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CLINICAL PHARMACOLOGY Mechanism Of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of participants. (See REFERENCES 3 and 4.) Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating in the US during the influenza season. Annual vaccination with the current vaccine is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year. Clinical Studies Immunogenicity Of Fluzone High-Dose In Adults 65 Years Of Age And Older Study 1 (NCT00391053) was a multi-center, double-blind pre-licensure trial conducted in the US in which adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2006-2007 formulation). The study compared the safety and immunogenicity of Fluzone High- Dose to those of Fluzone. For immunogenicity analyses, 2576 participants were randomized to Fluzone High-Dose and 1275 participants were randomized to Fluzone. Females accounted for 51.3% of participants in the Fluzone High-Dose group and 54.7% of participants in the Fluzone group. In both groups, the mean age was 72.9 years (ranged from 65 through 97 years in the Fluzone High-Dose group and 65 through 94 years in the Fluzone group); 35% of participants in the Fluzone High-Dose group and 36% of participants in the Fluzone group were 75 years of age or older. Most participants in the Fluzone High-Dose and Fluzone groups, respectively, were White (91.7% and 92.9%), followed by Hispanic (4.8% and 3.7%), and Black (2.7% and 2.7%). The primary endpoints of the study were HI GMTs and seroconversion rates 28 days after vaccination. Pre-specified statistical superiority criteria required that the lower limit (LL) of the 2-sided 95% CI of the GMT ratio (Fluzone High-Dose/Fluzone) be greater than 1.50 for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>0.67), and that the lower limit of the 2-sided 95% CI of the seroconversion rate difference (Fluzone High-Dose minus Fluzone) be greater than 10% for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>-10%). As shown in Table 3, statistically superior HI GMTs and seroconversion rates after vaccination with Fluzone High-Dose compared to Fluzone were demonstrated for influenza A subtypes, A (H1N1) and A (H3N2), but not for influenza type B. For strain B, non-inferiority of Fluzone High-Dose compared to Fluzone was demonstrated for both the HI GMTs and seroconversion rates. Table 3: Study 1 : Post-Vaccination HI Antibody GMTs and Seroconversion Rates and Analyses of Superiority of Fluzone High-Dose Relative to Fluzone, Adults 65 Years of Age and Older Influenza Strain GMT GMT Ratio Seroconversion %† Difference Met Both Pre-defined Superiority Criteria ‡ FluzoneHigh-Dose N §=2542- 2544 Fluzone N§ =1252 Dose over Fluzone (95% CI) Fluzone High- Dose N§ =2529- 2531 Fluzone N§ =1248- 1249 Fluzone High - Dose minus Fluzone (95% CI) A (H1N1) 115.8 67.3 1.7 (1.6; 1.8) 48.6 23.1 25.4 (22.4; 28.5) Yes A (H3N2) 608.9 332.5 1.8 (1.7; 2.0) 69.1 50.7 18.4 (15.1; 21.7) Yes B 69.1 52.3 1.3 (1.2; 1.4) 41.8 29.9 11.8 (8.6; 15.0) No *NCT00391053 †Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28) titer ≥1:4 0 or a minimum 4 -fold increase for participants with pre-vaccination titer ≥1:10 ‡Predefined superiority criterion for seroconversion: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (Fluzone High-Dose minus Fluzone) is >10%. Predefined superiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (Fluzone High-Dose divided by Fluzone) is >1.5 §N is the number of vaccinated participants with available data for the immunologic endpoint listed Efficacy Of Fluzone High-Dose In Adults 65 Years Of Age And Older Study 2 (NCT01427309) was a multi-center, double-blind post-licensure efficacy trial conducted in the US and Canada in which adults 65 years of age and older were randomized (1:1) to receive either Fluzone High-Dose or Fluzone. The study was conducted over two influenza seasons (2011-2012 and 2012-2013); 53% of participants enrolled in the first year of the study were re-enrolled and rerandomized in the second year. The per-protocol analysis set for efficacy assessments included 15,892 Fluzone High-Dose recipients and 15,911 Fluzone recipients. The majority (67%) of participants in the per-protocol analysis set for efficacy had one or more high-risk chronic comorbid conditions. In the per-protocol analysis set, females accounted for 57.2% of participants in the Fluzone High-Dose group and 56.1% of participants in the Fluzone group. In both groups, the median age was 72.2 years (range 65 through 100 years). Overall, most participants in the study were White (95%); approximately 4% of study participants were Black, and approximately 6% reported Hispanic ethnicity. The primary endpoint of the study was the occurrence of laboratory-confirmed influenza (as determined by culture or polymerase chain reaction) caused by any influenza viral type/subtype in association with influenza-like illness (ILI), defined as the occurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature >99.0°F, chills, tiredness, headaches or myalgia. Participants were monitored for the occurrence of a respiratory illness by both active and passive surveillance, starting 2 weeks post-vaccination for approximately 7 months. After an episode of respiratory illness, nasopharyngeal swab samples were collected for analysis; attack rates and vaccine efficacy were calculated (see Table 4). Table 4: Study 2 : Relative Efficacy Against Laboratory-Confirmed Influenza Regardless of Similarity to the Vaccine Components , Associated with Influenza-Like Illness , Adults 65 Years of Age and Older Fluzone High- Dose N §=15,892 n¶ (%) Fluzone N§ =15,911 n ¶(%) Relative Efficacy % (95% CI) Any type/subtype# 227 (1.43) 300 (1.89) 24.2 (9.7; 36.5)Þ Influenza A 190 (1.20) 249 (1.56) 23.6 (7.4; 37.1) A (H1N1) 8 (0.05) 9 (0.06) 11.0 (-159.9; 70.1) A (H3N2) 171 (1.08) 222 (1.40) 22.9 (5.4; 37.2) Influenza Bß 37 (0.23) 51 (0.32) 27.4 (-13.1; 53.8) *NCT014 27309 †Laboratory-confirmed: culture- or polymerase-chain-reaction-confirmed ‡Occurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature >99.0°F, chills, tiredness, headaches or myalgia §N is the number of vaccinated participants in the per-protocol analysis set for efficacy assessments ¶n is the number of participants with protocol-defined influenza-like illness with laboratory confirmation #Primary endpoint ÞThe pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95% CI of the vaccine efficacy of Fluzone High-Dose relative to Fluzone > 9.1%) was met. ßIn the first year of the study the influenza B component of the vaccine and the majority of influenza B cases were of the Victoria lineage; in the second year the influenza B component of the vaccine and the majority of influenza B cases were of the Yamagata lineage A secondary endpoint of the study was the occurrence of culture-confirmed influenza caused by viral types/subtypes antigenically similar to those contained in the respective annual vaccine formulations in association with a modified CDC-defined ILI, defined as the occurrence of a temperature > 99.0°F (> 37.2°C) with cough or sore throat. The efficacy of Fluzone High-Dose relative to Fluzone for this endpo int was 51.1% (95% CI: 16.8; 72.0). REFERENCES 3.Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138. 4.Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutinationinhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767-777.

CLINICAL PHARMACOLOGY Mechanism Of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some human studies, antibody titer of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects [see REFERENCES]. Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter. Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year [see REFERENCES]. Clinical Studies Between 1982 and 1991, twelve clinical studies were conducted in healthy adult and geriatric subjects and one in children between 4 and 12 years of age who were considered to be 'at risk'. Since 1991 an annual clinical study has been conducted in the UK in healthy adults aged 18 years or older. FLUVIRIN® was also used as a control in a US clinical trial in adults (18-49 years of age). In all the trials, blood samples were taken prior to vaccination and approximately three weeks after vaccination to assess the immunogenic response to vaccination by measurement of anti-HA antibodies. Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 'at risk' pediatric subjects received FLUVIRIN®. FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. TABLE 5 : Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Adult Subjects Year/Strain No. of subjects Seroconversion∞ HI titer ≥1:40¥ N % 95% CIφ n % 95% CIφ 1998-1999 A/H1N1 66 48 73 (62, 83) 50 76 (65, 86) A/H3N2 43 65 (54, 77) 47 71 (60, 82) B 42 64 (52, 75) 62 94 (88, 100) 1999-2000 A/H1N1 76 45 59 (48, 70) 50 66 (55, 76) A/H3N2 51 67 (57, 78) 66 87 (79, 94) B 53 70 (59, 80) 75 99 (96, 100) 2000-2001 A/H1N1 74 41 55 (44, 67) 41 55 (44, 67) A/H3N2 45 61 (50, 72) 52 84 (75, 92) B 50 68 (57, 78) 73 99 (96, 100) 2001-2002 A/H1N1 75 44 59 (48, 70) 48 64 (53, 75) A/H3N2 46 61 (50, 72) 68 91 (84, 97) B 42 56 (45, 67) 66 88 (81, 95) 2002-2003 A/H1N1 106 62 58 (49, 68) 73 69 (60, 78) A/H3N2 72 68 (59, 77) 93 88 (81, 94) B 78 74 (65, 82) 101 95 (91, 99) 2004-2005 A/H1N1 74 52 70 (59, 80) 66 89 (80, 95) A/H3N2 60 81 (70, 89) 73 99 (93, 100) B 57 77 (66, 86) 69 93 (85, 98) 2005-2006 A/H1N1 303 191 63 (57, 68) 296 98 (95, 99) A/H3N2 273 90 (86, 93) 294 97 (94, 99) B 213 70 (65, 75) 263 87 (82, 90) ∞Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:4 0 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer. ¥HI titer ≥1:4 0: proportion of subjects with a post-vaccination titer ≥ 1:4 0. φ95% CI: 95% confidence interval Immunogenicity In Adults (18 To 64 Years Of Age) Tables 5 and 6 show the immunogenicity data for the adult age group. The seven clinical studies presented enrolled a total of 774 adult subjects. In the adult group, for all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 40%; the geometric mean titer (GMT) increase was >2.5; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 70%. Immunogenicity In Geriatric Subjects (65 Years Of Age And Older) Tables 7 and 8 show the immunogenicity of FLUVIRIN® in the geriatric age group. The six clinical studies presented enrolled a total of 296 geriatric subjects. For each of the influenza antigens, the percentage of subjects who achieved seroconversion and the percentage of subjects who achieved HI titers of ≥1:40 are shown, as well as the fold increase in GMT. TABLE 6 : Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Preand Post-Immunization, for Adult Subjects Year/Strain No. of subjects Geometric Mean Titer (GMT) Pre- vaccination Post- vaccination Fold Increase (95% CI)* 1998-1999 A/H1N1 66 7.26 160.87 22.16 (14.25, 34.46) A/H3N2 8.23 87.02 10.57 (6.91, 16.16) B 20.97 231.07 110.2 (6.90, 17.59) 1999-2000 A/H1N1 76 7.43 58.95 7.93 (5.73, 10.97) A/H3N2 15.29 122.83 8.03 (5.80, 11.13) B 25.70 254.76 9.91 (6.97, 14.10) 2000-2001 A/H1N1 74 5.42 33.80 6.24 (4.49, 8.69) A/H3N2 15.98 126.01 7.89 (5.61, 11.09) B 26.24 308.25 11.75 (7.73, 17.85) 2001-2002 A/H1N1 75 7.76 54.78 7.06 (5.24, 9.52) A/H3N2 23.67 153.81 6.50 (4.78, 8.84) B 19.91 107.53 5.40 (3.95, 7.38) 2002-2003 A/H1N1 106 7.78 60.39 7.77 (5.81, 10.39) A/H3N2 23.32 292.03 12.52 (8.77, 17.87) B 30.20 314.11 10.40 (7.54, 14.34) 2004-2005 A/H1N1 74 13 159 12 (8.39, 17) A/H3N2 37 658 18 (12, 26) B 15 156 11 (7.87, 14) 2005-2006 A/H1N1 303 29 232 8 (6.68, 9.59) A/H3N2 14 221 15 (14, 17) B 13 83 6.5 (5.73, 7.37) * 95% CI: 95% confidence interval TABLE 7 : Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Geriatric Subjects Year/Strain No. of subjects Seroconversion∞ HI titer ≥1:40¥ N % 95% CIφ N % 95% CIφ 1998-1999 A/H1N1 42 33 79 (66, 91) 38 90 (82, 99) A/H3N2 33 79 (66, 91) 36 86 (75, 96) B 13 31 (17, 45) 42 100 (100, 100) 1999-2000 A/H1N1 34 10 29 (14, 45) 23 68 (52, 83) A/H3N2 18 53 (36, 70) 31 91 (82, 100) B 9 26 (12, 41) 32 94 (86, 100) 2000-2001 A/H1N1 35 5 14 (3, 26) 10 29 (14, 44) A/H3N2 22 63 (47, 79) 31 89 (78, 99) B 13 37 (21, 53) 33 94 (87, 100) 2001-2002 A/H1N1 35 5 14 (3, 26) 14 40 (24, 56) A/H3N2 15 43 (26, 59) 33 94 (87, 100) B 6 17 (5, 30) 32 91 (82, 100) 2002-2003 A/H1N1 89 24 27 (18, 36) 52 58 (48, 69) A/H3N2 42 47 (37, 58) 85 96 (91, 100) B 41 46 (36, 56) 86 97 (93, 100) 2004-2005 A/H1N1 61 17 28 (17, 41) 46 75 (63, 86) A/H3N2 29 48 (35, 61) 60 98 (91, 100) B 38 62 (49, 74) 51 84 (72, 92) ∞Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:4 0 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer ¥HI titer ≥1:4 0: proportion of subjects with a post-vaccination titer ≥1:4 0 φ95% CI: 95% confidence interval For all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post- vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 30%; the geometric mean titer (GMT) increase was >2.0; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 60%. The pre-specified efficacy criteria were met in each study, although a relatively lower immunogenicity of A/H1N1 strain was seen in the last four studies (the same strain was in each of the formulations). Immunogenicity In Pediatric Subjects A small-scale study, was conducted in 1987 to evaluate safety and immunogenicity of FLUVIRIN® in 38 'at risk' children, with diabetes and/or asthma, or lymphoid leukemia. Thirty-eight participants aged between 4 and 12 years of age were assessed. Ten subjects had diabetes, 21 had asthma, two had both diabetes and asthma, and one had lymphoid leukemia. There were four healthy control subjects. All participants received a single 0.5-mL dose of FLUVIRIN®. Immunogenicity results were obtained for 19 of the 38 subjects enrolled in the study. The point estimate of the percentage of subjects achieving a titer of ≥ 1:40 was 84% for the A/H1N1 strain 79% for the B strain, and 53% for the A/H3N2 strain. The GMT fold increases were 5.8 for the A/H1N1 strain, 40 for the B strain and 17.7 for the A/H3N2 strain. Three clinical studies were carried out between 1995 and 2004 in a total of 520 TABLE 8 : Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Preand Post-Immunization, for Geriatric Subjects Year/Strain No. of subjects Geometric Mean Titer (GMT) Pre- vaccination Post- vaccination Fold Increase (95% CI)* 1998-1999 A/H1N1 42 13.92 176.65 12.69 (8.24, 19.56) A/H3N2 10.69 124.92 11.69 (7.02, 19.46) B 114.1 273.56 2.40 (1.82, 3.17) 1999-2000 A/H1N1 34 15.82 50.58 3.20 (2.13, 4.80) A/H3N2 28.00 133.19 4.76 (2.92, 7.76) B 57.16 127.86 2.24 (1.56, 3.20) 2000-2001 A/H1N1 35 6.66 18.85 2.83 (1.91, 4.18) A/H3N2 25.87 140.68 5.44 (3.72, 7.96) B 61.24 191.23 3.12 (2.13, 4.59) 2001-2002 A/H1N1 35 12.69 26.65 2.10 (1.55, 2.84) A/H3N2 47.33 114.26 2.41 (1.73, 3.38) B 45.49 91.89 2.02 (1.47, 2.78) 2002-2003 A/H1N1 89 13.29 31.92 2.40 (1.90, 3.03) A/H3N2 65.86 272.79 4.14 (3.09, 5.55) B 74.87 288.57 3.85 (2.89, 5.13) 2004-2005 A/H1N1 61 21 64 3.13 (2.33, 4.2) A/H3N2 72 320 4.43 (3.13, 6.27) B 20 114 5.69 (4.39, 7.38) * 95% CI: 95% confidence interval pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 'at risk' pediatric subjects, received FLUVIRIN®. In a 1995/1996 clinical study, 41 subjects (aged 6-36 months) at increased risk for influenza-related complications received two 0.25-mL doses of FLUVIRIN®. At least 49% of subjects showed a ≥4- fold increase in HI antibody titer to all three strains. HI antibody titers of 1:40 or greater were seen in at least 71% of the subjects for all three influenza strains, with increases in geometric mean titer of 6.0- fold or greater to all three strains. Two clinical studies (1999-2000 and 2004) indicated a lower immunogenicity profile for FLUVIRIN® compared with two commercial split vaccines; in a study in the age group 6-47 months the comparator was a US licensed vaccine, Fluzone®, and in another study in the age group 6-36 months the comparator was a non-US licensed inactivated influenza vaccine. Despite the small sample size (a total of 285 healthy subjects received FLUVIRIN® in these two clinical studies) the lower immunogenicity profile of FLUVIRIN® was greatest versus the comparator vaccines in children <36months but was also evident in those 36-47 months of age, though the differences were less. FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. REFERENCES 1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004; 103:133-138. 2. Hobson D, Curry RL, Beare A, et. al. The role of serum hemagglutinin- inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777. 3. Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(33):1128-1132.

