% 4.9% 5.2% Respiratory, Thoracic and Mediastinal Disorders Rhinorrhea 2.0% 4.0% 3.8% 6.2% 3.8% Data presented in Tables 1 through 4 on solicited local reactions, and solicited and unsolicited systemic adverse events with incidence ≥ 5% following each dose of VAQTA are representative of other clinical trials of VAQTA in children 12 through 23 months of age. Across the five studies conducted in children 12-23 months of age, ≥ 39.9% of subjects experienced local adverse reactions and ≥ 55.7% of subjects experienced systemic adverse events. The majority of local and systemic adverse events were mild to moderate in intensity. The following additional unsolicited local adverse reactions and systemic adverse events were observed at a common frequency of ≥ 1% to < 10% in any individual clinical study. This listing includes only the adverse reactions not reported elsewhere in the label. These local adverse reactions and systemic adverse events occurred among recipients of VAQTA alone or VAQTA given concomitantly within 14 days following any dose of VAQTA across four clinical studies. Eye disorders: Conjunctivitis Gastrointestinal disorders: Constipation; vomiting General disorders and administration site conditions: Injection-site bruising; injection-site ecchymosis Infections and infestations: Otitis media; nasopharyngitis; rhinitis; viral infection; croup; pharyngitis streptococcal; laryngotracheobronchitis; viral exanthema; gastroenteritis viral; roseola Metabolism and nutrition disorders: Anorexia Psychiatric disorders: Insomnia; crying Respiratory, thoracic and mediastinal disorders: Cough; nasal congestion; respiratory congestion Skin and subcutaneous tissue disorders: Rash vesicular; measles-like/rubella-like rash; varicella-like rash; rash morbilliform Serious Adverse Events (Children 12 through 23 Months of Age): Across the five studies conducted in subjects 12-23 months of age, 0.7% (32/4374) of subjects reported a serious adverse event following any dose of VAQTA, and 0.1% (5/4374) of subjects reported a serious adverse event judged to be vaccine related by the study investigator. The serious adverse events were collected over the period defined in each protocol (14, 28, or 42 days). Vaccine-related serious adverse events which occurred following any dose of VAQTA with or without concomitant vaccines included febrile seizure(0.05%), dehydration(0.02%), gastroenteritis (0.02%), and celluitis (0.02%). Children/Adolescents — 2 Years through 18 Years of Age In 11 clinical trials, 2615 healthy children 2 years through 18 years of age received at least one dose of VAQTA. These studies included administration of VAQTA in varying doses and regimens (1377 children received one or more 25U doses).The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 84.7% Caucasian; 10.6% American Indian; 2.3% African-American; 1.5% Hispanic-American; 0.6% other; 0.2% Oriental. The distribution of subjects by gender was 51.2% male and 48.8% female. In a double-blind, placebo-controlled efficacy trial (i.e. The Monroe Efficacy Study), 1037 healthy children and adolescents 2 through 16 years of age.were randomized to receive a primary dose of 25U of VAQTA and a booster dose of VAQTA 6, 12, or 18 months later, or placebo (alum diluent). All study subjects were Caucasian: 51.5% were male and 48.5% were female Subjects were followed days 1 to 5 postvaccination for fever and local adverse reactions and days 1 to 14 for systemic adverse events. The most common adverse events/reactions were injection-site reactions, reported by 6.4% of subjects. Table 5 summarizes local adverse reactions and systemic adverse events reported in ≥ 1% of subjects. There were no significant differences in the rates of any adverse events or adverse reactions between vaccine and placebo recipients after Dose 1. Table 5 : Local Adverse Reactions and Systemic Adverse Events ( ≥ 1%) in Healthy Children and Adolescents from the Monroe Efficacy Study Adverse Event VAQTA (N=519) Placebo (Alum Diluent)*†‡ (N=518) Rate (Percent) Dose 1* Rate (Percent) Booster Rate (Percent) Injection Site§ n=515 n=475 n=510 Pain 6.4% 3.4% 6.3% Tenderness 4.9% 1.7% 6.1% Erythema 1.9% 0.8% 1.8% Swelling 1.7% 1.5% 1.6% Warmth 1.7% 0.6% 1.6% Systemic¶ n=519 n=475 n=518 Abdominal pain 1.2% 1.1% 1.0% Pharyngitis 1.2% 0% 