CLINICAL PHARMACOLOGY Mechanism Of Action Immune mechanisms conferring protection against influenza following receipt of FluMist Quadrivalent vaccine are not fully understood; serum antibodies, mucosal antibodies, and influenza-specific T cells may play a role. FluMist and FluMist Quadrivalent contain live attenuated influenza viruses that must infect and replicate in cells lining the nasopharynx of the recipient to induce immunity. Vaccine viruses capable of infection and replication can be cultured from nasal secretions obtained from vaccine recipients (shedding) [see Pharmacodynamics]. Pharmacodynamics Shedding Studies Shedding of vaccine viruses within 28 days of vaccination with FluMist was evaluated in (1) multi-center study MI-CP129 which enrolled healthy individuals 6 through 59 months of age (N = 200); and (2) multi-center study FM026 which enrolled healthy individuals 5 through 49 years of age (N = 344). In each study, nasal secretions were obtained daily for the first 7 days and every other day through either Day 25 and on Day 28 or through Day 28. In study MI-CP129, individuals with a positive shedding sample at Day 25 or Day 28 were to have additional shedding samples collected every 7 days until culture negative on 2 consecutive samples. Results of these studies are presented in Table 5. Table 5: Characterization of Shedding with FluMist in Specified Age Groups by Frequency, Amount, and Duration (Study MI-CP129a and Study FM026b) Age Number of Subjects Sheddingc Peak Titer (TCID50/mL)d Shedding After Day 11 Day of Last Positive Culture 6-23 monthse 99 89 < 5 log10 7.0 Day 23f 24-59 months 100 69 < 5 log10 1.0 Day 25g 5-8 years 102 50 < 5 log10 2.9 Day 23h 9-17 years 126 29 < 4 log10 1.6 Day 28h 18-49 years 115 20 < 3 log10 0.9 Day 17h a NCT00344305; see www.clinicaltrials.gov b NCT00192140; see www.clinicaltrials.gov c Proportion of subjects with detectable virus at any time point during the 28 days. d Peak titer at any time point during the 28 days among samples positive for a single vaccine virus. e FluMist and FluMist Quadrivalent are not approved for use in children younger than 24 months of age [see ADVERSE REACTIONS]. f A single subject who shed previously on Days 1-3; TCID50/mL was less than 1.5 log10 on Day 23. g A single subject who did not shed previously; TCID50/mL was less than 1.5 log10. h A single subject who did not shed previously; TCID50/mL was less than 1.0 log10. The highest proportion of subjects in each group shed one or more vaccine strains on Days 2-3 post vaccination. After Day 11 among individuals 2 through 49 years of age (n = 443), virus titers did not exceed 1.5 log10 TCID50/mL. Studies In Immunocompromised Individuals Safety and shedding of vaccine virus following FluMist administration were evaluated in 28 HIV-infected adults [median CD4 cell count of 541 cells/mm³] and 27 HIV-negative adults 18 through 58 years of age. No serious adverse events were reported during the one-month follow-up period. Vaccine strain (type B) virus was detected in 1 of 28 HIV-infected subjects on Day 5 only, and in none of the HIV-negative FluMist recipients. Safety and shedding of vaccine virus following FluMist administration were also evaluated in children in a randomized (1:1), cross-over, double-blind, AF-SPG placebo-controlled trial in 24 HIV-infected children [median CD4 cell count of 1013 cells/mm³] and 25 HIV-negative children 1 through 7 years of age, and in a randomized (1:1), open-label, inactivated influenza vaccine-controlled trial in 243HIV-infected children and adolescents 5 through 17 years of age receiving stable anti-retroviral therapy. Frequency and duration of vaccine virus shedding in HIV-infected individuals were comparable to that seen in healthy individuals. No adverse effects on HIV viral load or CD4 counts were identified following FluMist administration. In the 5 through 17 year old age group, one inactivated influenza vaccine recipient and one FluMist recipient experienced pneumonia within 28 days of vaccination (days 17 and 13, respectively). The effectiveness of FluMist and FluMist Quadrivalent in preventing influenza illness in HIV-infected individuals has not been evaluated. Twenty mild to moderately immunocompromised children and adolescents 5 through 17 years of age (receiving chemotherapy and/or radiation therapy or who had received chemotherapy in the 12 weeks prior to enrollment) were randomized 1:1 to receive FluMist or AF-SPG placebo. Frequency and duration of vaccine virus shedding in these immunocompromised children and adolescents were comparable to that seen in healthy children and adolescents. The effectiveness of FluMist and FluMist Quadrivalent in preventing influenza illness in immunocompromised individuals has not been evaluated. Transmission Study A prospective, randomized, double-blind, placebo-controlled trial was performed in a daycare setting in children younger than 3 years of age to assess the transmission of vaccine viruses from a vaccinated individual to a non-vaccinated individual. A total of 197 children 8 through 36 months of age were randomized to receive one dose of FluMist (N = 98) or AF-SPG placebo (N = 99). Virus shedding was evaluated for 21 days by culture of nasal swab specimens. Wild-type A (A/H3N2) influenza virus was documented to have circulated in the community and in the study population during the trial, whereas Type A (A/H1N1) and Type B strains did not. At least one vaccine strain was isolated from 80% of FluMist recipients; strains were recovered from 1-21 days post vaccination (mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca) and temperature-sensitive (ts) phenotypes were preserved in 135 tested of 250 strains isolated at the local laboratory. Ten influenza isolates (9 influenza A, 1 influenza B) were cultured from a total of seven placebo subjects. One placebo subject had mild symptomatic Type B virus infection confirmed as a transmitted vaccine virus by a FluMist recipient in the same playgroup. This Type B isolate retained the ca, ts, and att phenotypes of the vaccine strain and had the same genetic sequence when compared to a Type B virus cultured from a vaccine recipient within the same playgroup. Four of the influenza Type A isolates were confirmed as wild-type A/Panama (H3N2). The remaining isolates could not be further characterized. Assuming a single transmission event (isolation of the Type B vaccine strain), the probability of a young child acquiring vaccine virus following close contact with a single FluMist vaccinee in this daycare setting was 0.58% (95% CI: 0, 1.7) based on the Reed-Frost model. With documented transmission of one Type B in one placebo subject and possible transmission of Type A viruses in four placebo subjects, the probability of acquiring a transmitted vaccine virus was estimated to be 2.4% (95% CI: 0.13, 4.6) using the Reed-Frost model. Pharmacokinetics Biodistribution A biodistribution study of intranasally administered radiolabeled placebo was conducted in 7 healthy adult volunteers. The mean percentages of the delivered doses detected were as follows: nasal cavity 89.7%, stomach 2.6%, brain 2.4%, and lung 0.4%. The clinical significance of these findings is unknown. Clinical Studies The effectiveness of FluMist Quadrivalent is based on data demonstrating the clinical efficacy of FluMist in children and the effectiveness of FluMist in adults, and a comparison of post vaccination geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies between individuals receiving FluMist and FluMist Quadrivalent. The clinical experience with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see DESCRIPTION]. Efficacy Studies Of FluMist In Children And Adolescents A multinational, randomized, double-blind, active-controlled trial (MI-CP111) was performed to assess the efficacy of FluMist compared to an intramuscularly administered, inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. (active control) in children 6 months to less than 5 years of age during the 2004-2005 influenza season. A total number of 3916 children without severe asthma, without use of bronchodilator or steroids, and without wheezing within the prior 6 weeks were randomized to FluMist and 3936 were randomized to active control. Children who previously received any influenza vaccine received a single dose of study vaccine, while those who never previously received an influenza vaccination (or had an unknown history of influenza vaccination) received two doses. Participants were then followed through the influenza season to identify illness caused by influenza virus. As the primary endpoint, culture-confirmed modified CDC-ILI (CDC-defined influenza-like illness) was defined as a positive culture for a wild-type influenza virus associated within ±7 days of modified CDC-ILI. Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) with cough, sore throat, or runny nose/nasal congestion on the same or consecutive days. In the primary efficacy analysis, FluMist demonstrated a 44.5% (95% CI: 22.4, 60.6) reduction in influenza rate compared to active control as measured by culture-confirmed modified CDC-ILI caused by wild-type strains antigenically similar to those contained in the vaccine. See Table 6 for a description of the results by strain and antigenic similarity. Table 6: Comparative Efficacy Against Culture-Confirmed Modified CDC-ILIa Caused by Wild-Type Strains (Study MI-CP111)b,c FluMist Active Controld % Reduction inRate for FluMiste 95% CI N # of Cases Rate (cases/N) N # of Cases Rate (cases/N) Matched Strains All strains 3916 53 1.4% 3936 93 2.4% 44.5% 22.4, 60.6 A/H1N1 3916 3 0.1% 3936 27 0.7% 89.2% 67.7, 97.4 A/H3N2 3916 0 0.0% 3936 0 0.0% -- -- B 3916 50 1.3% 3936 67 1.7% 27.3% -4.8, 49.9 Mismatched Strains All strains 3916 102 2.6% 3936 245 6.2% 58.2% 47.4, 67.0 A/H1N1 3916 0 0.0% 3936 0 0.0% -- -- A/H3N2 3916 37 0.9% 3936 178 4.5% 79.2% 70.6, 85.7 B 3916 66 1.7% 3936 71 1.8% 6.3% -31.6,33.3 Regardless of Match All strains 3916 153 3.9% 3936 338 8.6% 54.9% 45.4, 62.9 A/H1N1 3916 3 0.1% 3936 27 0.7% 89.2% 67.7, 97.4 A/H3N2 3916 37 0.9% 3936 178 4.5% 79.2% 70.6, 85.7 B 3916 115 2.9% 3936 136 3.5% 16.1% -7.7, 34.7 ATP Population. a Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) plus cough, sore throat, or runny nose/nasal congestion on the same or consecutive days. b In children 6 months through 5 years of age c NCT00128167; see www.clinicaltrials.gov d Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly. e Reduction in rate was adjusted for country, age, prior influenza vaccination status, and wheezing history status. A randomized, double-blind, saline placebo-controlled trial (D153-P501) was performed to evaluate the efficacy of FluMist in children 12 through 35 months of age without high-risk medical conditions against culture-confirmed influenza illness. This study was performed in Asia over two successive seasons (2000-2001 and 2001-2002). The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza. Respiratory illness that prompted an influenza culture was defined as at least one of the following: fever ( ≥ 100.4°F rectal or ≥ 99.5°F axillary), wheezing, shortness of breath, pulmonary congestion, pneumonia, or otitis media; or two of the following: runny nose/nasal congestion, sore throat, cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting. A total of 3174 children were randomized 3:2 (vaccine: placebo) to receive 2 doses of study vaccine or placebo at least 28 days apart in Year 1. See Table 7 for a description of the results. During the second year of Study D153-P501, for children who received two doses in Year 1 and one dose in Year 2, FluMist demonstrated 84.3% (95% CI: 70.1, 92.4) efficacy against culture-confirmed influenza illness due to antigenically matched wild-type influenza. Study AV006 was a second multi-center, randomized, double-blind, AF-SPG placebo-controlled trial performed in U.S. children without high-risk medical conditions to evaluate the efficacy of FluMist against culture-confirmed influenza over two successive seasons (1996-1997 and 1997-1998). The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza in children who received two doses of vaccine in the first year and a single revaccination dose in the second year. Respiratory illness that prompted an influenza culture was defined as at least one of the following: fever ( ≥ 101°F rectal or oral; or ≥ 100.4°F axillary), wheezing, shortness of breath, pulmonary congestion, pneumonia, or otitis media; or two of the following: runny nose/nasal congestion, sore throat, cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting. During the first year of the study, 1602 children 15 through 71 months of age were randomized 2:1 (vaccine: placebo). See Table 7 for a description of the results. Table 7: Efficacya of FluMist vs. Placebo Against Culture-Confirmed Influenza Illness Due to Antigenically Matched Wild-Type Strains (Studies D153-P501b & AV006c, Year 1) D153-P501d AV006e FluMist nf (%) Placebo nf (%) % Efficacy (95% CI) FluMist nf (%) Placebo nf (%) % Efficacy (95% CI) Ng = 1653 Ng = 1111 Ng = 849 Ng = 410 Any strain 56 (3.4%) 139 (12.5%) 72.9%h (62.8, 80.5) 10 (1%) 73 (18%) 93.4% (87.5, 96.5) A/H1N1 23 (1.4%) 81 (7.3%) 80.9% (69.4, 88.5)i 0 0 -- A/H3N2 4 (0.2%) 27 (2.4%) 90.0% (71.4, 97.5) 4 (0.5%) 48 (12%) 96.0% (89.4, 98.5) B 29 (1.8%) 35 (3.2%) 44.3% (6.2, 67.2) 6 (0.7%) 31 (7%) 90.5% (78.0, 95.9) a D153-P501 and AV006 data are for subjects who received two doses of study vaccine. b In children 12 through 35 months of age c In children 15 through 71 months of age d NCT00192244; see www.clinicaltrials.gov e NCT00192179; see www.clinicaltrials.gov f Number and percent of subjects in per-protocol efficacy analysis population with culture-confirmed influenza illness. g Number of subjects in per-protocol efficacy analysis population of each treatment group of each study for the “any strain” analysis. h For D153-P501, influenza circulated through 12 months following vaccination. i Estimate includes A/H1N1 and A/H1N2 strains. Both were considered antigenically similar to the vaccine. During the second year of Study AV006, children remained in the same treatment group as in Year 1and received a single dose of FluMist or placebo. During the second year, the primary circulating strain was the A/Sydney/05/97 H3N2 strain, which was antigenically dissimilar from the H3N2 strain represented in the vaccine, A/Wuhan/359/95; FluMist demonstrated 87.0% (95% CI: 77.0, 92.6) efficacy against culture-confirmed influenza illness. Immune Response Study Of FluMist Quadrivalent In Children And Adolescents A multicenter, randomized, double-blind, active-controlled, non-inferiority study (MI-CP208) was performed to assess the immunogenicity of FluMist Quadrivalent compared to FluMist (active control) in children and adolescents 2 through 17 years of age. A total of 2312 subjects were randomized by site at a 3:1:1 ratio to receive either FluMist Quadrivalent or one of two formulations of comparator vaccine FluMist, each containing a B strain that corresponded to one of the two B strains in FluMist Quadrivalent (a B strain of the Yamagata lineage or a B strain of the Victoria lineage). Children 2 through 8 years of age received 2 doses of vaccine approximately 30 days apart; children 9 years of age and older received 1 dose. For children 2 through 8 years of age with a history of influenza vaccination, immunogenicity assessments were performed prior to vaccination and at 28 days after the first dose. For children 2 through 8 years of age without a history of influenza vaccination, immunogenicity assessments were performed prior to vaccination and 28 days after the second dose. For children 9 years of age and older, immunogenicity assessments were performed prior to vaccination and at 28 days post vaccination. Immunogenicity was evaluated by comparing the 4 strain-specific serum hemagglutination inhibition (HAI) antibody geometric mean titers (GMTs) post dosing and provided evidence that the addition of the second B strain did not result in immune interference to other strains included in the vaccine. Effectiveness Study Of FluMist In Adults AV009 was a U.S. multi-center, randomized, double-blind, AF-SPG placebo-controlled trial to evaluate effectiveness of FluMist in adults 18 through 64 years of age without high-risk medical conditions over the 1997-1998 influenza season. Participants were randomized 2:1 (vaccine: placebo). Cultures for influenza virus were not obtained from subjects in the trial, thus efficacy against culture-confirmed influenza was not assessed. The A/Wuhan/359/95 (H3N2) strain, which was contained in FluMist, was antigenically distinct from the predominant circulating strain of influenza virus during the trial period, A/Sydney/05/97 (H3N2). Type A/Wuhan (H3N2) and Type B strains also circulated in the U.S. during the study period. The primary endpoint of the trial was the reduction in the proportion of participants with one or more episodes of any febrile illness, and prospective secondary endpoints were severe febrile illness and febrile upper respiratory illness. Effectiveness for any of the three endpoints was not demonstrated in a subgroup of adults 50 through 64 years of age. Primary and secondary effectiveness endpoints from the age group 18 through 49 years are presented in Table 8. Effectiveness was not demonstrated for the primary endpoint in adults 18 through 49 years of age. Table 8: Effectiveness of FluMist to Prevent Febrile Illness in Adults 18 through 49 Years of Age During the 7-Week Site-Specific Outbreak Period (Study AV009) Endpoint FluMist N = 2411a n (%) Placebo N = 1226a n (%) Percent Reduction (95% CI) Participants with one or more events of:b Primary Endpoint: Any febrile illness 331 (13.73) 189 (15.42) 10.9 (-5.1, 24.4) Secondary Endpoints: Severe febrile illness 250 (10.37) 158 (12.89) 19.5 (3.0, 33.2) Febrile upper respiratory illness 213 (8.83) 142 (1 1.58) 23.7 (6.7, 37.5) a Number of evaluable subjects (92.7% and 93.0% of FluMist and placebo recipients, respectively). b The predominantly circulating virus during the trial period was A/Sydney/05/97 (H3N2), an antigenic variant not included in the vaccine. Effectiveness was shown in a post-hoc analysis using an endpoint of CDC-ILI in the age group 18 through 49 years of age. Immune Response Study Of FluMist Quadrivalent In Adults A multicenter, randomized, double-blind, active-controlled, and non-inferiority study (MI-CP185) was performed to assess the safety and immunogenicity of FluMist Quadrivalent compared to those of FluMist (active control) in adults 18 through 49 years of age. A total of 1800 subjects were randomized by site at a 4:1:1 ratio to receive either 1 dose of FluMist Quadrivalent or 1 dose of one of two formulations of comparator vaccine, FluMist, each containing a B strain that corresponded to one of the two B strains in FluMist Quadrivalent (a B strain of the Yamagata lineage and a B strain of the Victoria lineage). Immunogenicity in study MI-CP185 was evaluated by comparing the 4 strain-specific serum hemagglutination inhibition (HAI) antibody geometric mean titers (GMTs) post dosing and provided evidence that the addition of the second B strain did not result in immune interference to other strains included in the vaccine. Concomitantly Administered Live Virus Vaccines In Study AV018, concomitant administration of FluMist, MMR (manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) was studied in 1245 subjects 12 through 15 months of age. Subjects were randomized in a 1:1:1 ratio to MMR, Varicella vaccine and AF-SPG placebo (group 1); MMR, Varicella vaccine and FluMist (group 2); or FluMist alone (group 3). Immune responses to MMR and Varicella vaccines were evaluated 6 weeks post-vaccination while the immune responses to FluMist were evaluated 4 weeks after the second dose. No evidence of interference with immune response to measles, mumps, rubella, varicella and FluMist vaccines was observed. REFERENCES 1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992 - 1993 and 1993 - 1994 influenza vaccines. N Engl J Med 1998;339(25):1797-802.

CLINICAL PHARMACOLOGY Mechanism Of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Public health authorities recommend influenza vaccine strains annually. Inactivated influenza vaccines are standardized to contain the hemagglutinins of strains representing the influenza viruses likely to circulate in the United States during the influenza season. Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies, antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Annual revaccination is recommended because immunity declines during the year after vaccination and because circulating strains of influenza virus change from year to year. Clinical Studies Efficacy Against Influenza The efficacy of FLULAVAL QUADRIVALENT was evaluated in Trial 3, a randomized, observerblind, non-influenza vaccine-controlled trial conducted in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy subjects aged 3 through 8 years were randomized (1:1) to receive FLULAVAL QUADRIVALENT (n = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) influenza strains, or HAVRIX (n = 2,584), as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX [see ADVERSE REACTIONS]. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years. Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse transcriptase polymerase chain reaction (RT-PCR)-positive influenza A and/or B disease presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥100°F in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine efficacy was calculated based on the ATP cohort for efficacy (Table 6). Table 6: FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy against Influenza A and/or B in Children Aged 3 through 8 Yearsa (According-to-Protocol Cohort for Efficacy) Nb nc Influenza Attack Rate % (n/N) Vaccine Efficacy % (CI) All RT-PCR-Positive Influenza FLULAVAL QUADRIVALENT 2,379 58 2.4 55.4d (95% CI: 39.1, 67.3) HAVRIXe 2,398 128 5.3 — All Culture-Confirmed Influenzaf FLULAVAL QUADRIVALENT 2,379 50 2.1 55.9 (97.5% CI: 35.4, 69.9) HAVRIXe 2,398 112 4.7 — Antigenically Matched Culture-Confirmed Influenza FLULAVAL QUADRIVALENT 2,379 31 1.3 45.1g (97.5% CI: 9.3, 66.8) HAVRIXe 2,398 56 2.3 — CI = Confidence Interval; RT-PCR = Reverse transcriptase polymerase chain reaction. aTrial 3: NCT01218308. bAccording-to-protocol cohort for efficacy included subjects who met all eligibility criteria, were successfully contacted at least once post-vaccination, and complied with the protocol-specified efficacy criteria. cNumber of influenza cases. dVaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% for the lower limit of the 2-sided 95% CI. eHepatitis A Vaccine used as a control vaccine. fOf 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)]. gSince only 67% of cases could be typed, the clinical significance of this result is unknown. In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or B disease presenting as ILI was evaluated in subjects aged 3 through 4 years and 5 through 8 years; vaccine efficacy was 35.3% (95% CI: 1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), respectively. As the trial lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown. As a secondary objective in the trial, subjects with RT-PCR-positive influenza A and/or B were prospectively classified based on the presence of adverse outcomes that have been associated with influenza infection (defined as fever >102.2°F/39.0°C, physician-verified shortness of breath, pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary congestion, croup, and/or acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including myositis, encephalitis, seizure and/or myocarditis). The risk reduction of fever >102.2°F/39.0°C associated with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 7. Table 7: FLULAVAL QUADRIVALENT: Incidence of Advers e Outcomes As s ociated with RTPCR- Pos itive Influenza in Children Aged 3 through 8 Yearsa (Total Vaccinated Cohort)b Adverse Outcomed FLULAVAL QUADRIVALENT n = 2,584 HAVRIXc n = 2,584 Number of Events Number of Subjectse % Number of Events Number of Subjectse % Fever >102.2°F/ 39.0°C 16f 15 0.6 51f 50 1.9 Shortness of breath 0 0 0 5 5 0.2 Pneumonia 0 0 0 3 3 0.1 Wheezing 1 1 0 1 1 0 Bronchitis 1 1 0 1 1 0 Pulmonary congestion 0 0 0 1 1 0 Acute otitis media 0 0 0 1 1 0 Bronchiolitis 0 0 0 0 0 0 Croup 0 0 0 0 0 0 Encephalitis 0 0 0 0 0 0 Myocarditis 0 0 0 0 0 0 Myositis 0 0 0 0 0 0 Seizure 0 0 0 0 0 0 aTrial 3: NCT01218308. bTotal vaccinated cohort included all vaccinated subjects for whom data were available. cHepatitis A Vaccine used as a control vaccine. dIn subjects who presented with more than one adverse outcome, each outcome was counted in the respective category. eNumber of subjects presenting with at least one event in each group. fOne subject in each group had sequential influenza due to influenza type A and type B viruses. Immunological Evaluation Adults Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial conducted in subjects aged 18 years and older. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,246) or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 204 or TIV-2, n = 211), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see ADVERSE REACTIONS]. Immune responses, specifically hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoint was GMTs adjusted for baseline, performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results were available after vaccination. FLULAVAL QUADRIVALENT was noninferior to both TIVs based on adjusted GMTs (Table 8). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 8). Table 8: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) 21 Days Pos t-vaccination in Adults Aged 18 Years and Oldera (According-to- Protocol Cohort for Immunogenicity)b FLULAVAL QUADRIVALENTc TIV-1 (B Victoria)d TIV-2 (B Yamagata)e Geometric Mean Titers Against n = 1,245-1,246 (95% CI) n = 204 (95% CI) n = 210-211 (95% CI) A/California/7/2009 (H1N1) 204.6f (190.4, 219.9) 176.0 (149.1, 207.7) 149.0 (122.9, 180.7) A/Victoria/210/2009 (H3N2) 125.4f (117.4, 133.9) 147.5 (124.1, 175.2) 141.0 (118.1, 168.3) B/Brisbane/60/2008 (Victoria lineage) 177.7f (167.8, 188.1) 135.9 (118.1, 156.5) 71.9 (61.3, 84.2) B/Florida/4/2006 (Yamagata lineage) 399.7f (378.1, 422.6) 176.9 (153.8, 203.5) 306.6 (266.2, 353.3) CI = Confidence Interval. aTrial 1: NCT01196975. bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. cContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). dContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage). eContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage). fNoninferior to both TIVs based on adjusted GMTs [upper limit of the 2sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5]; superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5]. Children Trial 4 was a randomized, observer-blind, active-controlled trial in children aged 6 through 35 months which was conducted in the United States and Mexico. In this trial, subjects received 0.5 mL of FLULAVAL QUADRIVALENT containing 15 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,207); or 0.25 mL of control vaccine FLUZONE QUADRIVALENT (Influenza Vaccine) containing 7.5 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,217) [ see ADVERSE REACTIONS]. Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following completion of vaccination regimen. Previously vaccinated children received one dose and previously unvaccinated children (i.e., unprimed individuals) received 2 doses 4 weeks apart of FLULAVAL QUADRIVALENT or the comparator. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to the comparator for all 4 vaccine strains based on adjusted GMTs and seroconversion rates (Table 9). Table 9: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Comparator Quadrivalent Influenza Vaccine at 28 Days Post-vaccination in Children Aged 6 through 35 Monthsa (According-to-Protocol Cohort for Immunogenicity)b Adjusted Geometric Mean Titers Against FLULAVAL QUADRIVALENTc Active Comparatord n= 972-974 n= 980 A/California/07/2009 (H1N1) 99.6e 85.1 A/Texas/50/2012 (H3N2) 99.8e 84.6 B/Massachusetts/02/2012 (Yamagata lineage) 258.1e 167.3 B/Brisbane/60/2008 (Victoria lineage) 54.5e 33.7 Seroconversionf to: n= 972-974 % (95% CI) n= 980 % (95% CI) A/California/07/2009 (H1N1) 73.7e (70.8, 76.4) 67.3 (64.3, 70.3) A/Texas/50/2012 (H3N2) 76.1e (73.3, 78.8) 69.4 (66.4, 72.3) B/Massachusetts/02/2012 (Yamagata lineage) 85.5e (83.2, 87.7) 73.8 (70.9, 76.5) B/Brisbane/60/2008 (Victoria lineage) 64.9e (61.8, 67.9) 48.5 (45.3, 51.6) CI = Confidence Interval a Trial 4: NCT02242643. bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. cA 0.5-mL dose containing 15 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). dA 0.25-mL dose of U.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.) containing 7.5 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), eB/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). Noninferior to the comparator vaccine based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (comparator/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2sided 95% CI on difference of comparator vaccine minus FLULAVAL QUADRIVALENT ≤10%). fSeroconversion defined as a 4fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40. Trial 2 was a randomized, double-blind, active-controlled trial conducted in children aged 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 878), or one of 2 formulations of a comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 871 or TIV-2 n = 878), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see ADVERSE REACTIONS]. Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following one or 2 doses of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as at least a 4fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs and seroconversion rates (Table 10). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 10). Table 10: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) at 28 Days Post-vaccination in Children Aged 3 through 17 Yearsa (According-to- Protocol Cohort for Immunogenicity)b Geometric Mean Titers Against FLULAVAL QUADRIVALENTc TIV-1 (B Victoria)d TIV-2 (B Yamagata)e n= 878 (95% CI) n= 871 (95% CI) n= 877-878 (95% CI) A/California/7/2009 (H1N1) 362.7f (335.3, 392.3) 429.1 (396.5, 464.3) 420.2 (388.8, 454.0) A/Victoria/210/2009 (H3N2) 143.7f (134.2, 153.9) 139.6 (130.5, 149.3) 151.0 (141.0, 161.6) B/Brisbane/60/2008 (Victoria lineage) 250.5f (230.8, 272.0) 245.4 (226.9, 265.4) 68.1 (61.9, 74.9) B/Florida/4/2006 (Yamagata lineage) 512.5f (477.6, 549.9) 197.0 (180.7, 214.8) 579.0 (541.2, 619.3) Seroconversiong to: n= 876 % (95% CI) n= 870 % (95% CI) n= 876-877 % (95% CI) A/California/7/2009 (H1N1) 84.4f (81.8, 86.7) 86.8 (84.3, 89.0) 85.5 (83.0, 87.8) A/Victoria/210/2009 (H3N2) 70.1f (66.9, 73.1) 67.8 (64.6, 70.9) 69.6 (66.5, 72.7) B/Brisbane/60/2008 (Victoria lineage) 74.5f (71.5, 77.4) 71.5 (68.4, 74.5) 29.9 (26.9, 33.1) B/Florida/4/2006 (Yamagata lineage) 75.2f (72.2, 78.1) 41.3 (38.0, 44.6) 73.4 (70.4, 76.3) CI = Confidence Interval. aTrial 2: NCT01198756. bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. cContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). dContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage). eContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage). fNoninferior to both TIVs based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2sided 95% CI on difference of the TIV minus FLULAVAL QUADRIVALENT ≤10%); superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5] and seroconversion rates (lower limit of the 2sided 95% CI on difference of FLULAVAL QUADRIVALENT minus the TIV >10%). gSeroconversion defined as a 4fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40. REFERENCES 1 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138. 2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767- 777.

CLINICAL PHARMACOLOGY Mechanism Of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Public health authorities give annual influenza vaccine composition recommendations. Inactivated influenza vaccines are standardized to contain the hemagglutinins of influenza viruses representing the virus types or subtypes likely to circulate in the United States during the influenza season. Two influenza type B virus lineages (Victoria and Yamagata) are of public health importance because they have co-circulated since 2001. FLUARIX (trivalent influenza vaccine) contains 2 influenza A subtype viruses and one influenza type B virus. Specific levels of hemagglutination-inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the HI antibody titers have been used as a measure of vaccine activity. In some human challenge studies, HI antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virological basis for seasonal epidemics and the reason for the usual replacement of one or more influenza viruses in each year's influenza vaccine. Annual revaccination is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year. Clinical Studies Efficacy Against Culture-Confirmed Influenza The efficacy experience with FLUARIX is relevant to FLUARIX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions [see DESCRIPTION]. The efficacy of FLUARIX was evaluated in a randomized, double-blind, placebo-controlled trial conducted in 2 European countries during the 2006-2007 influenza season. Efficacy of FLUARIX, containing A/New Caledonia/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 influenza virus strains, was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects aged 18 through 64 years (mean age: 40 years) were randomized (2:1) to receive FLUARIX (n = 5,103) or placebo (n = 2,549) and monitored for influenza-like illnesses (ILI) starting 2 weeks postvaccination and lasting for approximately 7 months. In the overall population, 60% of subjects were female and 99.9% were white. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as at least one general symptom (fever ≥100°F and/or myalgia) and at least one respiratory symptom (cough and/or sore throat). After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated (Table 6). Table 6: FLUARIX (Trivalent Formulation): Attack Rates and Vaccine Efficacy against Culture- Confirmed Influenza A and/or B in Adults (Total Vaccinated Cohort) N n Attack Rates (n/N) Vaccine Efficacy % % LL UL Antigenically Matched Strainsa FLUARIX 5,103 49 1.0 66.9b 51.9 77.4 Placebo 2,549 74 2.9 — — — All Culture-Confirmed Influenza (Matched, Unmatched, and Untyped)c FLUARIX 5,103 63 1.2 61.6b 46.0 72.8 Placebo 2,549 82 3.2 — — — aThere were no vaccine matched culture-confirmed cases of A/New Caledonia/20/1999 (H1N1) or B/Malaysia/2506/2004 influenza virus strains with FLUARIX or placebo. bVaccine efficacy for FLUARIX exceeded a pre-defined threshold of 35% for the lower limit of the 2-sided 95% CI. cOf the 22 additional cases, 18 were unmatched and 4 were untyped; 15 of the 22 cases were A (H3N2) (11 cases with FLUARIX and 4 cases with placebo). In a post-hoc, exploratory analysis by age, vaccine efficacy (against culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains) in subjects aged 18 through 49 years was 73.4% (95% CI: 59.3, 82.8) (number of influenza cases: FLUARIX [n = 35/3,602] and placebo [n = 66/1,810]). In subjects aged 50 through 64 years, vaccine efficacy was 13.8% (95% CI: 137.0, 66.3) (number of influenza cases: FLUARIX [n = 14/1,501] and placebo [n = 8/739]). As the trial lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown. Immunological Evaluation Of FLUARIX QUADRIVALENT In Adults Trial 1 was a randomized, double-blind (2 arms) and open-label (one arm), active-controlled, safety, immunogenicity, and non-inferiority trial. In this trial, subjects received FLUARIX QUADRIVALENT (n = 1,809) or one of 2 formulations of comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 608 or TIV-2, n = 534), each containing an influenza type B virus that corresponded to one of the 2 type B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). Subjects aged 18 years and older (mean age: 58 years) were evaluated for immune responses to each of the vaccine antigens 21 days following vaccination. In the overall population, 57% of subjects were female; 69% were white, 27% were Asian, and 4% were of other racial/ethnic groups. The immunogenicity endpoints were GMTs of serum hemagglutination-inhibition (HI) antibodies adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a prevaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4fold increase in serum HI antibody titer over baseline to ≥1:40 following vaccination, performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results were available after vaccination. FLUARIX QUADRIVALENT was noninferior to both TIVs based on adjusted GMTs (upper limit of the 2sided 95% CI for the GMT ratio [TIV/FLUARIX QUADRIVALENT] ≤1.5) and seroconversion rates (upper limit of the 2sided 95% CI on difference of the TIV minus FLUARIX QUADRIVALENT ≤10%). The antibody response to influenza B strains contained in FLUARIX QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 7). Table 7: FLUARIX QUADRIVALENT: Immune Responses to Each Antigen 21 Days after Vaccination in Adults (ATP Cohort for Immunogenicity) GMTs FLUARIX QUADRIVALENTa Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)b TIV-2 (B Yamagata)c n = 1,809 (95% CI) n = 608 (95% CI) n = 534 (95% CI) A/California/7/2009 (H1N1) 201.1 (188.1, 215.1) 218.4 (194.2, 245.6) 213.0 (187.6, 241.9) A/Victoria/210/2009 (H3N2) 314.7 (296.8, 333.6) 298.2 (268.4, 331.3) 340.4 (304.3, 380.9) B/Brisbane/60/2008 (Victoria lineage) 404.6 (386.6, 423.4) 393.8 (362.7, 427.6) 258.5 (234.6, 284.8) B/Brisbane/3/2007 (Yamagata lineage) 601.8 (573.3, 631.6) 386.6 (351.5, 425.3) 582.5 (534.6, 634.7) Seroconversiond n = 1,801 % (95% CI) n = 605 % (95% CI) n = 530 % (95% CI) A/California/7/2009 (H1N1) 77.5 (75.5, 79.4) 77.2 (73.6, 80.5) 80.2 (76.5, 83.5) A/Victoria/210/2009 (H3N2) 71.5 (69.3, 73.5) 65.8 (61.9, 69.6) 70.0 (65.9, 73.9) B/Brisbane/60/2008 (Victoria lineage) 58.1 (55.8, 60.4) 55.4 (51.3, 59.4) 47.5 (43.2, 51.9) B/Brisbane/3/2007 (Yamagata lineage) 61.7 (59.5, 64.0) 45.6 (41.6, 49.7) 59.1 (54.7, 63.3) ATP = Accordingtoprotocol; GMT = Geometric mean antibody titer; CI = Confidence Interval. ATP cohort for immunogenicity included subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. aContained the same composition as FLUARIX (trivalent formulation) manufactured for the 2010-2011 season and an additional influenza type B virus of Yamagata lineage. bContained the same composition as FLUARIX manufactured for the 2010-2011 season (2 influenza A subtype viruses and an influenza type B virus of Victoria lineage). cContained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-2011 season and an influenza type B virus of Yamagata lineage. dSeroconversion defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4-fold increase in serum titers of HI antibodies to ≥1:40. Immunological Evaluation Of FLUARIX QUADRIVALENT In Children Trial 2 was a randomized, double-blind, active-controlled, safety, immunogenicity, and non-inferiority trial. In this trial, subjects received FLUARIX QUADRIVALENT (n = 791) or one of 2 formulations of comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 819 or TIV-2, n = 801), each containing an influenza type B virus that corresponded to one of the 2 type B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). In children aged 3 through 17 years, immune responses to each of the vaccine antigens were evaluated in sera 28 days following 1 or 2 doses. In the overall population, 52% of subjects were male; 56% were white, 29% were Asian, 12% were black, and 3% were of other racial/ethnic groups. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort for whom immunogenicity assay results were available after vaccination. FLUARIX QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs (upper limit of the 2sided 95% CI for the GMT ratio [TIV/FLUARIX QUADRIVALENT] ≤1.5) and seroconversion rates (upper limit of the 2sided 95% CI on difference of the TIV minus FLUARIX QUADRIVALENT ≤10%). The antibody response to influenza B strains contained in FLUARIX QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 8). Table 8: FLUARIX QUADRIVALENT: Immune Responses to Each Antigen 28 Days after Last Vaccination in Children Aged 3 through 17 Years (ATP Cohort for Immunogenicity) GMTs FLUARIX QUADRIVALENTa Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)b TIV-2 (B Yamagata)c n = 791 (95% CI) n = 818 (95% CI) n = 801 (95% CI) A/California/7/2009 (H1N1) 386.2 (357.3, 417.4) 433.2 (401.0, 468.0) 422.3 (390.5, 456.5) A/Victoria/210/2009 (H3N2) 228.8 (215.0, 243.4) 227.3 (213.3, 242.3) 234.0 (219.1, 249.9) B/Brisbane/60/2008 (Victoria lineage) 244.2 (227.5, 262.1) 245.6 (229.2, 263.2) 88.4 (81.5, 95.8) B/Brisbane/3/2007 (Yamagata lineage) 569.6 (533.6, 608.1) 224.7 (207.9, 242.9) 643.3 (603.2, 686.1) Seroconversiond n = 790% (95% CI) n = 818% (95% CI) n = 800% (95% CI) A/California/7/2009 (H1N1) 91.4 (89.2, 93.3) 89.9 (87.6, 91.8) 91.6 (89.5, 93.5) A/Victoria/210/2009 (H3N2) 72.3 (69.0, 75.4) 70.7 (67.4, 73.8) 71.9 (68.6, 75.0) B/Brisbane/60/2008 (Victoria lineage) 70.0 (66.7, 73.2) 68.5 (65.2, 71.6) 29.6 (26.5, 32.9) B/Brisbane/3/2007 (Yamagata lineage) 72.5 (69.3, 75.6) 37.0 (33.7, 40.5) 70.8 (67.5, 73.9) ATP = Accordingtoprotocol; GMT = Geometric mean antibody titer; CI = Confidence Interval. ATP cohort for immunogenicity included subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. aContained the same composition as FLUARIX (trivalent formulation) manufactured for the 2010-2011 season and an additional influenza type B virus of Yamagata lineage. bContained the same composition as FLUARIX manufactured for the 2010-2011 season (2 influenza A subtype viruses and an influenza type B virus of Victoria lineage). cContained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-2011 season and an influenza B virus of Yamagata lineage. dSeroconversion defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4-fold increase in serum titers of HI antibodies to ≥1:40. REFERENCES 1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res. 2004;103:133-138. 2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb. 1972;70:767-777.

CLINICAL PHARMACOLOGY Mechanism Of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977 antigenic variants of influenza A (H1N1 and H3N2) and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza vaccine have not been correlated with protection from influenza virus. In some human studies, antibody titers of 1:40 or greater have been associated with protection from influenza illness in up to 50% of subjects.2,3 Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change to one or more new strains in each year’s influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the HA of three strains (i.e., typically two type A and one type B) representing the influenza viruses likely to be circulating in the US during the upcoming winter. Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination and circulating strains of influenza virus change from year to year.1 Clinical Studies Efficacy Against Laboratory-Confirmed Influenza In Study 5, the efficacy of AFLURIA was demonstrated in a randomized, observer-blind, placebo-controlled study conducted in 15,044 subjects. Healthy subjects 18 through 64 years of age were randomized in a 2:1 ratio to receive a single dose of AFLURIA (enrolled subjects: 10,033; evaluable subjects: 9,889) or placebo (enrolled subjects: 5,011; evaluable subjects: 4,960). The mean age of all randomized subjects was 35.5 years. 54.4% were female and 90.2% were White. Laboratory-confirmed influenza was assessed by active and passive surveillance of influenza-like illness (ILI) beginning 2 weeks postvaccination until the end of the influenza season, approximately 6 months post-vaccination. ILI was defined as at least one respiratory symptom (e.g., cough, sore throat, nasal congestion) and at least one systemic symptom (e.g., oral temperature of 100.0°F or higher, feverishness, chills, body aches). Nasal and throat swabs were collected from subjects who presented with an ILI for laboratory confirmation by viral culture and real-time reverse transcription polymerase chain reaction. Influenza virus strain was further characterized using gene sequencing and pyrosequencing. Attack rates and vaccine efficacy, defined as the relative reduction in the influenza infection rate for AFLURIA compared to placebo, were calculated using the per protocol population. Vaccine efficacy against laboratoryconfirmed influenza infection due to influenza A or B virus strains contained in the vaccine was 60% with a lower limit of the 95% CI of 41% (Table 6). Table 6: Laboratory-Confirmed Influenza Infection Rate and Vaccine Efficacy in Adults 18 through 64 Years of Age (Study 5) Subjects a Laboratory- Confirmed Influenza Cases Influenza Infection Rate Vaccine Efficacy b N N n/N % % Lower Limit of the 95% CI Vaccine-matched Strains AFLURIA 9889 58 0.59 60 41 Placebo 4960 73 1.47 Any Influenza Virus Strain AFLURIA 9889 222 2.24 42 28 Placebo 4960 192 3.87 Abbreviations: CI, confidence interval a The Per Protocol Population was identical to the Evaluable Population in this study. b Vaccine efficacy = 1 minus the ratio of AFLURIA/placebo infection rates. The objective of the study was to demonstrate that the lower limit of the CI for vaccine efficacy was greater than 40%. Immunogenicity In Children — Administration Via Needle And Syringe Study 1 was a randomized, observer-blind, comparator-controlled study to evaluate the immunological non-inferiority of AFLURIA to a US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur, Inc.) in subjects 6 months through 17 years of age. Study vaccines were administered by needle and syringe. Results are presented for children 5 through 17 years of age (Table 7). A total of 832 subjects (aged 5 through 17 years) were enrolled. Subjects were randomized in a 1:1 ratio to receive AFLURIA (enrolled subjects: 417; evaluable subjects: 383) or the comparator vaccine (enrolled subjects: 415; evaluable subjects: 383). Children 6 months through 8 years of age with no history of influenza vaccination received 2 doses approximately 28 days apart. Children 6 months through 8 years of age with a history of influenza vaccination and children 9 years of age and older received 1 dose. Children 6 months through 35 months of age received 0.25 mL of AFLURIA or comparator influenza vaccine, and children 3 years of age and older received 0.5 mL of AFLURIA or comparator influenza vaccine. Nearly equal proportions of subjects were male (49.9%) and female (50.1%), and the majority were White (85.0%) or Black (10.3%). Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. The co-primary endpoints were HI Geometric Mean Titer (GMT) ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after the final vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 7, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For influenza type B, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects. Analysis of the 761 subjects aged 5 through 17 years reduced the power of the study and widened the confidence intervals. In the pre-specified analysis, AFLURIA was not inferior to the comparator vaccine for all three virus strains. Post-hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities. Table 7: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a US-Licensed Comparator, Subjects 5 through 17 Years of Age (Study 1) Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both predefined non-inferiority criteria? c Strain Comparator N=381 AFLURIA N=380 Comparator over AFLURIA (95% CI) Comparator N=381 AFLURIA N=380 Comparator minus AFLURIA (95% CI) A (H1N1) 526.2 507.4 1.03 (0.88, 1.21) 62.7 62.6 0.1 (-6.8, 7.0) Yes A (H3N2 1060.0 961.3 1.07 (0.94, 1.23) 72.2 69.7 2.4 (-4.0, 8.9) Yes B 123.3 110.1 1.10 (0.94, 1.29) 75.1 70.0 5.1 (-1.3, 11.4) No Abbreviations: CI, confidence interval; GMT, geometric mean titer. a GMT ratios are adjusted for baseline HI titers. b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40. c Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects. Immunogenicity In Adults And Older Adults— Administration Via Needle And Syringe Two randomized, controlled clinical studies of AFLURIA evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine in adults as compared to placebo (adults 18 through 64 years) or another USlicensed trivalent influenza vaccine (adults ≥ 65 years). In these studies, postvaccination immunogenicity was evaluated on sera obtained 21 days after administration of a single dose of AFLURIA. Study 4 was a randomized, double-blinded, placebo-controlled, multi-center study in healthy subjects ages 18 through 64 years. A total of 1,357 subjects were vaccinated (1,089 subjects with AFLURIA and 268 with a placebo). Subjects who received AFLURIA were vaccinated using either the preservativefree or thimerosal-containing presentation. The evaluable population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group). The mean age of the entire evaluable population receiving AFLURIA was 38 years. 62.5% of subjects were female, 81.3% were White, 12.1% were Black, and 6.2% were Asian. Serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 8). Similar responses were observed between genders. The study was not sufficiently diverse to assess immunogenicity by race or ethnicity. Table 8: Serum Antibody Responses in Subjects 18 through 64 Years of Age Receiving AFLURIA (Study 4) Strain Variable AFLURIA N=1077 value (95% CI) Placebo N=264 value (95% CI) A(H1N1) HI Titer ≥ 1:40 a 97.8% (96.7, 98.6) 74.6% (68.9, 79.8) Seroconversion Rate (%) b 48.7% (45.6, 51.7) 2.3% (0.8, 4.9) A(H3N2) HI Titer ≥ 1:40 a 99.9% (99.5, 100.0) 72.0% (66.1, 77.3) Seroconversion Rate (%) b 71.5% (68.7, 74.2) 0.0% (N/A) B HI Titer ≥ 1:40 a 94.2% (92.7, 95.6) 47.0% (40.8, 53.2) Seroconversion Rate (%) b 69.7% (66.9, 72.5) 0.4% (< 0.1, 2.1) a HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. Lower bound of 95% CI for HI antibody titer ≥ 1:40 should be > 70% for the study population. b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40. Lower bound of 95% CI for seroconversion should be > 40% for the study population. Study 6 was a randomized, observer-blind, comparator-controlled study that enrolled 1,268 subjects 65 years of age and older (Table 9). This study compared the immune response following administration of AFLURIA to that following a US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.). Subjects were randomized in a 1:1 ratio to receive a single vaccination of AFLURIA (enrolled subjects: 631; evaluable subjects: 605) or the comparator vaccine (enrolled subjects: 637; evaluable subjects: 610). Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. Most of the subjects in the per-protocol immunogenicity population were female (56.7%) and White (97.4%). 2.0% were Black and less than 1.0% were of other races or ethnicities. The co-primary endpoints were HI GMT ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 9, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For the B strain, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Post-hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities. Table 9: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a US-Licensed Comparator, Adults 65 Years of Age and Older (Study 6) Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined non-inferiority criteria? Strain Comparator N=610 AFLURIA N=605 Comparator over AFLURIA (95% CI) Comparator N=610 AFLURIA N=605 Comparator minus AFLURIA (95% CI) A(H1N1) 59.2 59.4 1.04 (0.92, 1.18) 43.0 38.8 4.1 (-1.4, 9.6) Yes A(H3N2) 337.7 376.8 0.95 (0.83, 1.08) 68.7 69.4 -0.7 (-5.9, 4.5) Yes B 33.4 30.4 1.12 (1.01, 1.25) 34.4 29.3 5.2 (-0.1, 10.4) No Abbreviations: CI, confidence interval; GMT, geometric mean titer. a Post-vaccination GMTs were adjusted for baseline HI titers. b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40. Immunogenicity In Adults – Administration Via Pharmajet Stratis Needle-Free Injection System Study 8 was a randomized, comparator-controlled non-inferiority study that enrolled 1,250 subjects 18 through 64 years of age. This study compared the immune response following administration of AFLURIA when delivered IM using either the PharmaJet Stratis Needle-Free Injection System or needle and syringe. Immunogenicity assessments were performed prior to vaccination and at 28 days after vaccination in the immunogenicity population (1,130 subjects, 562 PharmaJet Stratis Needle-Free Injection System group, 568 needle and syringe group). The co-primary endpoints were HI GMT ratios for each vaccine strain and the absolute difference in seroconversion rates for each vaccine strain 28 days after vaccination. As shown in Table 10, noninferiority of administration of AFLURIA by the PharmaJet Stratis Needle-Free Injection System compared to administration of AFLURIA by needle and syringe was demonstrated in the immunogenicity population for all strains. Post-hoc analyses of immunogenicity by age showed that younger subjects (18 through 49 years) elicited higher immunological responses than older subjects (50 through 64 years). Post-hoc analyses of immunogenicity according to gender and body mass index did not reveal significant influences of these variables on immune responses. The study population was not sufficiently diverse to assess immunogenicity by race or ethnicity. Table 10: Baseline and Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA Administered by PharmaJet Stratis Needle-Free Injection System or Needle and Syringe, Adults 18 through 64 Years of Age (Study 8) Baseline GMT Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined non-inferiority criteria? c Strain Needle and Syringe N=568 PharmaJet Stratis Needle-Free Injection System N=562 Needle and Syringe N=568 PharmaJet Stratis Needle-Free Injection System N=562 Needle and Syringe over PharmaJet Stratis Needle-Free Injection System (95% CI) Needle and Syringe N=568 PharmaJet Stratis Needle-Free Injection System N=562 Needle and Syringe minus PharmaJet Stratis Needle-Free Injection System (95% CI) A(H1N1) 79.5 83.7 280.6 282.9 0.99 (0.88, 1.12) 38.4 37.5 0.8 (-4.8, 6.5) Yes A(H3N2) 75.4 68.1 265.9 247.3 1.08 (0.96, 1.21) 45.1 43.8 1.3 (-4.5, 7.1) Yes B 12.6 13.5 39.7 42.5 0.94 (0.83, 1.06) 35.2 34.9 0.3 (-5.2, 5.9) Yes Abbreviations: CI, confidence interval; GMT, geometric mean titer a GMT ratio is defined as post-vaccination GMT for Needle and Syringe/PharmaJet Stratis Needle-Free Injection System b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40. c Non-inferiority (NI) criteria for the GMT ratio: upper bound of 2-sided 95% CI on the ratio of Needle and Syringe/PharmaJet Stratis Needle-Free Injection System. GMT should not exceed 1.5. NI criteria for the seroconversion rate (SCR) difference: upper bound of 2-sided 95% CI on the difference between SCR Needle and Syringe – SCR PharmaJet Stratis Needle-Free Injection System should not exceed 10%. REFERENCES 1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59 (RR-8):1-62. 2. Hannoun C, Megas F, Piercy J. Immunogenicity and Protective Efficacy of Influenza Vaccination. Virus Res 2004;103:133-138. 3. Hobson D, Curry RL, Beare AS, et al. The Role of Serum Hemagglutination-Inhibiting Antibody in Protection against Challenge Infection with Influenza A2 and B Viruses. J Hyg Camb 1972;70:767-777.