0.8% Headache 0.4% 0.8% 1.0% N=Number of subjects enrolled/randomized. Percent=percentage of subjects for whom data are available with adverse event n=number of subjects for whom adverse events available * No statistically significant differences between the two groups. † Second injection of placebo not administered because code for the trial was broken. ‡ Placebo (Alum diluent) = amorphous aluminum hydroxyphosphate sulfate. § Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination with VAQTA ¶Systemic adverse events reported Days 1-15 after vaccination, regardless of causality. Adults — 19 Years of Age and Older In an open-label clinical trial, 240 healthy adults 18 to 54 years of age were randomized to receive either VAQTA (50U/1-mL) with Typhim Vi3 (Typhoid Vi polysaccharide vaccine) and YF-Vax3 (yellow fever vaccine) concomitantly (N=80), typhoid Vi polysaccharide and yellow fever vaccines concomitantly (N=80), or VAQTA alone (N=80). Approximately 6 months later, subjects who received VAQTA were administered a second dose of VAQTA. The race distribution of the study subjects who received VAQTA with or without typhoid Vi polysaccharide and yellow fever vaccine was as follows: 78.3% Caucasian; 14.2% Oriental; 3.3% other; 2.1% African-American; 1.7% Indian; 0.4% Hispanic-American. The distribution of subjects by gender was 40.8% male and 59.2% female. Subjects were monitored for local adverse reactions and fever for 5 days and systemic adverse events for 14 days after each vaccination. In the 14 days after the first dose of VAQTA, the proportion of subjects with adverse events was similar between recipients of VAQTA given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines compared to recipients of typhoid Vi polysaccharide and yellow fever vaccines without VAQTA. Table 6 summarizes solicited local adverse reactions and Table 7 summarizes unsolicited systemic adverse events reported in ≥ 5% in adults who received one or two doses of VAQTA alone and for subjects who received VAQTA concomitantly with typhoid Vi polysaccharide and yellow fever vaccines. There were no solicited systemic complaints reported at a rate ≥ 5%. Fever ≥ 101°F occurred in 1.3% of subjects in each group. Table 6 :Incidences of Solicited Local Adverse Reactions in Healthy Adults ≥ 19 Years of Age Occurring at ≥ 5% After Any Dose Adverse Event VAQTA administered alone (N=80) VAQTA + ViCPS* and Yellow Fever vaccines administered concomitantly† (N=80) Rate (Percent) Injection-site‡ Pain/tenderness/soreness 78.8% 70.3% Warmth 23.7% 23.7% Swelling 16.2% 8.8% Erythema 17.5% 6.3% N=Number of subjects enrolled/randomized. Percent=percentage of subjects with adverse event. *ViCPS=Typhoid Vi polysaccharide vaccine. †VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines. ‡ Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination Table 7 : Incidences of Unsolicited Systemic Adverse Events in Adults ≥ 19 Years of Age Occurring at ≥ 5% After Any Dose Body System Adverse Event VAQTA administered alone (N=80) VAQTA + ViCPS* and Yellow Fever vaccines administered concomitantly† (N=80) Rate (Percent) General disorders and administration site reactions Asthenia/fatigue 7.5% 11.3% Chills 1.3% 7.5% Gastrointestinal disorders Nausea 7.5% 12.5% Musculoskeletal and connective tissue disorders Myalgia 5.0% 10.0% Arm pain 0.0% 6.3% Nervous system disorders Headache 23.8% 26.3% Infections and infestations Upper respiratory infection 7.5% 3.8% Pharyngitis 2.5% 6.3% N=Number of subjects enrolled/randomized with data available. Percent=percentage of subjects with adverse event for whom data are available. *ViCPS=Typhoid Vi polysaccharide vaccine. †VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines. †Systemic Adverse Events reported Days 1-15 after vaccination, regardless of causality. In four clinical trials involving 1645 healthy adults 19 years of age and older who received one or more 50U doses of hepatitis A vaccine, subjects were followed for fever and local adverse reactions 1 to 5 days postvaccination and for systemic adverse events 1 to 14 days postvaccination. One single-blind study evaluated doses of VAQTA with varying amounts of viral antigen and/or alum content in healthy adults ≥ 170 pounds and ≥ 30 years of age (N=210 adults administered 50U/1-mL dose). One open-label study evaluated VAQTA given with immune globulin or alone (N=164 adults who received VAQTA alone). A third study was single-blind and evaluated 3 different lots of VAQTA (N=1112). The fourth study that was also single-blind evaluated doses of VAQTA with varying amounts of viral antigen in healthy adults ≥ 170 pounds and ≥ 30 years of age (N=159 adults administered the 50U/1-mL dose). Overall, the race distribution of the study subjects who received at least one dose of VAQTA was as follows: 94.2% Caucasian; 2.2% Black; 1.5% Hispanic; 1.5% Oriental; 0.4% other; 0.2% American Indian. 