Fluzone® (influenza) Suspension for Intramuscular Injection DESCRIPTION Fluzone High-Dose (Influenza Vaccine) for intramuscular injection is an inactivated influenza vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, octylphenol ethoxylate (Triton® X-100), producing a "split virus". The split virus is further purified and then suspended in sodium phosphatebuffered isotonic sodium chloride solution. The Fluzone High-Dose process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. Fluzone High-Dose suspension for injection is clear and slightly opalescent in color. Neither antibiotics nor preservative are used in the manufacture of Fluzone High-Dose. The Fluzone High-Dose prefilled syringe presentation is not made with natural rubber latex. Fluzone High-Dose is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following three influenza strains recommended for the 2017- 2018 influenza season: A/Michigan/45/2015 X-275 (H1N1), A/Hong Kong/4801/2014 X-263-B(H3N2), and B/Brisbane/60/2008(B Victoria Lineage). The amounts of HA and other ingredients per dose of vaccine are listed in Table 2. Table 2: Fluzone High-Dose Ingredients Ingredient Quantity (per dose) Fluzone High-Dose 0.5 mL Dose Active Substance: Split influenza virus , inactivated strains* : 180 mcg HA total A (H1N1) 60 mcg HA A (H3N2) 60 mcg HA B 60 mcg HA Other: Sodium phosphate-buffered isotonic sodium chloride solution QS† to appropriate volume Formaldehyde ≤100 mcg Octylphenol ethoxylate ≤250 mcg Gelatin None Preservative None *per United States Public Health Service (USPHS) requirement †Quantity Sufficient

FLUVIRIN® (influenza virus vaccine) Suspension for Intramuscular Injection DESCRIPTION FLUVIRIN® is a trivalent, sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens' eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with betapropiolactone. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of nonylphenol ethoxylate, a process which removes most of the internal proteins. The nonylphenol ethoxylate is removed from the surface antigen preparation. FLUVIRIN® is a homogenized, sterile, slightly opalescent suspension in a phosphate buffered saline. FLUVIRIN® has been standardized according to USPHS requirements for the 2017/2018 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 viruses: A/Singapore/GP1908/2015,IVR-180 (an A/Michigan/45/2015 (H1N1)pdm09- like virus; A/Hong Kong/4801/2014, NYMC X-263B (H3N2) (an A/Hong Kong/4801/2014- like virus); and B/Brisbane/60/2008, wild type (a B/Brisbane/60/2008-like virus). The 0.5-mL prefilled syringe presentation is formulated without preservative. However, thimerosal, a mercury derivative used during manufacturing, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose). The 5-mL multidose vial formulation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury. Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), polymyxin (≤ 3.75 mcg), neomycin (≤ 2.5 mcg), betapropiolactone (not more than 0.5 mcg) and nonylphenol ethoxylate (not more than 0.015% w/v). The tip caps of the FLUVIRIN® prefilled syringes may contain natural rubber latex. The multidose vial stopper and the syringe stopper/plunger do not contain latex.

FluMist® Quadrivalent (Influenza Vaccine Live) Intranasal Spray DESCRIPTION FluMist Quadrivalent (Influenza Vaccine Live, Intranasal) is a live quadrivalent vaccine for administration by intranasal spray. FluMist Quadrivalent contains four vaccine virus strains: an A/H1N1 strain, an A/H3N2 strain and two B strains. FluMist Quadrivalent contains B strains from both the B/Yamagata/16/88 and the B/Victoria/2/87 lineages. FluMist Quadrivalent is manufactured according to the same process as FluMist. The influenza virus strains in FluMist Quadrivalent are (a) cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wild-type influenza viruses); (b) temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently); and (c) attenuated (att) (i.e., they do not produce classic influenza-like illness in the ferret model of human influenza infection). No evidence of reversion has been observed in the recovered vaccine strains that have been tested (135 of possible 250 recovered isolates) using FluMist [see CLINICAL PHARMACOLOGY]. For each of the four reassortant strains in FluMist Quadrivalent, the six internal gene segments responsible for ca, ts, and att phenotypes are derived from a master donor virus (MDV), and the two segments that encode the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant wild-type influenza viruses. Thus, the four viruses contained in FluMist Quadrivalent maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses. For the Type A MDV, at least five geneYeah. It hatic loci in three different internal gene segments contribute to the ts and att phenotypes. For the Type B MDV, at least three genetic loci in two different internal gene segments contribute to both the ts and att properties; five genetic loci in three gene segments control the ca property. Each of the reassortant strains in FluMist Quadrivalent express the HA and NA of wild- type viruses that are related to strains expected to circulate during the 2016-2017 influenza season. Three of the viruses (A/H1N1, A/H3N2 and one B strain) have been recommended by the United States Public Health Service (USPHS) for inclusion in the annual trivalent and quadrivalent influenza vaccine formulations. An additional B strain has been recommended by the USPHS for inclusion in the quadrivalent influenza vaccine formulation. Specific pathogen-free (SPF) eggs are inoculated with each of the reassortant strains and incubated to allow vaccine virus replication. The allantoic fluid of these eggs is harvested, pooled, and then clarified by filtration. The virus is concentrated by ultracentrifugation and diluted with stabilizing buffer to obtain the final sucrose and potassium phosphate concentrations. The viral harvests are then sterile filtered to produce the monovalent bulks. Each lot is tested for ca, ts, and att phenotypes and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. Monovalent bulks from the four strains are subsequently blended and diluted as required to attain the desired potency with stabilizing buffers to produce the quadrivalent bulk vaccine. The bulk vaccine is then filled directly into individual sprayers for nasal administration. Each pre-filled refrigerated FluMist Quadrivalent sprayer contains a single 0.2 mL dose. Each 0.2 mL dose contains 106.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants of each of the four strains: A/Bolivia/559/2013 (H1N1) (an A/California/7/2009 (H1N1)pdm09-like virus), A/New Caledonia/71/2014 (H3N2) (an A/Hong Kong/4801/2014 (H3N2)-like virus), B/Phuket/3073/2013 (B/Yamagata/16/88 lineage), and B/Brisbane/60/2008 (B/Victoria/2/87 lineage). Each 0.2 mL dose also contains 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, and 0.96 mg/dose monobasic potassium phosphate. Each dose contains residual amounts of ovalbumin ( < 0.24 mcg/dose), and may also contain residual amounts of gentamicin sulfate ( < 0.015 mcg/mL), and ethylenediaminetetraacetic acid (EDTA) ( < 0.37 mcg/dose). FluMist Quadrivalent contains no preservatives. The tip attached to the sprayer is equipped with a nozzle that produces a fine mist that is primarily deposited in the nose and nasopharynx. FluMist Quadrivalent is a colorless to pale yellow suspension and is clear to slightly cloudy.

FLULAVAL QUADRIVALENT (influenza vaccine) Suspension for Intramuscular Injection DESCRIPTION FLULAVAL QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a quadrivalent, splitvirion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of  embryonated hens' eggs. Each of the influenza viruses is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate. FLULAVAL QUADRIVALENT is a sterile, opalescent, translucent to off-white suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension. FLULAVAL QUADRIVALENT has been standardized according to USPHS requirements for the 20172018 influenza season and is formulated to contain 60 micrograms (mcg) hemagglutinin (HA) per 0.5mL dose in the recommended ratio of 15 mcg HA of each of the following 4 viruses (2 A strains and 2 B strains): A/Singapore/GP1908/2015 (H1N1) IVR 180 (an A/Michigan/45/2015 (H1N1) pdm09- like virus), A/Hong Kong/4801/2014 (H3N2) X-263B, B/Brisbane/60/2008, and B/Phuket/3073/2013. The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 0.5-mL dose from the multi-dose vial contains 50 mcg thimerosal (<25 mcg mercury); thimerosal, a mercury derivative, is added as a preservative. Each 0.5mL dose of either presentation may also contain residual amounts of ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), α-tocopheryl hydrogen succinate (≤320 mcg), and polysorbate 80 (≤887 mcg) from the manufacturing process. Antibiotics are not used in the manufacture of this vaccine. The tip caps and plungers of the prefilled syringes are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

FLUARIX QUADRIVALENT (influenza vaccine) Suspension for Intramuscular Injection DESCRIPTION FLUARIX QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a sterile, colorless, and slightly opalescent suspension. FLUARIX QUADRIVALENT is prepared from influenza viruses propagated in embryonated chicken eggs. Each of the influenza viruses is produced and purified separately. After harvesting the virus-containing fluids, each influenza virus is concentrated and purified by zonal centrifugation using a linear sucrose density gradient solution containing detergent to disrupt the viruses. Following dilution, the vaccine is further purified by diafiltration. Each influenza virus solution is inactivated by the consecutive effects of sodium deoxycholate and formaldehyde leading to the production of a “split virus.” Each split inactivated virus is then suspended in sodium phosphate-buffered isotonic sodium chloride solution. Each vaccine is formulated from the split inactivated virus solutions. FLUARIX QUADRIVALENT has been standardized according to US Public Health Service (USPHS) requirements for the 20172018 influenza season and is formulated to contain 60 micrograms (mcg) hemagglutinin (HA) per 0.5mL dose, in the recommended ratio of 15 mcg HA of each of the following 4 influenza virus strains: A/Singapore/GP1908/2015 (H1N1) IVR-180 (an A/Michigan/45/2015 (H1N1) pdm09-like virus), A/Hong Kong/4801/2014 (H3N2) NYMC X-263B, B/Brisbane/60/2008, and B/Phuket/3073/2013. FLUARIX QUADRIVALENT is formulated without preservatives. FLUARIX QUADRIVALENT does not contain thimerosal. Each 0.5mL dose also contains octoxynol-10 (TRITON®X-100) ≤0.115 mg, α-tocopheryl hydrogen succinate ≤0.135 mg, and polysorbate 80 (Tween 80) ≤0.550 mg. Each dose may also contain residual amounts of hydrocortisone ≤0.0016 mcg, gentamicin sulfate ≤0.15 mcg, ovalbumin ≤0.050 mcg, formaldehyde ≤5 mcg, and sodium deoxycholate ≤65 mcg from the manufacturing process. The tip caps and plungers of the prefilled syringes of FLUARIX QUADRIVALENT are not made with natural rubber latex.

AFLURIA (influenza vaccine) for Intramuscular Injection DESCRIPTION AFLURIA, Influenza Vaccine for intramuscular injection, is a sterile, clear, colorless to slightly opalescent suspension with some sediment that resuspends upon shaking to form a homogeneous suspension. AFLURIA is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. Following harvest, the virus is purified in a sucrose density gradient using continuous flow zonal centrifugation. The purified virus is inactivated with beta-propiolactone, and the virus particles are disrupted using sodium taurodeoxycholate to produce a “split virion”. The disrupted virus is further purified and suspended in a phosphate buffered isotonic solution. AFLURIA is standardized according to USPHS requirements for the 2016-2017 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA for each of the three influenza strains recommended for the 2016-2017 Northern Hemisphere influenza season: A/California/7/2009 (H1N1), NYMC X-181, A/Hong Kong/4801/2014 (H3N2), NYMC X-263B and B/Brisbane/60/2008. Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose presentations; therefore these products contain no preservative. The multi-dose presentation contains thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury. A single 0.5 mL dose of AFLURIA contains sodium chloride (4.1 mg), monobasic sodium phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). From the manufacturing process, each 0.5 mL dose may also contain residual amounts of sodium taurodeoxycholate (≤10 ppm), ovalbumin (<1 mcg), sucrose (<10 mcg), neomycin sulfate (≤3 nanograms [ng]), polymyxin B (≤0.5 ng), and beta-propiolactone (≤2 ng). The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers used for the multi-dose vial were not made with natural rubber latex.

INDICATIONS Fluzone® High-Dose is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus contained in the vaccine. Fluzone High-Dose is approved for use in persons 65 years of age and older. DOSAGE AND ADMINISTRATION For intramuscular use only Dose And Schedule Fluzone High-Dose should be administered as a single 0.5 mL injection by the intramuscular route in adults 65 years of age and older. Administration Inspect Fluzone High-Dose visually for particulate matter and/or discoloration prior to administration. If either of these conditions exist, the vaccine should not be administered. Before administering a dose of vaccine, shake the prefilled syringe. The preferred site for intramuscular injection is the deltoid muscle. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk. Do not administer this product intravenously or subcutaneously. Fluzone High-Dose should not be combined through reconstitution or mixed with any other vaccine. HOW SUPPLIED Dosage Forms And Strengths Fluzone High-Dose is a suspension for injection. Fluzone High-Dose is supplied in prefilled syringes (gray syringe plunger rod), 0.5 mL, for adults 65 years of age and older. Storage And Handling Single-dose, prefilled syringe, without needle, 0.5 mL (NDC 49281-401-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-401-65). Store Fluzone High-Dose refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen. Do not use after the expiration date shown on the label. Manufactured by: Sanofi Pasteur Inc. Swiftwater, PA 18370 USA. Revised: July 2017

INDICATIONS FLUVIRIN® is an inactivated influenza virus vaccine indicated for immunization of persons 4 years of age and older against influenza virus disease caused by influenza virus subtypes A and type B contained in the vaccine [see Dosage Forms And Strengths]. FLUVIRIN® is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group. DOSAGE AND ADMINISTRATION Preparation For Administration Shake the syringe vigorously before administering the vaccine and shake the multidose vial preparation each time before withdrawing a dose of vaccine. Inspect FLUVIRIN® syringes and multidose vials visually for particulate matter and/or discoloration prior to administration [see DESCRIPTION]. If either of these conditions exists, the vaccine should not be administered. Between uses, return the multidose vial to the recommended storage conditions between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. A separate sterile syringe and needle must be used for each injection to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and not recapped. It is recommended that small syringes (0.5 mL or 1 mL) should be used to minimize any product loss. For intramuscular us e only. Recommended Dose And Schedule The dose and schedule for Fluvirin is presented in Table 1. TABLE 1 : Fluvirin Dose and Schedule Age Dose Schedule 4 years through 8 years One or two dosesa, 0.5 mL each If 2 doses, administer at least 1 month apart 9 years and older One dose, 0.5 mL - a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines. “-” indicates information is not applicable In children, the needle size may range from 7/8 to 1¼ inches, depending on the size of the child's deltoid muscle, and should be of sufficient length to penetrate the muscle tissue. The anterolateral thigh can be used, but the needle should be longer, usually 1 inch. In adults, a needle of ≥1 inch is preferred because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults. The preferred site for intramuscular injection is the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal region or areas where there may be a major nerve trunk. HOW SUPPLIED Dosage Forms And Strengths FLUVIRIN®, a sterile suspension for intramuscular injection, is supplied in two presentations: 0.5 mL single-dose prefilled syringe 5.0 mL multi-dose vial containing 10 doses (each dose is 0.5 mL) FLUVIRIN® product presentations are listed in Table 9 below: TABLE 9 : Fluvirin Product Presentations Presentation Carton NDC Number Components Pre-filled syringe 70461-120-02 0.5 mL single dose pre-filled syringe, package of 10 syringes per carton (may contain latex) [NDC 70461-120-12] Multi-dose vial 70461-120-10 5.0 mL multi-dose vial, individually packaged in a carton (contains no latex) [NDC 70461-120-11] Storage And Handling Store FLUVIRIN® refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Do not use after the expiration date. Between uses, return the multidose vial to the recommended storage conditions. Manufactured by: Seqirus Vaccines Limited, Speke, Liverpool, UK. Distributed by: Seqirus USA Inc. 25 Deforest Avenue, Summit, NJ 07901, USA, 1-855-358-8966. Revised: Mar 2017

INDICATIONS FluMist® Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine [see DESCRIPTION]. FluMist Quadrivalent is approved for use in persons 2 through 49 years of age. DOSAGE AND ADMINISTRATION FOR INTRANASAL ADMINISTRATION BY A HEALTHCARE PROVIDER. Dosing Information Administer FluMist Quadrivalent according to the following schedule: Age Dose Schedule 2 years through 8 years 1 or 2 dosesa, If 2 doses, administerat least 1 month apart 0.2 mLb each 9 years through 49 years 1 dose, 0.2 mLb - a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines. b Administer as 0.1 mL per nostril. “-” indicates information is not applicable Administration Instructions Each sprayer contains a single dose (0.2 mL) of FluMist Quadrivalent; administer approximately one half of the contents of the single-dose intranasal sprayer into each nostril (each sprayer contains 0.2 mL of vaccine). Refer to Figure 1 for step-by-step administration instructions. Following administration, dispose of the sprayer according to the standard procedures for medical waste (e.g., sharps container or biohazard container). Figure 1 Note: Active inhalation (i.e., sniffing) is not required by the patient during vaccine administration. HOW SUPPLIED Dosage Forms And Strengths Each 0.2 mL dose is a suspension supplied in a single-dose pre-filled intranasal sprayer. FluMist Quadrivalent is supplied in a package of 10 pre-filled, single-dose (0.2 mL) intranasal sprayers. The single-use intranasal sprayer is not made with natural rubber latex.Carton containing 10 intranasal sprayers: NDC 66019-303-10 Single intranasal sprayer: NDC 66019-303-01 Storage And Handling The cold chain [2-8°C (35-46°F)] must be maintained when transporting FluMist Quadrivalent. FLUMIST QUADRIVALENT SHOULD BE STORED IN A REFRIGERATOR BETWEEN 2-8°C (35-46°F) UPON RECEIPT. THE PRODUCT MUST BE USED BEFORE THE EXPIRATION DATE ON THE SPRAYER LABEL. DO NOT FREEZE. Keep FluMist Quadrivalent sprayer in outer carton in order to protect from light. A single temperature excursion up to 25°C (77°F) for 12 hours has been shown to have no adverse impact on the vaccine. After a temperature excursion, the vaccine should be returned immediately to the recommended storage condition (2°C - 8°C) and used as soon as feasible. Subsequent excursions are not permitted. Once FluMist Quadrivalent has been administered or has expired, the sprayer should be disposed of according to the standard procedures for medical waste (e.g., sharps container or biohazard container). Manufactured by: MedImmune, LLC, Gaithersburg, MD 20878, 1-877-633-4411, U.S. Government License No. 1799. Revised: July 2016.

INDICATIONS FLULAVAL® QUADRIVALENT is indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FLULAVAL QUADRIVALENT is approved for use in persons aged 6 months and older. DOSAGE AND ADMINISTRATION For intramuscular injection only. Dosage And Schedule The dose and schedule for FLULAVAL QUADRIVALENT are presented in Table 1. Table 1: FLULAVAL QUADRIVALENT: Dosing Age Vaccination Status Dose and Schedule 6 months through 8 years Not previously vaccinated with influenza vaccine Two doses (0.5mL each) at least 4 weeks apart Vaccinated with influenza vaccine in a previous season One or 2 dosesa (0.5mL each) 9 years and older Not applicable One 0.5mL dose aOne dose or 2 doses (0.5mL each) depending on vaccination history as per the annual Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and control of influenza with vaccines. If 2 doses, administer each 0.5mL dose at least 4 weeks apart. Administration Instructions Shake well before administration. 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. Attach a sterile needle to the prefilled syringe and administer intramuscularly. For the multi-dose vial, use a sterile needle and sterile syringe to withdraw the 0.5mL dose from the multi-dose vial and administer intramuscularly. A sterile syringe with a needle bore no larger than 23 gauge is recommended for administration. It is recommended that small syringes (0.5 mL or 1 mL) be used to minimize any product loss. Use a separate sterile needle and syringe for each dose withdrawn from the multi-dose vial. Between uses, return the multi-dose vial to the recommended storage conditions, between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Once entered, a multi-dose vial, and any residual contents, should be discarded after 28 days. The preferred sites for intramuscular injection are the anterolateral thigh for children aged 6 through 11 months and the deltoid muscle of the upper arm for persons aged 12 months and older. Do not inject in the gluteal area or areas where there may be a major nerve trunk. Do not administer this product intravenously, intradermally, or subcutaneously. HOW SUPPLIED Dosage Forms And Strengths FLULAVAL QUADRIVALENT is a suspension for injection available in 0.5-mL prefilled TIPLOK syringes and 5mL multi-dose vials containing 10 doses (each dose is 0.5 mL). Storage And Handling FLULAVAL QUADRIVALENT is available in 0.5-mL single-dose disposable prefilled TIP-LOK syringes (packaged without needles) and in 5-mL multi-dose vials containing 10 doses (0.5 mL each). NDC 19515-912-41 Syringe in Package of 10: NDC 19515-912-52 NDC 19515-896-01 Multi-Dose Vial (containing 10 doses) in Package of 1: NDC 19515-896-11 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Once entered, a multi-dose vial should be discarded after 28 days. Manufactured by ID Biomedical Corporation of Quebec, Quebec City, QC, Canada, U.S. License 1739. Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Jul 2017

INDICATIONS FLUARIX® QUADRIVALENT is indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine [see DESCRIPTION]. FLUARIX QUADRIVALENT is approved for use in persons aged 3 years and older. DOSAGE AND ADMINISTRATION For intramuscular injection only. Dosage And Schedule The dose and schedule for FLUARIX QUADRIVALENT are presented in Table 1. Table 1: FLUARIX QUADRIVALENT: Dosing Age Vaccination Status Dose and Schedule 3 through 8 years Not previously vaccinated with influenza vaccine Two doses (0.5-mL each) at least 4 weeks apart Vaccinated with influenza vaccine in a previous season One or 2 dosesa (0.5-mL each) 9 years and older Not applicable One 0.5-mL dose aOne dose or 2 doses (0.5mL each) depending on vaccination history as per the annual Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and control of influenza with vaccines. If 2 doses, administer each 0.5mL dose at least 4 weeks apart. Administration Instructions Shake well before administration. 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. Attach a sterile needle to the prefilled syringe and administer intramuscularly. The preferred site for intramuscular injection is the deltoid muscle of the upper arm. Do not inject in the gluteal area or areas where there may be a major nerve trunk. Do not administer this product intravenously, intradermally, or subcutaneously. HOW SUPPLIED Dosage Forms And Strengths FLUARIX QUADRIVALENT is a suspension for injection. Each 0.5mL dose is supplied in singledose prefilled TIPLOK® syringes. Storage And Handling NDC 58160-907-41 Syringe in Package of 10: NDC 58160-907-52 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Manufactured by: GlaxoSmithKline Biologicals , Dresden, Germany, a branch of SmithKline Beecham Pharma GmbH & Co. KG, Munich, Germany. Licensed by GlaxoSmithKline Biologicals , Rixensart, Belgium, U.S. License 1617. Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709. Revised:  Jul 2017

INDICATIONS AFLURIA® is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B present in the vaccine. AFLURIA is approved for use in persons 5 years of age and older. DOSAGE AND ADMINISTRATION For intramuscular (IM) injection only, by needle and syringe (5 years of age and older) or by PharmaJet® Stratis® Needle-Free Injection System (18 through 64 years of age). A single dose is 0.5 mL. The dose and schedule for AFLURIA are presented in Table 1. Table 1: AFLURIA Schedule Age Schedule 5 years through 8 years One dose or two doses at least 1 month apart a 9 years and older One dose a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines. Shake thoroughly and inspect visually before use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever suspension and container permit. If either of these conditions exists, the vaccine should not be administered. May be administered by needle and syringe (5 years of age and older) or PharmaJet Stratis Needle-Free Injection System (18 through 64 years of age only). When using the single-dose pre-filled syringe, shake the syringe thoroughly and administer the dose immediately. When using the multi-dose vial, shake the vial thoroughly before withdrawing each dose, and administer the dose immediately. Needle and Syringe: Draw up the exact dose using a separate sterile needle and syringe for each individual patient. It is recommended that small syringes (0.5 mL or 1 mL) be used to minimize any product loss. PharmaJet Stratis Needle-Free Injection System: For instructions on withdrawal of a 0.5 mL dose and use of the PharmaJet Stratis Needle- Free Injection System, refer to the Instructions For Use for the PharmaJet Stratis Needle-Free Injection System. The preferred site for intramuscular injection is the deltoid muscle of the upper arm. Between uses, return the multi-dose vial to the recommended storage conditions between 2-8°C (36-46°F). Do not freeze. Discard if the vaccine has been frozen. HOW SUPPLIED Dosage Forms And Strengths AFLURIA is a sterile suspension for intramuscular injection (see DESCRIPTION). AFLURIA is supplied in two presentations: 0.5 mL pre-filled syringe (single dose). 5 mL multi-dose vial (ten 0.5 mL doses). Storage And Handling Each product presentation includes a package insert and the following components: Presentation Carton NDC Number Components Pre-Filled Syringe 33332-016-01 Ten 0.5 mL single-dose syringes fitted with a Luer-LokTM attachment without needles [NDC 33332-016-02] Multi-Dose Vial 33332-116-10 One 5 mL vial, which contains ten 0.5 mL doses [NDC 33332-116-11] Storage And Handling Store refrigerated at 2-8°C (36-46°F). Do not freeze. Discard if product has been frozen. Protect from light. Do not use AFLURIA beyond the expiration date printed on the label. Once the stopper of the multi-dose vial has been pierced the vial must be discarded within 28 days. Manufactured by: Seqirus Pty Ltd, Parkville, Victoria, 3052, Australia. Revised: April 2016

PATIENT INFORMATION Fluzone® High-Dose Influenza Vaccine Please read this information sheet before getting Fluzone High-Dose vaccine. This summary is not intended to take the place of talking with your healthcare provider. If you have questions or would like more information, please talk with your healthcare provider. What is Fluzone High-Dose vaccine? Fluzone High-Dose is a vaccine that helps protect against influenza illness (flu). Fluzone High-Dose vaccine is for people 65 years of age and older. Vaccination with Fluzone High-Dose vaccine may not protect all people who receive the vaccine. Who should not get Fluzone High-Dose vaccine? You should not get Fluzone High-Dose vaccine if you: ever had a severe allergic reaction to eggs or egg products. ever had a severe allergic reaction after getting any flu vaccine. are younger than 65 years of age. Tell your healthcare provider if you have or have had: Guillain-Barré syndrome (severe muscle weakness) after getting a flu vaccine. problems with your immune system as the immune response may be diminished. How is Fluzone High-Dose vaccine given? Fluzone High-Dose vaccine is a shot given into the muscle of the arm. What are the possible side effects of Fluzone High-Dose vaccine? The most common side effects of Fluzone High-Dose vaccine are: pain, redness, and swelling where you got the shot muscle ache tiredness headache These are not all of the possible side effects of Fluzone High-Dose vaccine. You can ask your healthcare provider for a list of other side effects that is available to healthcare professionals. Call your healthcare provider for advice about any side effects that concern you. You may report side effects to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 or http://vaers.hhs.gov. Why should I get Fluzone High-Dose vaccine instead of Fluzone vaccine? An efficacy study in adults 65 years of age and older has demonstrated that Fluzone High-Dose vaccine offers better protection against influenza than Fluzone vaccine. What are the ingredients in Fluzone High-Dose vaccine? Fluzone High-Dose vaccine contains 3 killed flu virus strains. Inactive ingredients include formaldehyde and octylphenol ethoxylate.

PATIENT INFORMATION Vaccine recipients and guardians should be informed by their health care provider of the potential benefits and risks of immunization with FLUVIRIN®. When educating vaccine recipients and guardians regarding the potential side effects, clinicians should emphasize that (1) FLUVIRIN® contains noninfectious particles and cannot cause influenza and (2) FLUVIRIN® is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against all respiratory illness. Vaccine recipients and guardians should be instructed to report any severe or unusual adverse reactions to their healthcare provider. Vaccine recipients and guardians should be instructed that annual vaccination is recommended.

PATIENT INFORMATION FluMist® Quadrivalent (pronounced FLEW-mist Kwä-dre-VA-lent) (Influenza Vaccine Live, Intranasal) Please read this Patient Information carefully before you or your child is vaccinated with FluMist Quadrivalent. This is a summary of information about FluMist Quadrivalent. It does not take the place of talking with your healthcare provider about influenza vaccination. If you have questions or would like more information, please talk with your healthcare provider. What is FluMist Quadrivalent? FluMist Quadrivalent is a vaccine that is sprayed into the nose to help protect against influenza. It can be used in children, adolescents, and adults ages 2 through 49. FluMist Quadrivalent is similar to MedImmune's trivalent Influenza Vaccine Live, Intranasal (FluMist) except FluMist Quadrivalent provides protection against an additional influenza strain. FluMist Quadrivalent may not prevent influenza in everyone who gets vaccinated. Who should not get FluMist Quadrivalent? You should not get FluMist Quadrivalent if you: have a severe allergy to eggs or to any inactive ingredient in the vaccine (see “What are the ingredients in FluMist Quadrivalent?”) have ever had a life-threatening reaction to influenza vaccinations are 2 through 17 years old and take aspirin or medicines containing aspirin. Children or adolescents should not be given aspirin for 4 weeks after getting FluMist or FluMist Quadrivalent unless your healthcare provider tells you otherwise. Please talk to your healthcare provider if you are not sure if the items listed above apply to you or your child. Children under 2 years old have an increased risk of wheezing (difficulty with breathing) after getting FluMist Quadrivalent. Who may not be able to get FluMist Quadrivalent? Tell your healthcare provider if you or your child: are currently wheezing have a history of wheezing if under 5 years old have had Guillain-Barré syndrome have a weakened immune system or live with someone who has a severely weakened immune system have problems with your heart, kidneys, or lungs have diabetes are pregnant or nursing are taking Tamiflu®, Relenza®, amantadine, or rimantadine If you or your child cannot take FluMist Quadrivalent, you may still be able to get an influenza shot. Talk to your healthcare provider about this. How is FluMist Quadrivalent given? FluMist Quadrivalent is a liquid that is sprayed into the nose. You can breathe normally while getting FluMist Quadrivalent. There is no need to inhale or “sniff” it. People 9 years of age and older need one dose of FluMist Quadrivalent each year. Children 2 through 8 years old may need 2 doses of FluMist Quadrivalent, depending on their history of previous influenza vaccination. Your healthcare provider will decide if your child needs to come back for a second dose. What are the possible side effects of FluMist Quadrivalent? The most common side effects are: runny or stuffy nose sore throat fever over 100 degrees F Other possible side effects include: decreased appetite headache irritability muscle ache tiredness chills cough Call your healthcare provider or go to the emergency department right away if you or your child experience: hives or a bad rash trouble breathing swelling of the face, tongue, or throat These are not all the possible side effects of FluMist Quadrivalent. You can ask your healthcare provider for a complete list of side effects that is available to healthcare professionals. Call your healthcare provider for medical advice about side effects. You may report side effects to VAERS at 1-800-822-7967 or http://vaers.hhs.gov. What are the ingredients in FluMist Quadrivalent? Active Ingredient: FluMist Quadrivalent contains 4 influenza virus strains that are weakened (A(H1N1), A(H3N2), B Yamagata lineage, and B Victoria lineage). Inactive Ingredients: monosodium glutamate, gelatin, arginine, sucrose, dibasic potassium phosphate, monobasic potassium phosphate, and gentamicin. FluMist Quadrivalent does not contain preservatives. How is FluMist Quadrivalent Stored? FluMist Quadrivalent is stored in a refrigerator (not the freezer) between 35-46 degrees F (2-8 degrees C) upon receipt. FluMist Quadrivalent sprayer must be kept in the carton until use in order to protect from light. FluMist Quadrivalent must be used before the expiration date on the sprayer label. If you would like more information, talk to your healthcare provider or visit www.flumistquadrivalent.com or call 1-877-633-4411.

PATIENT INFORMATION Provide the following information to the vaccine recipient or guardian: Inform of the potential benefits and risks of immunization with FLULAVAL QUADRIVALENT. Educate regarding potential side effects, emphasizing that (1) FLULAVAL QUADRIVALENT contains non-infectious killed viruses and cannot cause influenza, and (2) FLULAVAL QUADRIVALENT is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against all respiratory illness. Encourage women exposed to FLULAVAL QUADRIVALENT during pregnancy to enroll in the pregnancy registry [see Use In Specific Populations]. Give the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 prior to each immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines). Instruct that annual revaccination is recommended. FLUARIX, FLULAVAL, HAVRIX, and TIP-LOK are registered trademarks of the GSK group of companies. The other brand listed is a trademark of the respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products.

OVERDOSE No Information Provided CONTRAINDICATIONS A severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see DESCRIPTION], including egg protein, or to a previous dose of any influenza vaccine is a contraindication to administration of Fluzone High-Dose.

OVERDOSE No information provided. CONTRAINDICATIONS Hypersensitivity Do not administer FLUVIRIN® to anyone with known history of severe allergic reactions (e.g., anaphylaxis) to egg proteins (eggs or egg products), or to any component of FLUVIRIN®, or who has had a life-threatening reaction to previous influenza vaccinations.

OVERDOSE No information provided. CONTRAINDICATIONS Severe Allergic Reactions Do not administer FluMist Quadrivalent to persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see DESCRIPTION] including egg protein, or after a previous dose of any influenza vaccine. Concomitant Aspirin Therapy And Reye's Syndrome In Children And Adolescents Do not administer FluMist Quadrivalent to children and adolescents through 17 years of age who are receiving aspirin therapy or aspirin-containing therapy because of the association of Reye's syndrome with aspirin and wild-type influenza infection [see DRUG INTERACTIONS].

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer FLULAVAL QUADRIVALENT to anyone with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or following a previous dose of any influenza vaccine [see DESCRIPTION].

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer FLUARIX QUADRIVALENT to anyone with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or following a previous administration of any influenza vaccine [see DESCRIPTION].

OVERDOSE No Information Provided CONTRAINDICATIONS AFLURIA is contraindicated in individuals with known severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine including egg protein, or to a previous dose of any influenza vaccine (see DESCRIPTION).

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trial(s) of a vaccine cannot be directly compared to rates in the clinical trial(s) of another vaccine and may not reflect the rates observed in practice. Two clinical studies have evaluated the safety of Fluzone High-Dose. Study 1 (NCT00391053, see http://clinicaltrials.gov) was a multi-center, double-blind pre-licensure trial conducted in the US. In this study, adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2006-2007 formulation). The study compared the safety and immunogenicity of Fluzone High-Dose to those of Fluzone. The safety analysis set included 2573 Fluzone High-Dose recipients and 1260 Fluzone recipients. Table 1 summarizes solicited injection-site reactions and systemic adverse events reported within 7 days post-vaccination via diary cards. Onset was usually within the first 3 days after vaccination and a majority of the reactions resolved within 3 days. Solicited injection-site reactions and systemic adverse events were more frequent after vaccination with Fluzone High-Dose compared to Fluzone. Table 1: Study 1 : Frequency of Solicited Injection-Site Reactions and Systemic Adverse Events Within 7 Days After Vaccination with Fluzone High-Dose or Fluzone, Adults 65 Years of Age and Older Fluzone High-Dose (N† =2569-2572) Percentage Fluzone (N† =1258-1260) Percentage Any Moderate‡ Severe§ Any Moderate‡ Severe§ Injection-Site Pain 35.6 3.7 0.3 24.3 1.7 0.2 Injection-Site Erythema 14.9 1.9 1.8 10.8 0.8 0.6 Injection-Site Swelling 8.9 1.6 1.5 5.8 1.3 0.6 Myalgia 21.4 4.2 1.6 18.3 3.2 0.2 Malaise 18.0 4.7 1.6 14.0 3.7 0.6 Headache 16.8 3.1 1.1 14.4 2.5 0.3 Fever ¶(≥99.5°F) 3.6 1.1 0.0 2.3 0.2 0.1 *NCT00391053 †N is the number of vaccinated participants with available data for the events listed ‡Moderate - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injectionsite erythema and Injection-site swelling: ≥2.5 cm to <5 cm; Fever: >100.4 °F to ≤102.2°F; Myalgia, Malaise, and Headache: interferes with daily activities §Severe - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema and Injection-site swelling: ≥5 cm; Fever: >102.2°F; Myalgia, Malaise, and Headache: prevents daily activities ¶Fever - The percentage of temperature measurements that were taken by oral route or not recorded were 97.9% and 2.1%, respectively, for Fluzone High-Dose; and 98.6% and 1.4 %, respectively, for Fluzone Within 6 months post-vaccination, 156 (6.1%) Fluzone High-Dose recipients and 93 (7.4%) Fluzone recipients experienced a serious adverse event (SAE). No deaths were reported within 28 days postvaccination. A total of 23 deaths were reported during Days 29 – 180 post-vaccination: 16 (0.6%) among Fluzone High-Dose recipients and 7 (0.6%) among Fluzone recipients. The majority of these participants had a medical history of cardiac, hepatic, neoplastic, renal, and/or respiratory diseases. These data do not provide evidence for a causal relationship between deaths and vaccination with Fluzone High-Dose. Study 2 (NCT01427309, see http://clinicaltrials.gov) was a multi-center, double-blind post-licensure efficacy trial conducted in the US and Canada over two influenza seasons. In this study, adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2011-2012 and 2012-2013 formulations). The study compared the efficacy and safety of Fluzone High-Dose to those of Fluzone. The safety analysis set included 15,992 Fluzone High-Dose recipients and 15,991 Fluzone recipients. Within the study surveillance period (approximately 6 to 8 months post-vaccination), 1323 (8.3%) Fluzone High-Dose recipients and 1442 (9.0%) Fluzone recipients experienced an SAE. Within 30 days post-vaccination, 204 (1.3%) Fluzone High-Dose recipients and 200 (1.3%) Fluzone recipients experienced an SAE. The majority of these participants had one or more chronic comorbid illnesses. A total of 167 deaths were reported within 6 to 8 months post-vaccination: 83 (0.5%) among Fluzone High-Dose recipients and 84 (0.5%) among Fluzone recipients. A total of 6 deaths were reported within 30 days post-vaccination: 6 (0.04%) among Fluzone High-Dose recipients and 0 (0 %) among Fluzone recipients. These data do not provide evidence for a causal relationship between deaths and vaccination with Fluzone High-Dose. Post-Marketing Experience The following events have been spontaneously reported during the post-approval use of Fluzone or Fluzone High-Dose. 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 vaccine exposure. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Fluzone or Fluzone High- Dose. Events Reported During Post-Approval Use of Fluzone Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema) Eye Disorders: Ocular hyperemia Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell's palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paresthesia Vascular Disorders: Vasculitis, vasodilatation/flushing Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis, cough, wheezing, throat tightness Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in extremities, chest pain Gastrointestinal Disorders: Vomiting Other Events Reported During Post-Approval Use of Fluzone High-Dose Gastrointestinal Disorders: Nausea, diarrhea General Disorders and Administration Site Conditions: Chills DRUG INTERACTIONS Data evaluating the concomitant administration of Fluzone High-Dose with other vaccines are not available.