47.6% of subjects were male and 52.4% were female. The most common adverse event/reaction was injection-site pain/soreness/tenderness reported by 67.0% of subjects. Of all reported injection-site reactions 99.8% were mild (i.e., easily tolerated with no medical intervention) or moderate (i.e., minimally interfered with usual activity possibly requiring little medical intervention). Listed below in Table 8 are the local adverse reactions and systemic adverse events reported by ≥ 5% of subjects, in decreasing order of frequency within each body system. Table 8 : Incidences of Local Adverse Reactions and Systemic Adverse Events ≥ 5% in Adults 19 Years of Age and Older Body System VAQTA (Any Dose) (N=1645) Adverse Events Rate (n/total n) Nervous system disorders* n=1641 Headache 16.1% General disorders and administration site reactions† n=1640 Injection-site pain/tenderness/soreness 67.0% Injection-site warmth 18.2% Injection-site swelling 14.7% Injection-site erythema 13.7% N=Number of subjects enrolled/randomized. n=Number of subjects in each category with data available. Percent=percentage of subjects for whom data are available with adverse event. *Systemic Adverse Events reported Days 1 to 14 after vaccination, regardless of causality. †Adverse Reactions at the injection site (VAQTA) and measured fever Days 1 to 5 after vaccination. The following additional unsolicited systemic adverse events were observed among recipients of VAQTA that occurred within 14 days at a common frequency of ≥ 1% to < 10% following any dose not reported elsewhere in the label. These adverse reactions have been reported across 4 clinical studies. Musculoskeletal and connective tissue disorders: Back pain; stiffness Reproductive system and breast disorders: Menstruation disorders Post-Marketing Experience The following additional adverse events have been reported with use of the marketed vaccine. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to a vaccine exposure. Blood and lymphatic disorders: Thrombocytopenia. Nervous system disorders: Guillain-Barré syndrome; cerebellar ataxia; encephalitis. Post-Marketing Observational Safety Study In a post-marketing, 60-day safety surveillance study, conducted at a large health maintenance organization in the United States, a total of 42,110 individuals ≥ 2 years of age received 1 or 2 doses of VAQTA (13,735 children/adolescents and 28,375 adult subjects). Safety was passively monitored by electronic search of the automated medical records database for emergency room and outpatient visits, hospitalizations, and deaths. Medical charts were reviewed when an event was considered to be possibly vaccine-related by the investigator. None of the serious adverse events identified were assessed as being related to vaccine by the investigator. Diarrhea/gastroenteritis, resulting in outpatient visits, was determined by the investigator to be the only vaccine-related nonserious adverse reaction in the study. There was no vaccine-related adverse reaction identified that had not been reported in earlier clinical trials with VAQTA. DRUG INTERACTIONS Use With Other Vaccines Do not mix VAQTA with any other vaccine in the same syringe or vial. Use separate injection sites and syringes for each vaccine. Please refer to package inserts of coadministered vaccines. In clinical trials in children, VAQTA was concomitantly administered with one or more of the following US licensed vaccines: Measles, Mumps, and Rubella Virus Vaccine, Live; Varicella Vaccine, Live; Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine, Adsorbed; Measles, Mumps, Rubella, and Varicella Vaccine, Live; Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197); and Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate). Safety