SIDE EFFECTS Overall Adverse Reaction Profile Serious allergic reactions, including anaphylactic shock, have been observed in individuals receiving FLUVIRIN® during postmarketing surveillance. Clinical Trial Experience Adverse event information from clinical trials provides a basis for identifying adverse events that appear to be related to vaccine use and for approximating the rates of these events. However, because clinical trials are conducted under widely varying conditions, the 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 rates observed in clinical practice. Adult And Geriatric Subjects Safety data were collected in a total of 2768 adult and geriatric subjects (18 years of age and older) who have received FLUVIRIN® in 29 clinical studies since 1982. In 9 clinical studies since 1997, among 1261 recipients of FLUVIRIN®, 745 (59%) were women; 1211 (96%) were White, 23 (2%) Asian, 15 (1%) Black and 12 (1%) other; 370 (29%) of subjects were elderly (≥65 years of age). All studies have been conducted in the UK, apart from a study run in the US in 2005-2006 where FLUVIRIN® was used as a comparator for an unlicensed vaccine. After vaccination, the subjects were observed for 30 minutes for hypersensitivity or other immediate reactions. Subjects were instructed to complete a diary card for three days following immunization (i.e. Day 1 to 4) to collect local and systemic reactions (see Tables 2 and 3). All local and systemic adverse events were considered to be at least possibly related to the vaccine. Local and systemic reactions mostly began between day 1 and day 2. The overall adverse events reported in clinical trials since 1998 in at least 5% of the subjects are summarized in Table 4. Adults (18 To 64 Years Of Age) In adult subjects, solicited local adverse events occurred with similar frequency in all trials. The most common solicited adverse events occurring in the first 96 hours after administration (Tables 2 and 3) were associated with the injection site (such as pain, erythema, mass, induration and swelling) but were generally mild/moderate and transient. The most common solicited systemic adverse events were headache and myalgia. The most common overall events in adult subjects (18-64 years of age) were headache, fatigue, injection site reactions (pain, mass, erythema, and induration) and malaise (Table 4). Geriatric Subjects (65 Years Of Age And Older) In geriatric subjects, solicited local and systemic adverse events occurred less frequently than in adult subjects. The most common solicited local and systemic adverse events were injection site pain, and headache (Tables 2 and 3). All were considered mild/moderate and were transient. The most common overall events in elderly subjects (≥65 years of age) were headache and fatigue. Only 11 serious adverse events in adult and geriatric subjects (18 years and older) have been reported to date from all the trials performed. These serious adverse events were a minor stroke experienced by a 67 year old subject 14 days after vaccination (1990), death of an 82 year old subject 35 days after TABLE 2 : Solicited Adverse Events in the First 72-96 Hours After Administration of FLUVIRIN® in Adult (18-64 years of age) and Geriatric (≥65 years of age) Subjects 1998-1999*§ 1999-2000*§ 2000-2001*§ 18-64 yrs N = 66 ≥ 65 yrs N = 44 18-64 yrs N = 76 ≥ 65 yrs N = 34 18-64 yrs N = 75 ≥ 65 yrs N = 35 Local Adverse Events Pain 16 (24%) 4 (9%) 16 (21%) - 9 (12%) - Mass 7 (11%) 1 (2%) 4 (5%) - 8 (11%) 1 (3%) Inflammation 5 (8%) 2 (5%) 6 (8%) - 7 (9%) 1 (3%) Ecchymosis 4 (6%) 1 (2%) 3 (4%) 1 (3%) 4 (5%) - Edema 2 (3%) 1 (2%) 1 (1%) 2 (6%) 3 (4%) 1 (3%) Reaction 2 (3%) - 2 (3%) - 4 (5%) 1 (3%) Hemorrhage - - 1 (1%) - - - Systemic Adverse Events Headache 7 (11%) 1 (2%) 17 (22%) 3 (9%) 4 (5%) - Fatigue 3 (5%) 2 (5%) 4 (5%) 1 (3%) 3 (4%) - Malaise 2 (3%) 1 (2%) 2 (3%) 1 (3%) 1 (1%) - Myalgia 1 (2%) - 2 (3%) - - - Fever 1 (2%) - 1 (1%) - - - Arthralgia - 1 (2%) - 1 (3%) - - Sweating - - 3 (4%) - 1 (1%) 1 (3%) 2001-2002*^ 2002-2003*^ 2004-2005*^ 18-64 yrs N = 75 ≥ 65 yrs N = 35 18-64 yrs N = 107 ≥ 65 yrs N = 88 18-64 yrs N = 74 ≥ 65 yrs N = 61 Local Adverse Events Pain 12 (16%) 1 (3%) 14 (13%) 7 (8%) 15 (20%) 9 (15%) Mass 4 (5%) 1 (3%) - - - - Ecchymosis 2 (3%) - 3 (3%) 3 (3%) 2 (3%) 1 (2%) Edema 2 (3%) 1 (3%) 6 (6%) 2 (2%) - - Erythema 5 (7%) - 11 (10%) 5 (6%) 16 (22%) 5 (8%) Swelling - - - - 11 (15%) 4 (7%) Reaction - - 2 (2%) - - - Induration - - 14 (13%) 3 (3%) 11 (15%) 1 (2%) Pruritus - - 1 (1%) - - - Systemic Adverse Events Headache 8 (11%) 1 (3%) 12 (11%) 9 (10%) 14 (19%) 3 (5%) Fatigue 1 (1%) 1 (3%) - - 5 (7%) 2 (3%) Malaise 3 (4%) - 3 (3%) 4 (5%) 1 (1%) 1 (2%) Myalgia 3 (4%) - 5 (5%) 3 (3%) 8 (11%) 1 (2%) Fever - - - 1 (1%) - - Arthralgia - - 2 (2%) - 1 (1%) - Sweating 3 (4%) 1 (3%) - 2 (2%) - - Shivering - - - 1 (1%) - - Results reported to the nearest whole percent; Fever defined as >38°C – not reported * Solicited adverse events in the first 72 hours after administration of FLUVIRIN §Solicited adverse events reported by COSTART preferred term ^ Solicited adverse events reported by MEDDRA preferred term TABLE 3 : Solicited Adverse Events in the First 72 Hours After Administration of FLUVIRIN® in Adult Subjects (18-49 years of age). 2005-2006 US Trial FLUVIRIN® N = 304 Local Adverse Events Pain 168 (55%) Erythema 48 (16%) Ecchymosis 22 (7%) Induration 19 (6%) Swelling 16 (5%) Systemic Adverse Events Headache 91 (30%) Myalgia 64 (21%) Malaise 58 (19%) Fatigue 56 (18%) Sore throat 23 (8%) Chills 22 (7%) Nausea 21 (7%) Arthralgia 20 (7%) Sweating 17 (6%) Cough 18 (6%) Wheezing 4 (1%) Chest tightness 4 (1%) Other difficulties breathing 3 (1%) Facial edema - Results reported to the nearest whole percent – not reported TABLE 4 : Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998 1998-1999§ 1999-2000§ 2000-2001§ 18-64 yrs N=66 ≥ 65 yrs N = 44 18-64 yrs N=67 ≥ 65 yrs N = 34 18-64 yrs N=75 ≥ 65 yrs N=35 Adverse Events Fatigue 8 (12%) 2 (5%) 8 (11%) 2 (6%) 5 (7%) - Back pain 4 (6%) 3 (7%) - - - - Cough increased 2 (3%) 2 (5%) - - - - Ecchymosis 4 (6%) 1 (2%) 4 (5%) 1 (3%) 5 (7%) - Fever 3 (5%) - - - - - Headache 12 (18%) 5 (11%) 22 (29%) 5 (15%) 14 (19%) 2 (6%) Infection 3 (5%) 2 (5%) - - - - Malaise 4 (6%) 4 (9%) 4 (5%) 1 (3%) - - Migraine 4 (6%) 1 (2%) - - - - Myalgia 4 (6%) 1 (2%) - - - - Sweating 5 (8%) 1 (2%) - - - - Rhinitis 3 (5%) 1 (2%) - - 5 (7%) 2 (6%) Pharingitis 6 (9%) 1 (2%) 10 (13%) - 6 (8%) - Arthralgia - - - 2 (6%) - - Injection site pain 16 (24%) 4 (9%) 16 (21%) - 9 (12%) - Injection site ecchymosis 4 (6%) 1 (2%) - - 4 (5%) - Injection site mass 7 (11%) 1 (2%) 4 (5%) - 8 (11%) 1 (3%) Injection site edema - - 1 (1%) 2 (6%) - - Injection site inflammation 5 (8%) 2 (5%) 6 (8%) - 7 (9%) 1 (3%) Injection site reaction - - - - 4 (5%) 1 (3%) 2001-2002^ 2002-2003^ 2004-2005^ 18-64 yrs N = 75 ≥ 65 yrs N = 35 18-64 yrs N = 107 ≥ 65 yrs N = 88 18-64 yrs N = 74 ≥ 65 yrs N = 61 Adverse Events Fatigue 5 (7%) 4 (11%) 11 (10%) 8 (9%) 4 (5%) 2 (3%) Hypertension - - 1 (1%) 4 (5%) - - Rinorrhea - - 2 (2%) 5 (6%) - - Headache 20 (27%) 2 (6%) 35 (33%) 18 (20%) 12 (16%) 1 (2%) Malaise 6 (8%) 1 (3%) 13 (12%) 8 (9%) - - Myalgia 4 (5%) 1 (3%) 10 (9%) 4 (5%) - - Sweating 3 (4%) 3 (9%) 2 (2%) 5 (6%) - - Rhinitis 4 (5%) - - - - - Pharingitis - - - - 6 (8%) - Arthralgia - - 5 (5%) 4 (5%) - - Sore throat 4 (5%) 1 (3%) 5 (5%) 4 (5%) - - Injection site pain 13 (17%) 3 (9%) 14 (13%) 7 (8%) 6 (8%) 2 (3%) Injection site ecchymosis 4 (5%) 1 (3%) 4 (4%) 4 (5%) - - Injection site erythema 5 (7%) 2 (6%) 11 (10%) 5 (6%) 4 (5%) - Injection site mass 4 (5%) 1 (3%) - - - - Injection site edema - - 6 (6%) 2 (2%) 4 (5%) 1 (2%) Injection site induration - - 14 (13%) 3 (3%) 7 (9%) - Results reported to the nearest whole percent; Fever defined as >38°C – not reaching the cut-off of 5% §Solicited adverse events reported by COSTART preferred term ^ Solicited adverse events reported by MEDDRA preferred term vaccination (1990) in very early studies; death of a 72 year old subject 19 days after vaccination (1998- 1999), a hospitalization for hemorrhoidectomy of a 38 year old male subject (1999-2000), a severe respiratory tract infection experienced by a 74 year old subject 12 days after vaccination (2002-2003), a planned transurethral resection of the prostate in a subject with prior history of prostatism (2004-2005), two cases of influenza (2005-2006), a drug overdose (2005-2006), cholelithiasis (2005-2006) and a nasal septal operation (2005- 2006). None of these events were considered causally related to vaccination. Clinical Trial Experience In Pediatric Subjects In 1987 a clinical study was carried out in 38 'at risk' children aged between 4 and 12 years (17 females and 21 males). To record the safety of FLUVIRIN®, participants recorded their symptoms on a diary card during the three days after vaccination and noted any further symptoms they thought were attributable to the vaccine. The only reactions recorded were tenderness at the site of vaccination in 21% of the participants on day 1, which was still present in 16% on day 2 and 5% on day 3. In one child, the tenderness was also accompanied by redness at the site of injection for two days. The reactions were not age-dependent and there was no bias towards the younger children. Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6 - 47 months). Of these, 285 healthy subjects plus 41'at risk'subjects received FLUVIRIN®. No serious adverse events were reported. FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. Postmarketing Experience The following additional adverse reactions have been reported during post- approval use of FLUVIRIN®. Because these reactions 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 vaccine exposure. Adverse events described here are included because: a) they represent reactions which are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) the frequency of reporting. Body as a whole: Local injection site reactions (including pain, pain limiting limb movement, redness, swelling, warmth, ecchymosis, induration), hot flashes/flushes; chills; fever; malaise; shivering; fatigue; asthenia; facial edema. Immune system disorders: Hypersensitivity reactions (including throat and/ or mouth edema). In rare cases, hypersensitivity reactions have lead to anaphylactic shock and death. Cardiovascular disorders: Vasculitis (in rare cases with transient renal involvement), presyncope, syncope shortly after vaccination. Digestive disorders: Diarrhea; nausea; vomiting; abdominal pain. Blood and lymphatic disorders: Local lymphadenopathy; thrombocytopenia (some very rare cases were severe with platelet counts less than 5,000 per mm³). Metabolic and nutritional disorders: Loss of appetite. Musculoskeletal: Arthralgia; myalgia; myasthenia. Nervous system disorders: Headache; dizziness; neuralgia; paraesthesia; confusion; febrile  convulsions; Guillain-Barré Syndrome; myelitis (including encephalomyelitis and transverse myelitis); neuropathy (including neuritis); paralysis (including Bell's Palsy). Respiratory disorders: Dyspnea; chest pain; cough; pharyngitis; rhinitis. Skin and appendages: Stevens-Johnson syndrome; sweating; pruritus; urticaria; rash (including nonspecific, maculopapular, and vesiculobulbous). General disorders and administration site conditions: Injection site cellulitis- like reaction (very rare cases of swelling, pain, and redness were large and extended to the entire arm) Other Adverse Reactions Associated With Influenza Vaccination Anaphylaxis has been reported after administration of FLUVIRIN®. Although FLUVIRIN® contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS]. The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated. Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy have been reported. Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination. DRUG INTERACTIONS Concomitant Administration With Other Vaccines There are no data to assess the concomitant administration of FLUVIRIN® with other vaccines. If FLUVIRIN® is to be given at the same time as another injectable vaccine(s), the vaccines should always be administered at different injection sites. FLUVIRIN® should not be mixed with any other vaccine in the same syringe or vial. Concurrent Use With 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 FLUVIRIN®.

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. This safety experience with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see DESCRIPTION]. A total of 9537 children and adolescents 1 through 17 years of age and 3041 adults 18 through 64 years of age received FluMist in randomized, placebo-controlled Studies D153-P501, AV006, D153-P526, AV019, and AV009 [3 used Allantoic Fluid containing Sucrose-Phosphate-Glutamate (AF-SPG) placebo, and 2 used saline placebo] described below. In addition, 4179 children 6 through 59 months of age received FluMist in Study MI-CP111, a randomized, active-controlled trial. Among pediatric FluMist recipients 6 months through 17 years of age, 50% were female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526, AV019, and AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black (6%), and Other (5%), while in D153-P501, 99% of subjects were Asian. A total of 1382 children and adolescents 2 through 17 years of age and 1198 adults 18 through 49 years of age received FluMist Quadrivalent in randomized, active-controlled Studies MI-CP208 and MI-CP185. Among pediatric FluMist Quadrivalent recipients 2 through 17 years of age, 51% were female; in the study of adults, 55% were female. In Studies MI-CP208 and MI-CP185, subjects were White (73%), Asian (1%), Black or African-American (19%), and Other (7%); overall, 22% were Hispanic or Latino. FluMist In Children And Adolescents The safety of FluMist was evaluated in an AF-SPG placebo-controlled study (AV019) conducted in a Health Maintenance Organization (HMO) in children 1 through 17 years of age (FluMist = 6473, placebo = 3216). An increase in asthma events, captured by review of diagnostic codes, was observed in children younger than 5 years of age who received FluMist compared to those who received placebo (Relative Risk 3.53, 90% CI: 1.1, 15.7). In Study MI-CP111, children 6 through 59 months of age were randomized to receive FluMist or inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia was prospectively monitored from randomization through 42 days post last vaccination. Hospitalization due to all causes was prospectively monitored from randomization through 180 days post last vaccination. Increases in wheezing and hospitalization (for any cause) were observed in children 6 months through 23 months of age who received FluMist compared to those who received inactivated Influenza Virus Vaccine, as shown in Table 1. Table 1: Percentages of Children with Hospitalizations and Wheezing from Study MI-CP111a Adverse Reaction Age Group FluMist (n/N) Active Controlb (n/N) Hospitalizationsc 6-23 months 4.2%(84/1992) 3.2%(63/1975) 24-59 months 2.1%(46/2187) 2.5%(56/2198) Wheezingd 6-23 months 5.9%(117/1992) 3.8%(75/1975) 24-59 months 2.1%(47/2187) 2.5%(56/2198) a NCT00128167; see www.clinicaltrials.gov b Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly. c Hospitalization due to any cause from randomization through 180 days post last vaccination. d Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia evaluated from randomization through 42 days post last vaccination. Most hospitalizations observed were due to gastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. In post-hoc analysis, rates of hospitalization in children 6 through 11 months of age were 6.1% (42/684) in FluMist recipients and 2.6% (18/683) in inactivated Influenza Virus Vaccine recipients. Table 2 shows pooled solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1% rate difference after rounding) compared to placebo post Dose 1 for Studies D153-P501 and AV006, and solicited adverse reactions post Dose 1 for Study MI-CP111. Solicited adverse reactions were those about which parents/guardians were specifically queried after receipt of FluMist, placebo, or control vaccine. In these studies, solicited reactions were documented for 10 days post vaccination. Solicited reactions following the second dose of FluMist were similar to those following the first dose and were generally observed at a lower frequency. Table 2: Summary of Solicited Adverse Reactions Observed Within 10 Days after Dose 1 for FluMist and Either Placebo or Active Control Recipients in Children 2 through 6 Years of Age Studies D153-P501a & AV006 Study MI CP111b FluMist N = 876-1759e Placeboc N = 424-1034e FluMist N = 2170e Active Controld N =2165e Event % % % % Runny Nose/ Nasal Congestion 58 50 51 42 Decreased Appetite 21 17 13 12 Irritability 21 19 12 11 Decreased Activity (Lethargy) 14 11 7 6 Sore Throat 11 9 5 6 Headache 9 7 3 3 Muscle Aches 6 3 2 2 Chills 4 3 2 2 Fever > 100°F Oral 16 11 13 11 > 100 - ≤ 101°F Oral 9 6 6 4 > 101 - ≤ 102°F Oral 4 3 4 3 a NCT00192244; see www.clinicaltrials.gov b NCT00128167; see www.clinicaltrials.gov c Study D153-P501 used saline placebo; Study AV006 used AF-SPG placebo. d Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly. e Number of evaluable subjects (those who returned diary cards) for each reaction. Range reflects differences in data collection between the 2 pooled studies. In clinical studies D153-P501 and AV006, unsolicited adverse reactions in children occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1% rate difference after rounding) compared to placebo were abdominal pain (2% FluMist vs. 0% placebo) and otitis media (3% FluMist vs. 1% placebo). An additional adverse reaction identified in the active-controlled trial MI-CP111 occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1% rate difference after rounding) compared to active control was sneezing (2% FluMist vs. 1% active control). In a separate saline placebo-controlled trial (D153-P526) in a subset of older children and adolescents 9 through 17 years of age who received one dose of FluMist, the solicited adverse reactions as well as unsolicited adverse reactions reported were generally consistent with observations from the trials in Table 2. Abdominal pain was reported in 12% of FluMist recipients compared to 4% of placebo recipients and decreased activity was reported in 6% of FluMist recipients compared to 0% of placebo recipients. In Study AV018, in which FluMist was concomitantly administered with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) to children 12 through 15 months of age, adverse reactions were similar to those seen in other clinical trials of FluMist. FluMist Quadrivalent In Children And Adolescents In the randomized, active-controlled Study MI-CP208 that compared FluMist Quadrivalent and FluMist in children and adolescents 2 through 17 years of age, the rates of solicited adverse reactions reported were similar between subjects who received FluMist Quadrivalent and FluMist. Table 3 includes solicited adverse reactions post Dose 1 from Study MI-CP208 that either occurred at a higher rate ( ≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in previous FluMist clinical studies (see Table 2). In this study, solicited adverse reactions were documented for 14 days post vaccination. Solicited adverse reactions post Dose 2 were observed at a lower frequency compared to those post Dose 1 for FluMist Quadrivalent and were similar between subjects who received FluMist Quadrivalent and FluMist. Table 3: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP208b in Children and Adolescents 2 through 17 Years of Age FluMist Quadrivalent N = 1341-1377d FluMistc N =901-920d Event % % Runny Nose/Nasal Congestion 32 32 Headache 13 12 Decreased Activity (Lethargy) 10 10 Sore Throat 9 10 Decreased Appetite 6 7 Muscle Aches 4 5 Fever > 100°F by any route 7 5 > 100 - ≤ 101°F by any route 3 2 > 101 - ≤ 102°F by any route 2 2 a Solicited adverse reactions that occurred at a higher rate ( ≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in previous FluMist trials (see Table 2). b NCT01091246; see www.clinicaltrials.gov c Represents pooled data from the two FluMist study arms [see Clinical Studies]. d Number of evaluable subjects for each event. In Study MI-CP208, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients. FluMist In Adults In adults 18 through 49 years of age in Study AV009, solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1% rate difference after rounding) compared to AF-SPG placebo include runny nose (44% FluMist vs. 27% placebo), headache (40% FluMist vs. 38% placebo), sore throat (28% FluMist vs. 17% placebo), tiredness/weakness (26% FluMist vs. 22% placebo), muscle aches (17% FluMist vs. 15% placebo), cough (14% FluMist vs. 11% placebo), and chills (9% FluMist vs. 6% placebo). In Study AV009, unsolicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1% rate difference after rounding) compared to placebo were nasal congestion (9% FluMist vs. 2% placebo) and sinusitis (4% FluMist vs. 2% placebo). FluMist Quadrivalent In Adults In the randomized, active-controlled Study MI-CP185 that compared FluMist Quadrivalent and FluMist in adults 18 through 49 years of age, the rates of solicited adverse reactions reported were generally similar between subjects who received FluMist Quadrivalent and FluMist. Table 4 presents solicited adverse reactions that either occurred at a higher rate ( ≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009. Table 4: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP185b in Adults 18 through 49 Years of Age FluMist Quadrivalent N = 1197d FluMistc N = 597d Event % % Runny Nose/Nasal Congestion 44 40 Headache 28 27 Sore Throat 19 20 Decreased Activity (Lethargy) 18 18 Cough 14 13 Muscle Aches 10 10 Decreased Appetite 6 5 a Solicited adverse reactions that occurred at a higher rate ( ≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009. b NCT00860067; see www.clinicaltrials.gov c Represents pooled data from the two FluMist study arms [see Clinical Studies]. d Number of evaluable subjects for each event. In Study MI-CP185, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients. Postmarketing Experience The following events have been spontaneously reported during post approval use of FluMist. 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 vaccine exposure. Cardiac disorders: Pericarditis Congenital, familial, and genetic disorders: Exacerbation of symptoms of mitochondrial encephalomyopathy (Leigh syndrome) Gastrointestinal disorders: Nausea, vomiting, diarrhea Immune system disorders: Hypersensitivity reactions (including anaphylactic reaction, facial edema, and urticaria) Nervous system disorders: Guillain-Barré syndrome, Bell's Palsy, meningitis, eosinophilic meningitis, vaccine-associated encephalitis Respiratory, thoracic, and mediastinal disorders: Epistaxis Skin and subcutaneous tissue disorders: Rash DRUG INTERACTIONS Aspirin Therapy Do not administer FluMist Quadrivalent to children and adolescents through 17 years of age who are receiving aspirin therapy or aspirin-containing therapy because of the association of Reye's syndrome with aspirin and wild-type influenza [see CONTRAINDICATIONS]. Avoid aspirin-containing therapy in these age groups during the first 4 weeks after vaccination with FluMist Quadrivalent unless clearly needed. Antiviral Agents Against Influenza A and/or B Antiviral drugs that are active against influenza A and/or B viruses may reduce the effectiveness of FluMist Quadrivalent if administered within 48 hours before, or within 2 weeks after vaccination. The concurrent use of FluMist Quadrivalent with antiviral agents that are active against influenza A and/or B viruses has not been evaluated. If antiviral agents and FluMist Quadrivalent are administered concomitantly, revaccination should be considered when appropriate. Concomitant Administration With Inactivated Vaccines The safety and immunogenicity of FluMist Quadrivalent when administered concomitantly with inactivated vaccines have not been determined. Studies of FluMist and FluMist Quadrivalent excluded subjects who received any inactivated or subunit vaccine within two weeks of enrollment. Concomitant Administration With Other Live Vaccines Concomitant administration of FluMist Quadrivalent with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) or the Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) has not been studied. Concomitant administration of FluMist with MMR and the varicella vaccine was studied in children 12 through 15 months of age [see Clinical Studies]. Concomitant administration of FluMist with the MMR and the varicella vaccine in children older than 15 months of age has not been studied. Intranasal Products There are no data regarding co-administration of FluMist Quadrivalent with other intranasal preparations.

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 with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of FLULAVAL QUADRIVALENT could reveal adverse reactions not observed in clinical trials. In adults who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (60%); the most common (≥10%) solicited systemic adverse events were muscle aches (26%), headache (22%), fatigue (22%), and arthralgia (15%). In children aged 6 through 35 months who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (40%); the most common (≥10%) solicited systemic adverse events were irritability (49%), drowsiness (37%), and loss of appetite (29%). In children aged 3 through 17 years who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (65%). In children aged 3 through 4 years, the most common (≥10%) solicited systemic adverse events were irritability (26%), drowsiness (21%), and loss of appetite (17%). In children aged 5 through 17 years, the most common (≥10%) systemic adverse events were muscle aches (29%), fatigue (22%), headache (22%), arthralgia (13%), and gastrointestinal symptoms (10%). FLULAVAL QUADRIVALENT has been administered in 8 clinical trials to 1,384 adults aged 18 years and older, 1,965 children aged 6 through 35 months, and 3,516 children aged 3 through 17 years. FLULAVAL QUADRIVALENT In Adults Trial 1 (NCT01196975) was a randomized, double-blind, active-controlled, safety and immunogenicity trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,272), or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 213 or TIV-2, n = 218), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 18 years and older (mean age: 50 years) and 61% were female; 61% of subjects were white, 3% were black, 1% were Asian, and 35% were of other racial/ethnic groups. Solicited adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in adults are shown in Table 2. Table 2: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Vaccination in Adults Aged 18 Years and Olderb (Total Vaccinated Cohort) FLULAVAL QUADRIVALENTc n = 1,260 % Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)d n = 208 % TIV-2 (B Yamagata)e n = 216 % Any Grade 3f Any Grade 3f Any Grade 3f Local Adverse Reactions Pain 59.5 1.7 44.7 1.0 41.2 1.4 Swelling 2.5 0.0 1.4 0.0 3.7 0.0 Redness 1.7 0.0 2.9 0.0 1.4 0.0 Systemic Adverse Events Muscle aches 26.3 0.8 25.0 0.5 18.5 1.4 Headache 21.5 0.9 19.7 0.5 22.7 0.0 Fatigue 21.5 0.8 21.6 1.0 17.1 1.9 Arthralgia 14.8 0.8 16.7 1.0 14.6 2.9 Gastrointestinal symptomsg 9.3 0.8 10.1 1.9 6.9 0.5 Shivering 8.8 0.6 7.7 0.5 6.0 0.9 Feverh 1.3 0.4 0.5 0.0 1.4 0.5 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. a7 days included day of vaccination and the subsequent 6 days. bTrial 1: NCT01196975. cContained 2 A strains and 2 B strains, one of Victoria lineage and one of Yamagata lineage. dContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Victoria lineage. eContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Yamagata lineage. fGrade 3 pain: Defined as significant pain at rest; prevented normal everyday activities. Grade 3 swelling, redness: Defined as >100 mm. Grade 3 muscle aches, headache, fatigue, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity. Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C). gGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. hFever: Defined as ≥100.4°F (38.0°C) Unsolicited adverse events occurring within 21 days of vaccination were reported in 19%, 23%, and 23% of subjects who received FLULAVAL QUADRIVALENT (n = 1,272), TIV-1 (B Victoria) (n = 213), or TIV-2 (B Yamagata) (n = 218), respectively. The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included nasopharyngitis, upper respiratory tract infection, headache, cough, and oropharyngeal pain. Serious adverse events occurring within 21 days of vaccination were reported in 0.4%, 0%, and 0% of subjects who received FLULAVAL QUADRIVALENT, TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively. FLULAVAL QUADRIVALENT In Children Trial 4 (NCT02242643) was a randomized, observer-blind, active-controlled immunogenicity and safety trial. The trial included subjects aged 6 through 35 months who received FLULAVAL QUADRIVALENT (n = 1,207) or FLUZONE QUADRIVALENT, a U.S.-licensed inactivated influenza vaccine (n = 1,217) used as comparator, manufactured by Sanofi Pasteur Inc. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or the comparator vaccine approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or the comparator vaccine. In the overall population, 53% were male; 64% were white, 16% were black, 3% were Asian, and 17% were of other racial/ethnic groups. The mean age of subjects was 20 months. Subjects were followed for safety for 6 months; solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days) postvaccination. The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 3. Table 3: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 6 through 35 Monthsb (Total Vaccinated Cohort) FLULAVAL QUADRIVALENT % Active Comparatorc % Any Grade 3d Any Grade 3d Local Adverse Reactions n = 1,151 n= 1,146 Pain 40.3 2.4 37.4 1.4 Swelling 1.0 0.0 0.4 0.0 Redness 1.3 0.0 1.3 0.0 Systemic Adverse Events n = 1,155 n = 1,148 Irritability 49.4 3.8 45.9 3.0 Drowsiness 36.7 2.7 36.9 2.6 Loss of appetite 28.9 1.6 28.6 1.3 Fever e 5.6 1.4 5.8 1.0 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available (i.e., diary card completed for solicited symptoms). n = number of subjects with diary card completed. a7 days included day of vaccination and the subsequent 6 days. bTrial 4: NCT02242643. cU.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc). Grade 3 pain: Defined as cried when limb was moved/spontaneously painful. Grade 3 swelling, redness: Defined as >100 mm. Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity. Grade 3 drowsiness: Defined as prevented normal activity. Grade 3 loss of appetite: Defined as not eating at all. Grade 3 (or higher) fever: Defined as >102.2°F (39.0°C). eFever: Defined as ≥100.4°F (38.0°C). In children who received a second dose of FLULAVAL QUADRIVALENT or the comparator vaccine, the incidences of solicited adverse events following the second dose were generally similar or lower than those observed after the first dose. Unsolicited adverse events occurring within 28 days of vaccination were reported in 46% and 44% of subjects who received FLULAVAL QUADRIVALENT (n = 1,207) and the comparator vaccine (n = 1,217), respectively. The unsolicited adverse reactions that occurred most frequently (≥1%) for FLULAVAL QUADRIVALENT included upper respiratory tract infection, cough, diarrhea, pyrexia, vomiting, and rash. Serious adverse events occurring during the study period (approximately 6 months) were reported in 2% of subjects who received FLULAVAL QUADRIVALENT and in 2% of subjects who received the comparator vaccine. There were no deaths reported during the study period. Trial 2 (NCT01198756) was a randomized, double-blind, active-controlled trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 932) or one of 2 formulations of a comparator trivalent influenza vaccine [FLUARIX (Influenza Vaccine), TIV-1 (B Victoria), n = 929 or TIV-2 (B Yamagata), n = 932], each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 3 through 17 years (mean age: 9 years) and 53% were male; 65% were white, 13% were Asian, 9% were black, and 13% were of other racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccination received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of influenza vaccination and children aged 9 years and older received one dose. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 4. Table 4: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 3 through 17 Yearsb (Total Vaccinated Cohort) FLULAVAL QUADRIVALENTc % Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)d % TIV-2 (B Yamagata)e % Any Grade 3f Any Grade 3f Any Grade 3f Aged 3 through 17 Years Local Adverse Reactions n = 913 n = 911 n = 915 Pain 65.4 3.2 54.6 1.8 55.7 2.4 Swelling 6.2 0.1 3.3 0.0 3.8 0.0 Redness 5.3 0.1 3.2 0.0 3.5 0.0 Aged 3 through 4 Years Systemic Adverse Events n = 185 n = 187 n = 189 Irritability 25.9 0.5 16.6 0.0 21.7 1.6 Drowsiness 21.1 0.0 19.8 1.6 23.3 0.5 Loss of appetite 17.3 0.0 16.0 1.6 13.2 1.1 Feverg 4.9 0.5 5.9 1.1 3.7 1.6 Aged 5 through 17 Years Systemic Adverse Events n = 727 n = 724 n = 725 Muscle aches 28.5 0.7 24.9 0.6 24.7 1.0 Fatigue 22.1 0.7 23.6 1.8 23.0 1.0 Headache 22.0 1.0 22.1 1.0 20.1 1.2 Arthralgia 12.9 0.4 11.9 0.6 10.5 0.1 Gastrointestinal symptomsh 9.6 1.0 9.7 1.0 9.0 0.7 Shivering 7.0 0.4 6.9 1.2 6.9 0.6 Feverg 1.9 0.6 3.6 1.1 2.5 0.3 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. 7 days included day of vaccination and the subsequent 6 days. aTrial 2: NCT01198756. bContained 2 A strains and 2 B strains, one of Victoria lineage and one of Yamagata lineage. cContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Victoria lineage. dContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Yamagata lineage. eGrade 3 pain: Defined as cried when limb was moved/spontaneously painful (children 5 years), or significant pain at rest, prevented normal everyday activities (children ≥5 years). Grade 3 swelling, redness: Defined as >100 mm. Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity. Grade 3 drowsiness: Defined as prevented normal activity. Grade 3 loss of appetite: Defined as not eating at all. Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C). Grade 3 muscle aches, fatigue, headache, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity. gFever: Defined as ≥100.4°F (38.0°C). hGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. In children who received a second dose of FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), the incidences of adverse events following the second dose were generally lower than those observed after the first dose. Unsolicited adverse events occurring within 28 days of vaccination were reported in 30%, 31%, and 30% of subjects who received FLULAVAL QUADRIVALENT (n = 932), FLUARIX TIV-1 (B Victoria) (n = 929), or TIV-2 (B Yamagata) (n = 932), respectively. The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included vomiting, pyrexia, bronchitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.1%, 0.2%, and 0.2% of subjects who received FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively. Trial 3 (NCT01218308) was a randomized, observer-blind, non-influenza vaccine-controlled trial evaluating the efficacy of FLULAVAL QUADRIVALENT. The trial included subjects aged 3 through 8 years who received FLULAVAL QUADRIVALENT (n = 2,584) or HAVRIX (Hepatitis A Vaccine) (n = 2,584) as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart (this dosing regimen for HAVRIX is not a U.S.-licensed schedule). Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 5. Table 5: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 3 through 8 Yearsb (Total Vaccinated Cohort) FLULAVAL QUADRIVALENT % HAVRIXc % Any Grade 3d Any Grade 3d Aged 3 through 8 Years Local Adverse Reactions n = 2,546 n = 2,551 Pain 39.4 0.9 27.8 0.7 Swelling 1.0 0.0 0.3 0.0 Redness 0.4 0.0 0.2 0.0 Aged 3 through 4 Years Systemic Adverse Events n = 898 n = 895 Loss of appetite 9.0 0.3 8.2 0.4 Irritability 8.1 0.4 7.5 0.1 Drowsiness 7.7 0.4 7.3 0.0 Fevere 3.8 1.2 4.4 1.3 Aged 5 through 8 Years Systemic Adverse Events n = 1,648 n = 1,654 Muscle aches 12.0 0.1 9.7 0.2 Headache 10.5 0.4 10.6 0.8 Fatigue 8.4 0.1 7.1 0.3 Arthralgia 6.3 0.1 4.5 0.1 Gastrointestinal symptomsf 5.5 0.2 5.9 0.3 Shivering 3.0 0.1 2.5 0.1 Fevere 2.7 0.6 2.7 0.7 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. a7 days included day of vaccination and the subsequent 6 days. bTrial 3: NCT01218308. cHepatitis A Vaccine used as a control vaccine. dGrade 3 pain: Defined as cried when limb was moved/spontaneously painful (children 5 years), or significant pain at rest, prevented normal everyday activities (children ≥5 years). Grade 3 swelling, redness: Defined as >100 mm. Grade 3 loss of appetite: Defined as not eating at all. Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity. Grade 3 drowsiness: Defined as prevented normal activity. Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C). Grade 3 muscle aches, headache, fatigue, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity. eFever: Defined as ≥100.4°F (38.0°C). fGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. In children who received a second dose of FLULAVAL QUADRIVALENT or HAVRIX, the incidences of adverse events following the second dose were generally lower than those observed after the first dose. The frequency of unsolicited adverse events occurring within 28 days of vaccination was similar in both groups (33% for both FLULAVAL QUADRIVALENT and HAVRIX). The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included diarrhea, pyrexia, gastroenteritis, nasopharyngitis, upper respiratory tract infection, varicella, cough, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.7% of subjects who received FLULAVAL QUADRIVALENT and in 0.2% of subjects who received HAVRIX. Postmarketing Experience The following adverse events have been spontaneously reported during postapproval use of FLULAVAL QUADRIVALENT or FLULAVAL (trivalent influenza vaccine). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their incidence rate or establish a causal relationship to the vaccine. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to FLULAVAL QUADRIVALENT or FLULAVAL. Blood And Lymphatic System Disorders Lymphadenopathy. Eye Disorders Eye pain, photophobia. Gastrointestinal Disorders Dysphagia, vomiting. General Disorders And Administration Site Conditions Chest pain, injection site inflammation, asthenia, injection site rash, influenza-like symptoms, abnormal gait, injection site bruising, injection site sterile abscess. Immune System Disorders Allergic reactions including anaphylaxis, angioedema. Infections And Infestations Rhinitis, laryngitis, cellulitis. Musculoskeletal And Connective Tissue Disorders Muscle weakness, arthritis. Nervous System Disorders Dizziness, paresthesia, hypoesthesia, hypokinesia, tremor, somnolence, syncope, Guillain-Barré syndrome, convulsions/seizures, facial or cranial nerve paralysis, encephalopathy, limb paralysis. Psychiatric Disorders Insomnia. Respiratory, Thoracic, And Mediastinal Disorders Dyspnea, dysphonia, bronchospasm, throat tightness. Skin And Subcutaneous Tissue Disorders Urticaria, localized or generalized rash, pruritus, sweating. Vascular Disorders Flushing, pallor. DRUG INTERACTIONS Concomitant Administration With Other Vaccines FLULAVAL QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial. There are insufficient data to assess the concomitant administration of FLULAVAL QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites. 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 FLULAVAL QUADRIVALENT.