and immunogenicity were similar for concomitantly administered vaccines compared to separately administered vaccines. In clinical trials in adults, VAQTA was concomitantly administered with typhoid Vi polysaccharide and yellow fever vaccines [see ADVERSE REACTIONS and Clinical Studies]. Safety and immunogenicity were similar for concomitantly administered vaccines compared to separately administered vaccines. Use With Immune Globulin VAQTA may be administered concomitantly with Immune Globulin, human, using separate sites and syringes. The recommended vaccination regimen for VAQTA should be followed. Consult the manufacturer's product circular for the appropriate dosage of Immune Globulin. A booster dose of VAQTA should be administered at the appropriate time as outlined in the recommended regimen for VAQTA [see Clinical Studies]. Immunosuppressive Therapy If VAQTA is administered to a person receiving immunosuppressive therapy, an adequate immunologic response may not be obtained.

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 safety of HAVRIX has been evaluated in 61 clinical trials involving more than 34,000 individuals receiving doses of 360 EL.U., 720 EL.U., or 1440 EL.U. Of solicited adverse events in clinical trials of adults, who received HAVRIX 1440 EL.U., and children (2 years of age and older), who received either HAVRIX 360 EL.U. or 720 EL.U., the most frequently reported was injection-site soreness (56% of adults and 21% of children); less than 0.5% of soreness was reported as severe. Headache was reported by 14% of adults and less than 9% of children. Other solicited and unsolicited events occurring during clinical trials are listed below. Incidence 1% to 10% of Injections Metabolism and Nutrition Disorders: Anorexia. Gastrointestinal Disorders: Nausea. General Disorders and Administration Site Conditions: Fatigue, fever > 99.5°F (37.5°C), induration, redness, and swelling of the injection site; malaise. Incidence < 1% of Injections Infections and Infestations: Pharyngitis, upper respiratory tract infections. Blood and Lymphatic System Disorders: Lymphadenopathy. Psychiatric Disorders: Insomnia. Nervous System Disorders: Dysgeusia, hypertonia. Eye Disorders: Photophobia. Ear and Labyrinth Disorders: Vertigo. Gastrointestinal Disorders: Abdominal pain, diarrhea, vomiting. Skin and Subcutaneous Tissue Disorders: Pruritus, rash, urticaria. Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia. General Disorders and Administration Site Conditions: Injection site hematoma. Investigations: Creatine phosphokinase increased. Studies of HAVRIX 720 EL.U./0.5 mL in Children 11 to 25 Months of Age In 4 studies, 3,152 children 11 to 25 months of age received at least one dose of HAVRIX 720 EL.U. administered alone or concomitantly with other routine childhood vaccinations [see Clinical Studies]. The studies included HAV 210 (N = 1,084), HAV 232 (N = 394), HAV 220 (N = 433), and HAV 231 (N = 1,241). In the largest of these studies (HAV 231) conducted in the US, 1,241 children 15 months of age were randomized to receive: Group 1) HAVRIX alone; Group 2) HAVRIX concomitantly with measles, mumps, and rubella (MMR) vaccine (manufactured by Merck and Co.) and varicella vaccine (manufactured by Merck and Co.); or Group 3) MMR and varicella vaccines. Subjects in Group 3 who received MMR and varicella vaccines received the first dose of HAVRIX 42 days later. A second dose of HAVRIX was administered to all subjects 6 to 9 months after the first dose of HAVRIX. Solicited local adverse reactions and general events were recorded by parents/guardians on diary cards for 4 days (days 0 to 3) after vaccination. Unsolicited adverse events were recorded on the diary card for 31 days after vaccination. Telephone follow-up was conducted 6 months after the last vaccination to inquire about serious adverse events, new onset chronic illnesses and medically significant events. A total of 1,035 children completed the 6-month follow-up. Among subjects in all groups combined, 53% were male; 69% of subjects were white, 16% were Hispanic, 9% were black and 6% were other racial/ethnic groups. Percentages of subjects with solicited local adverse reactions and general adverse events following HAVRIX administered alone (Group 1) or concomitantly with MMR and varicella vaccines (Group 2) are presented in Table 1. The solicited adverse events from the 3 additional coadministration studies conducted with HAVRIX were comparable to those from Study HAV 231. Table 1: Solicited Local Adverse Reactions and General Adverse Events Occurring Within 4 Days of Vaccinationa in Children 15 to 24 Months of Age With HAVRIX Administered Alone or Concomitantly With MMR and Varicella Vaccines (TVC) Group 1 HAVRIX Dose 1 % Group 2 HAVRIX+ MMR+Vb Dose 1 % Group 1 HAVRIX Dose 2 % Group 2 HAVRIX Dose 2 % Local (at injection site for HAVRIX) N 298 411 272 373 Pain, any 23.8 23.6 24.3 30.3 Redness, any 20.1 20.0 22.8 23.9 Swelling, any 8.7 10.2 9.6 9.9 General N 300 417 271 375 Irritability, any 33.3 43.9 31.0 27.2 Irritability, grade 3 0.3 1.9 1.5 0.3 Drowsiness, any 22.3 35.3 21.0 20.8 Drowsiness, grade 3 1.0 2.2 1.1 0.0 Loss of appetite, any 18.3 26.1 19.9 20.5 Loss of appetite, grade 3 1.0 1.4 0.4 0.3 Fever ≥ 100.6°F (38.1°C) 3.0 4.8 3.3 2.7 Fever ≥ 101.5°F (38.6°C) 2.0 2.6 1.8 1.6 Fever ≥ 102.4°F (39.1°C) 0.7 0.7 0.4 1.1 Total vaccinated cohort (TVC) = all subjects who received at least one dose of vaccine. N = number of subjects who received at least one dose of vaccine and for whom diary card information was available. Grade 3: drowsiness defined as prevented normal daily activities; irritability/fussiness defined as crying that could not be comforted/prevented normal daily activities; loss of appetite defined as no eating at all. a Within 4 days of vaccination defined as day of vaccination and the next 3 days. b MMR = measles, mumps, and rubella vaccine; V = varicella vaccine. Serious Adverse Events in Children 11 to 25 Months of Age Among these 4 studies, 0.9% (29/3,152) of subjects reported a serious adverse event within the 31-day period following vaccination with HAVRIX. Among subjects administered HAVRIX alone 1.0% (13/1,332) reported a serious adverse event. Among subjects who received HAVRIX concomitantly with other childhood vaccines, 0.9% (8/909) reported a serious adverse event. In these 4 studies, there were 4 reports of seizure within 31 days post-vaccination: these occurred 2, 9, and 27 days following the first dose of HAVRIX administered alone and 12 days following the second dose of HAVRIX. In one subject who received INFANRIX and Hib conjugate vaccine followed by HAVRIX 6 weeks later, bronchial hyperreactivity and respiratory distress were reported on the day of administration of HAVRIX alone. Postmarketing Experience In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for HAVRIX since market introduction of this vaccine are listed below. This list includes serious adverse events or events which have a suspected causal connection to components of HAVRIX or other vaccines or drugs. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Infections and Infestations: Rhinitis. Blood and Lymphatic System Disorders: Thrombocytopenia. Immune System Disorders: Anaphylactic reaction, anaphylactoid reaction, serum sickness-like syndrome. Nervous System Disorders: Convulsion, dizziness, encephalopathy, Guillain-Barre syndrome, hypoesthesia, multiple sclerosis, myelitis, neuropathy, paresthesia, somnolence, syncope. Vascular Disorders: Vasculitis. Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea. Hepatobiliary Disorders: Hepatitis, jaundice. Skin and Subcutaneous Tissue Disorders: Angioedema, erythema multiforme, hyperhidrosis. Congenital, Familial, and Genetic Disorders: Congenital anomaly. Musculoskeletal and Connective Tissue Disorders: Musculoskeletal stiffness. General Disorders and Administration Site Conditions: Chills, influenza-like symptoms, injection site reaction, local swelling. DRUG INTERACTIONS Concomitant Administration With Vaccines And Immune Globulin In clinical studies HAVRIX was administered concomitantly with the following vaccines [see ADVERSE REACTIONS and Clinical Studies]: INFANRIX (DTaP); Hib conjugate vaccine; pneumococcal 7-valent conjugate vaccine; MMR vaccine; varicella vaccine. HAVRIX 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 HAVRIX with any other vaccine or product in the same syringe or vial. Immunosuppressive Therapies Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to HAVRIX.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Prevention And Management Of Allergic Vaccine Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine [see CONTRAINDICATIONS]. Hypersensitivity To Latex The vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber that may cause allergic reactions in latex-sensitive individuals [see HOW SUPPLIED/Storage and Handling]. Altered Immunocompetence Immunocompromised persons, including individuals receiving immunosuppressive therapy, may have a diminished immune response to VAQTA and may not be protected against HAV infection after vaccination [see Use in Specific Populations]. Limitations Of Vaccine Effectiveness Hepatitis A virus has a relatively long incubation period (approximately 20 to 50 days). VAQTA may not prevent hepatitis A infection in individuals who have an unrecognized hepatitis A infection at the time of vaccination. Vaccination with VAQTA may not result in a protective response in all susceptible vaccinees. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility VAQTA has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility. Use In Specific Populations Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with VAQTA. It is also not known whether VAQTA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VAQTA should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether VAQTA is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VAQTA is administered to a nursing woman. Pediatric Use The safety of VAQTA has been evaluated in 4374 children 12 through 23 months of age, and 2615 children/adolescents 2 through 18 years of age who received at least one 25U dose of VAQTA [see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION]. Safety and effectiveness in infants below 12 months of age have not been established. Geriatric Use In the post-marketing observational safety study which included 42,110 persons who received VAQTA [see ADVERSE REACTIONS], 4769 persons were 65 years of age or older and 1073 persons were 75 years of age or older. There were no adverse events judged by the investigator to be vaccine-related in the geriatric study population. In other clinical studies, 68 subjects 65 years of age or older were vaccinated with VAQTA, 10 of whom were 75 years of age or older. No overall differences in safety and immunogenicity were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Immunocompromised Individuals Immunocompromised persons may have a diminished immune response to VAQTA and may not be protected against HAV infection.

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 HAVRIX. 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. Preventing And Managing Allergic Vaccine Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine [see CONTRAINDICATIONS]. Altered Immunocompetence Immunocompromised persons may have a diminished immune response to HAVRIX, including individuals receiving immunosuppressant therapy. Limitations Of Vaccine Effectiveness Hepatitis A virus has a relatively long incubation period (15 to 50 days). HAVRIX may not prevent hepatitis A infection in individuals who have an unrecognized hepatitis A infection at the time of vaccination. Additionally, vaccination with HAVRIX may not protect all individuals. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility HAVRIX has not been evaluated for its carcinogenic potential, mutagenic potential, or potential for impairment of fertility. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with HAVRIX. It is also not known whether HAVRIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HAVRIX should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether HAVRIX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HAVRIX is administered to a nursing woman. Pediatric Use The safety and effectiveness of HAVRIX, doses of 360 EL.U. or 720 EL.U., have been evaluated in more than 22,000 subjects 1 year to 18 years of age. The safety and effectiveness of HAVRIX have not been established in subjects younger than 12 months of age. Geriatric Use Clinical studies of HAVRIX did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in overall safety between these subjects and younger adult subjects. Hepatic Impairment Subjects with chronic liver disease had a lower antibody response to HAVRIX than healthy subjects [see Clinical Studies].