SIDE EFFECTS The safety experience with FLUARIX (trivalent influenza vaccine) is relevant to FLUARIX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions [see DESCRIPTION]. 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 with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of FLUARIX QUADRIVALENT could reveal adverse reactions not observed in clinical trials. In adults who received FLUARIX QUADRIVALENT, the most common (≥10%) injection site adverse reaction was pain (36%). The most common (≥10%) systemic adverse events were muscle aches (16%), headache (16%), and fatigue (16%). In children aged 3 through 17 years who received FLUARIX QUADRIVALENT, injection site adverse reactions were pain (44%), redness (23%), and swelling (19%). In children aged 3 through 5 years, the most common (≥10%) systemic adverse events were drowsiness (17%), irritability (17%), and loss of appetite (16%); in children aged 6 through 17 years, the most common systemic adverse events were fatigue (20%), muscle aches (18%), headache (16%), arthralgia (10%), and gastrointestinal symptoms (10%). FLUARIX QUADRIVALENT In Adults Trial 1 (NCT01204671) was a randomized, double-blind (2 arms) and open-label (one arm), activecontrolled, safety, and immunogenicity trial. In this trial, subjects received FLUARIX QUADRIVALENT (n = 3,036) or one of 2 formulations of comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 1,010 or TIV-2, n = 610), each containing an influenza type B virus that corresponded to one of the 2 type B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 18 years and older (mean age: 58 years) and 57% were female; 69% were white, 27% were Asian, and 4% were of other racial/ethnic groups. Solicited events were collected for 7 days (day of vaccination and the next 6 days). The frequencies of solicited adverse events are shown in Table 2. Table 2: FLUARIX QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Vaccination in Adultsb (Total Vaccinated Cohort) FLUARIX QUADRIVALENTc n = 3,011-3,015 % Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)d n = 1,003 % TIV-2 (B Yamagata)e n = 607 % Any Grade 3f Any Grade 3f Any Grade 3f Local Pain 36.4 0.8 36.8 1.2 31.3 0.5 Redness 1.9 0.0 1.7 0.0 2.0 0.0 Swelling 2.1 0.0 2.1 0.0 1.3 0.0 Systemic Muscle aches 16.4 0.5 19.4 0.8 16.1 0.5 Headache 15.9 0.9 16.4 0.8 13.2 0.7 Fatigue 15.8 0.7 18.4 0.6 14.8 0.5 Arthralgia 8.4 0.5 10.4 0.7 9.4 0.3 Gastrointestinal symptomsg 6.5 0.4 6.5 0.2 5.9 0.3 Shivering 4.2 0.4 5.0 0.3 4.3 0.2 Feverh 1.6 0.0 1.2 0.0 1.5 0.0 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. aSeven days included day of vaccination and the subsequent 6 days. bTrial 1: NCT01204671. cContained the same composition as FLUARIX (trivalent formulation) manufactured for the 2010-2011 season and an additional influenza type B virus of Yamagata lineage. dContained the same composition as FLUARIX manufactured for the 2010-2011 season (2 influenza A subtype viruses and an influenza type B virus of Victoria lineage). eContained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-2011 season and an influenza type B virus of Yamagata lineage. fGrade 3 pain: Defined as significant pain at rest; prevented normal everyday activities. Grade 3 redness, swelling: Defined as >100 mm. Grade 3 muscle aches, headache, fatigue, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity. Grade 3 fever: Defined as >102.2°F (39.0°C). gGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. hFever: Defined as ≥99.5°F (37.5°C). Unsolicited events occurring within 21 days of vaccination (Day 0 to 20) were reported in 13%, 14%, and 15% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. The unsolicited adverse reactions that occurred most frequently (≥0.1% for FLUARIX QUADRIVALENT) included dizziness, injection site hematoma, injection site pruritus, and rash. Serious adverse events occurring within 21 days of vaccination were reported in 0.5%, 0.6%, and 0.2% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. FLUARIX QUADRIVALENT In Children Trial 2 (NCT01196988) was a randomized, double-blind, active-controlled, safety, and immunogenicity trial. In this trial, subjects received FLUARIX QUADRIVALENT (n = 915) or one of 2 formulations of comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 912 or TIV-2, n = 911), each containing an influenza type B virus that corresponded to one of the 2 type B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). Subjects were aged 3 through 17 years and 52% were male; 56% were white, 29% were Asian, 12% were black, and 3% were of other racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccination received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of influenza vaccination and children aged 9 years and older received one dose. Solicited local adverse reactions and systemic adverse events were collected using diary cards for 7 days (day of vaccination and the next 6 days). The frequencies of solicited adverse events are shown in Table 3. Table 3: FLUARIX QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa after First Vaccination in Children Aged 3 through 17 Yearsb (Total Vaccinated Cohort) FLUARIX QUADRIVALENTc % Trivalent Influenza Vaccine (TIV) TIV-1 (B Victoria)d % TIV-2 (B Yamagata)e % Any Grade 3f Any Grade 3f Any Grade 3f Aged 3 through 17 Years Local n = 903 n = 901 n = 905 Paing 43.7 1.6 42.4 1.8 40.3 0.8 Redness 23.0 1.0 21.3 0.2 20.9 0.7 Swelling 18.5 0.8 17.2 1.1 14.9 0.2 Aged 3 through 5 Years Systemic n = 291 n = 314 n = 279 Drowsiness 17.2 1.0 12.4 0.3 13.6 0.7 Irritability 16.8 0.7 13.4 0.3 14.3 0.7 Loss of appetite 15.5 0.3 8.0 0.0 10.4 0.7 Feverh 8.9 0.3 8.9 0.3 8.2 1.1 Aged 6 through 17 Years Systemic n = 613 n = 588 n = 626 Fatigue 19.7 1.5 18.5 1.4 15.5 0.5 Muscle aches 17.5 0.7 16.0 1.4 15.8 0.5 Headache 16.3 1.3 19.2 0.7 15.2 0.6 Arthralgia 9.8 0.3 9.4 0.7 7.3 0.2 Gastrointestinal symptomsi 9.8 1.0 9.5 0.7 7.2 0.3 Shivering 6.4 0.5 4.4 0.5 5.0 0.0 Feverh 6.0 1.1 8.5 0.5 6.1 0.3 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available.  n = number of subjects with diary card completed. aSeven days included day of vaccination and the subsequent 6 days. bTrial 2: NCT01196988. cContained the same composition as FLUARIX (trivalent formulation) manufactured for the 2010-2011 season and an additional influenza type B virus of Yamagata lineage. dContained the same composition as FLUARIX manufactured for the 2010-2011 season (2 influenza A subtype viruses and an influenza type B virus of Victoria lineage). eContained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-2011 season and an influenza type B virus of Yamagata lineage. fGrade 3 pain: Defined as cried when limb was moved/spontaneously painful (children 6 years), or significant pain at rest, prevented normal everyday activities (children ≥6 years). Grade 3 redness, swelling: Defined as >50 mm. Grade 3 drowsiness: Defined as prevented normal activity. Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity. Grade 3 loss of appetite: Defined as not eating at all. Grade 3 fever: Defined as >102.2°F (39.0°C). Grade 3 fatigue, muscle aches, headache, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity. gPercentage of subjects with any pain by age subgroup: 39%, 38%, and 37% for FLUARIX QUADRIVALENT, TIV-1, and TIV-2, respectively, in children aged 3 through 8 years and 52%, 50%, and 46% for FLUARIX QUADRIVALENT, TIV-1, and TIV-2, respectively, in children aged 9 through 17 years. hFever: Defined as ≥99.5°F (37.5°C). iGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. In children who received a second dose of FLUARIX QUADRIVALENT, TIV-1, or TIV-2, the incidences of adverse events following the second dose were generally lower than those observed after the first dose. Unsolicited adverse events occurring within 28 days of any vaccination were reported in 31%, 33%, and 34% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. The unsolicited adverse reactions that occurred most frequently (≥0.1% for FLUARIX QUADRIVALENT) included injection site pruritus and rash. Serious adverse events occurring within 28 days of any vaccination were reported in 0.1%, 0.1%, and 0.1% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. FLUARIX (Trivalent Formulation) FLUARIX has been administered to 10,317 adults aged 18 through 64 years, 606 subjects aged 65 years and older, and 2,115 children aged 6 months through 17 years in clinical trials. The incidence of solicited adverse events in each age-group is shown in Tables 4 and 5. Table 4: FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 4 Daysa of Vaccination in Adults (Total Vaccinated Cohort) Trial 3b Trial 4c Aged 18 through 64 Years Aged 65 Years and Older FLUARIX n = 760 % Placebo n = 192 % FLUARIX n = 601-602 % Comparator n = 596 % Any Gr 3d Any Gr 3d Any Gr 3d Any Gr 3d Local Pain 54.7 0.1 12.0 0.0 19.1 0.0 17.6 0.0 Redness 17.5 0.0 10.4 0.0 10.6 0.2 13.1 0.7 Swelling 9.3 0.1 5.7 0.0 6.0 0.0 8.9 0.7 Systemic Muscle aches 23.0 0.4 12.0 0.5 7.0 0.3 6.5 0.0 Fatigue 19.7 0.4 17.7 1.0 9.0 0.3 9.6 0.7 Headache 19.3 0.1 21.4 1.0 7.5 0.3 7.9 0.3 Arthralgia 6.4 0.1 6.3 0.5 5.5 0.5 5.0 0.2 Shivering 3.3 0.1 2.6 0.0 1.7 0.2 2.2 0.0 Fevere 1.7 0.0 1.6 0.0 1.7 0.0 0.5 0.0 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. Gr 3 = Grade 3. aFour days included day of vaccination and the subsequent 3 days. bTrial 3 was a randomized, double-blind, placebo-controlled, safety, and immunogenicity trial (NCT00100399). cTrial 4 was a randomized, single-blind, active-controlled, safety, and immunogenicity trial (NCT00197288). The active control was FLUZONE , a U.S.-licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur Inc.). dGrade 3 pain, muscle aches, fatigue, headache, arthralgia, shivering: Defined as prevented normal activity. Grade 3 redness, swelling: Defined as >50 mm. Grade 3 fever: Defined as >102.2°F (39.0°C). eFever: Defined as ≥100.4°F (38.0°C) in Trial 3, and ≥99.5°F (37.5°C) in Trial 4. Table 5: FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 4 Daysa of First Vaccination in Children Aged 3 through 17 Yearsb (Total Vaccinated Cohort) Aged 3 through 4 Years Aged 5 through 17 Years FLUARIX n = 350 % Comparator n = 341 % FLUARIX n = 1,348 % Comparator n = 451 % Any Gr 3c Any Gr 3c Any Gr 3c Any Gr 3c Local Pain 34.9 1.7 38.4 1.2 56.2 0.8 56.1 0.7 Redness 22.6 0.3 19.9 0.0 17.7 1.0 16.4 0.7 Swelling 13.7 0.0 13.2 0.0 13.9 1.5 13.3 0.7 Systemic Irritability 20.9 0.9 22.0 0.0 Loss of appetite 13.4 0.9 15.0 0.9 — — — — Drowsiness 13.1 0.6 19.6 0.9 — — — — Feverd 6.6 1.4 7.6 1.5 4.2 0.3 3.3 0.2 Muscle aches — — — — 28.8 0.4 28.8 0.4 Fatigue — — — — 19.9 1.0 18.8 1.1 Headache — — — — 15.1 0.5 16.4 0.9 Arthralgia — — — — 5.6 0.1 6.2 0.2 Shivering — — — — 3.1 0.1 3.5 0.2 Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed. Gr 3 = Grade 3. aFour days included day of vaccination and the subsequent 3 days. bTrial 6 was a single-blind, active-controlled, safety, and immunogenicity U.S. trial (NCT00383123). The active control was FLUZONE, a U.S.-licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur Inc.). cGrade 3 pain, irritability, loss of appetite, drowsiness, muscle aches, fatigue, headache, arthralgia, shivering: Defined as prevented normal activity. Grade 3 swelling, redness: Defined as >50 mm. Grade 3 fever: Defined as >102.2°F (39.0°C). dFever: Defined as ≥99.5°F (37.5°C). In children who received a second dose of FLUARIX or the comparator vaccine, the incidences of adverse events following the second dose were similar to those observed after the first dose. Serious Adverse Events In the 4 clinical trials in adults (N = 10,923), there was a single case of anaphylaxis within one day following administration of FLUARIX (<0.01%). Postmarketing Experience Beyond those events reported above in the clinical trials for FLUARIX QUADRIVALENT or FLUARIX, the following adverse events have been spontaneously reported during postapproval use of FLUARIX (trivalent influenza vaccine). This list includes serious events or events which have causal connection to FLUARIX. 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. Blood And Lymphatic System Disorders Lymphadenopathy. Cardiac Disorders Tachycardia. Ear And Labyrinth Disorders Vertigo. Eye Disorders Conjunctivitis, eye irritation, eye pain, eye redness, eye swelling, eyelid swelling. Gastrointestinal Disorders Abdominal pain or discomfort, swelling of the mouth, throat, and/or tongue. General Disorders And Administration Site Conditions Asthenia, chest pain, feeling hot, injection site mass, injection site reaction, injection site warmth, body aches. Immune System Disorders Anaphylactic reaction including shock, anaphylactoid reaction, hypersensitivity, serum sickness. Infections And Infestations Injection site abscess, injection site cellulitis, pharyngitis, rhinitis, tonsillitis. Nervous System Disorders Convulsion, encephalomyelitis, facial palsy, facial paresis, Guillain-Barré syndrome, hypoesthesia, myelitis, neuritis, neuropathy, paresthesia, syncope. Respiratory, Thoracic, And Mediastinal Disorders Asthma, bronchospasm, dyspnea, respiratory distress, stridor. Skin And Subcutaneous Tissue Disorders Angioedema, erythema, erythema multiforme, facial swelling, pruritus, Stevens-Johnson syndrome, sweating, urticaria. Vascular Disorders Henoch-Schönlein purpura, vasculitis. DRUG INTERACTIONS Concomitant Vaccine Administration FLUARIX QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial. There are insufficient data to assess the concurrent administration of FLUARIX QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites. 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 FLUARIX QUADRIVALENT.

SIDE EFFECTS In children 5 through 17 years of age, the most common injection-site reactions observed in clinical studies with AFLURIA administered by needle and syringe were pain (≥60%), redness (≥20%) and swelling (≥10%). The most common systemic adverse events were headache, myalgia (≥20%), irritability, malaise and fever (≥10%). In adults 18 through 64 years of age, the most common injection-site adverse reactions observed in clinical studies with AFLURIA administered by needle and syringe were tenderness (≥60%), pain (≥40%), swelling (≥20%), redness and itching (≥10%). The most common systemic adverse events observed were muscle aches (≥30%), headache and malaise (≥20%). In adults 18 through 64 years of age, using the PharmaJet Stratis Needle-Free Injection System, the most common injection-site adverse reactions observed in a clinical study with AFLURIA up to 7 days post-vaccination were tenderness (≥80%), swelling, pain, redness (≥60%), itching (≥20%) and bruising (≥10%). The most common systemic adverse events within this period were myalgia, malaise (≥30%) and headache (≥20%). In adults 65 years of age and older, the most common injection-site adverse reactions observed in clinical studies with AFLURIA administered by needle and syringe were tenderness (≥30%) and pain (≥10%). No systemic adverse reactions occurred in ≥10% of subjects in this age group. Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to rates in the clinical studies of another vaccine and may not reflect the rates observed in clinical practice. Children In clinical studies, AFLURIA has been administered to, and safety information collected for, 3,009 children ages 6 months through 17 years. The exposure in children includes 1,601 ages 6 months to less than 5 years, 756 children ages 5 years to less than 9 years and 652 children ages 9 years through 17 years. Clinical safety data for AFLURIA in children are presented from three clinical studies (Studies 1, 2 and 3). Data from a comparator-controlled trial (Study 1) are presented, followed by pooled data from two open label studies (Studies 2 and 3). Subjects 6 months through 8 years of age received one or two vaccinations, administered by needle and syringe, as determined by previous vaccination history (for further details on clinical study design, dosing and demographics see Clinical Studies). Study 1 included 1,468 subjects for safety analysis, ages 6 months through 17 years, randomized to receive AFLURIA (735 subjects) or another US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur, Inc.) (733 subjects). Study 2 included 1,976 subjects for safety analysis, ages 6 months through 17 years. All subjects received AFLURIA. Study 3 included 298 subjects for safety analysis, ages 6 months through 8 years. All subjects received AFLURIA. The safety assessment was similar for the three pediatric studies. Local (injection site) adverse reactions and systemic adverse events were solicited for 7 days post-vaccination (Tables 2 and 3). Unsolicited adverse events were collected for 30 days post-vaccination. All adverse events are presented regardless of any treatment causality assigned by study investigators. Among the pediatric studies, there were no vaccine-related deaths or vaccinerelated serious adverse events reported in children 5 years of age and older. In this section, safety data from the pediatric studies are limited to children 5 years of age and older. AFLURIA is not approved for use in children less than 5 years of age. See Warnings and Precautions [5.1] and Use in Specific Populations [8.4] for risks of AFLURIA in children less than 5 years of age. In the comparator-controlled trial (Study 1), the rate of fever after the first dose of AFLURIA in subjects aged 5 through 8 years was 16% as compared to 8% in subjects who received the comparator. The rate of fever in subjects aged 9 through 17 years following a single dose of AFLURIA was 6% as compared to 4% in subjects who received the comparator. In all three pediatric studies, the rates of fever in subjects aged 5 through 8 years who received AFLURIA were lower after dose 2 than dose 1. Data in Tables 2 and 3 are presented for children 5 years and older. Table 2: Proportion of Subjects 5 through 17 Years of Age with Solicited Local Adverse Reactions or Systemic Adverse Events within 7 Days after Administration of First or Second Dose of AFLURIA, Irrespective of Causality (Study 1) Percentagea of Subjects in each Age Group Reporting Event Subjects 5 through 8 years Subjects 9 through 17 years AFLURIA N=161b Comparator N=165b AFLURIA N=254b Comparator N=250b After the First Dose Local Adverse Reactions Pain 63 60 66 60 Redness 23 27 17 17 Induration 17 17 15 16 Systemic Adverse Events Myalgia 34 30 40 37 Malaise 24 13 22 20 Headache 21 19 27 26 Any Fever 16 8 6 4 Fever ≥102.2°F 5 1 3 1 Nausea/ Vomiting 12 8 9 10 Diarrhea 7 7 8 10 AFLURIA N=39b Comparator N=53b After the Second Dose Local Adverse Reactions Pain 36 38 - - Redness 10 19 - - Induration 8 17 - - Systemic Adverse Events Diarrhea 13 6 - - Headache 13 13 - - Myalgia 13 17 - - Malaise 5 8 - - Nausea/ Vomiting 3 8 - - Any Fever 0 2 - - Fever ≥102.2°F 0 0 - - a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). b N = number of subjects in the Safety Population for each treatment group. Table 3: Proportion of Subjects 5 through 17 Years of Age with Solicited Local Adverse Reactions or Systemic Adverse Events Within 7 Days after Administration of AFLURIA, Irrespective of Causality (Studies 2 and 3) Percentagea of Subjects in each Age Group Reporting Event Studies 2 and 3 Subjects 5 through 8 years Study 2 Subjects 9 through 17 years Dose 1 N=82-595b Dose 2 N=82-426b Dose 1 N=397b Local Adverse Reactions Pain 61 56 68 Erythema 24 23 17 Swelling 17 17 13 Systemic Adverse Events Irritabilityd 18 16 - Headache 16 10 27 Malaise or feeling generally unwellc 16 8 17 Any Fever 13 6 5 Fever ≥ 102.2°F 3 2 1 General Muscle Ache (Myalgia) 12 8 20 Nausea/Vomitingc 7 3 5 Vomiting/Diarrhead 5 6 - Loss of appetited 5 4 - Diarrheac 4 2 5 a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). b N = number of subjects in the Safety Population for each treatment group. Denominators for Dose 1 were: N=82 for Vomiting/Diarrhea, Irritability, Loss of appetite, N=513 for Malaise, Diarrhea, Nausea/ Vomiting and N=593-595 for all other parameters. Denominators for Dose 2 were: N=82 for Vomiting/ Diarrhea, Irritability, Loss of appetite, N=344 for Malaise, Diarrhea and Nausea/Vomiting and N=421-426 for all other parameters. c These preferred terms were used to describe Solicited Adverse Events in Study 2. d These preferred terms were used to describe Solicited Adverse Events in Study 3. In Study 1, unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 5 years through 8 years following the first or second dose included cough (15%) and pyrexia (9%). Unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 9 years through 17 years following the first dose included cough (7%), oropharyngeal pain (7%), headache (7%) and nasal congestion (6%). In Studies 2 and 3, unsolicited adverse events that occurred in ≥ 5% of subjects ages 5 years through 8 years after the first or second dose included the following: upper respiratory tract infection (13%), cough (10%), rhinorrhea (7%), headache (5%), nasopharyngitis (5%) and pyrexia (5%). Unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 9 years through 17 years following the first dose included upper respiratory tract infection (9%) and headache (8%). Adults In clinical studies comparing AFLURIA to placebo or a comparator trivalent inactivated influenza vaccine, a single dose of AFLURIA was administered to, and safety information collected for, 11,104 subjects ages 18 through 64 years and 836 subjects ages 65 years and older. Clinical safety data for AFLURIA in adults are presented from three clinical studies (Studies 4 through 6) conducted in the US and one clinical study (Study 7) conducted in the UK. Study 4 included 1,357 subjects for safety analysis, ages 18 through 64 years, randomized to receive AFLURIA (1,089 subjects) or placebo (268 subjects) (see Clinical Studies). Study 5 included 15,020 subjects for safety analysis, ages 18 through 64 years, randomized to receive AFLURIA (10,015 subjects) or placebo (5,005 subjects) (see Clinical Studies). Study 6 included 1,266 subjects for safety analysis, ages 65 years and older, randomized to receive AFLURIA (630 subjects) or another US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.) as an active comparator (636 subjects) (see Clinical Studies). Study 7 included 275 subjects for safety analysis, ages 65 year and older, randomized to receive AFLURIA (206 subjects) or a UK-licensed trivalent inactivated influenza vaccine (manufactured by GSK) as an active comparator (69 subjects). The safety assessment was identical for the four adult studies. Local (injectionsite) adverse reactions and systemic adverse events were solicited for 5 days post-vaccination (Table 4, studies 4 through 6). Unsolicited adverse events were collected for 21 days post-vaccination. All adverse events are presented regardless of any treatment causality assigned by study investigators. Among adult studies, there were no vaccine-related deaths or vaccine-related serious adverse events reported. Table 4: Proportion of Subjects 18 Years of Age and Older with Solicited Local Adverse Reactions or Systemic Adverse Events within 5 Days after Administration of AFLURIA or Placebo, Irrespective of Causality (Studies 4, 5 and 6) Percentage a of Subjects in each Age Group Reporting Event Study 4 Subjects 18 through 64 years Study 5 Subjects 18 through 64 years Study 6 Subjects ≥ 65 years AFLURIA N=1087- 1088 b Placebo N=266 b AFLURIA N=10,015 b Placebo N=5005 b AFLURIA N=630 b Comparator N=636 b Local Adverse Reactions Tenderness (Pain on touching) 60 18 69 17 36 31 Pain (without touching) 40 9 48 11 15 14 Redness 16 8 4 <1 3 1 Swelling 9 1 4 <1 7 8 Bruising 5 1 1 1 <1 1 Systemic Adverse Events Headache 26 26 25 23 9 11 Malaise 19 19 29 26 7 6 Muscle aches 13 9 21 12 9 8 Nausea 6 9 7 6 2 1 Chills/ Shivering 3 2 5 4 2 2 Fever 1 1 3 2 <1 1 a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). b N = number of subjects in the Safety Population for each treatment group. In Study 4, headache was the only unsolicited adverse event that occurred in ≥ 5% of subjects who received AFLURIA or placebo (8% versus 6%, respectively). In Study 5, unsolicited adverse events that occurred in ≥5% of subjects who received AFLURIA or placebo included headache (AFLURIA 12%, placebo 11%) and oropharyngeal pain (AFLURIA 5%, placebo 5%). In Study 6, headache was the only unsolicited adverse event that occurred in ≥5% of subjects who received AFLURIA (5%). Studies 1 to 7 were all conducted when AFLURIA was administered by needle and syringe. Additionally, safety information has been collected in a clinical study of AFLURIA administered using the PharmaJet Stratis Needle-Free Injection System (Study 8). Study 8 included 1,247 subjects for safety analysis, ages 18 through 64 years, randomized to receive AFLURIA by either the PharmaJet Stratis Needle-Free Injection System (624 subjects) or needle and syringe (623 subjects). No deaths or vaccine-related serious adverse events were reported in Study 8. Local (injection-site) adverse reactions and systemic adverse events were solicited for 7 days post-vaccination (Table 5). Table 5: Proportion of Subjects 18 through 64 Years of Age with Solicited Local Adverse Reactions or Systemic Adverse Events within 7 Days after Administration of AFLURIA by PharmaJet Stratis Needle-Free Injection System or Needle and Syringe Irrespective of Causality (Study 8). Percentage a of Subjects Reporting Event Study 8 Subjects 18 through 64 years AFLURIA PharmaJet Stratis Needle- Free Injection System N=540-616 b Needle and Syringe N=599-606 b Local Adverse Reactions Tenderness 89 78 Swelling 65 20 Pain 64 49 Redness 60 19 Itching c 28 10 Bruising 18 5 Systemic Adverse Events Myalgia 36 36 Malaise 31 28 Headache 25 22 Chills 7 7 Nausea 7 7 Vomiting 1 2 Fever 0 0 a Proportion of subjects reporting each local adverse reaction or systemic adverse event by treatment group based on the number of subjects contributing at least one data value for an individual sign/ symptom (individual event denominators). b N = number of subjects in the Safety Population for each treatment group. Denominators for the PharmaJet Stratis Needle-Free Injection System group were: N=540 for itching and N=605-616 for all other parameters. Denominators for the needle and syringe group were: N=527 for itching and N=599- 606 for all other parameters. c A total of 155 subjects (approximately randomly distributed between PharmaJet Stratis Needle-Free Injection System and needle and syringe groups) received Diary Cards without itching listed as a solicited symptom. In Study 8, no unsolicited adverse events occurred in ≥5% of subjects who received AFLURIA administered via PharmaJet Stratis Needle-Free Injection System up to 28 days post-vaccination. Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. The adverse reactions described have been included in this section because they: 1) represent reactions that are known to occur following immunizations generally or influenza immunizations specifically; 2) are potentially serious; or 3) have been reported frequently. These adverse reactions reflect experience in both children and adults and include those identified during post-approval use of AFLURIA outside the US since 1985. Blood And Lymphatic System Disorders Thrombocytopenia Immune System Disorders Allergic or immediate hypersensitivity reactions including anaphylactic shock and serum sickness Nervous System Disorders Neuralgia, paresthesia, convulsions (including febrile seizures), encephalomyelitis, encephalopathy, neuritis or neuropathy, transverse myelitis, and GBS Vascular Disorders Vasculitis which may be associated with transient renal involvement Skin And Subcutaneous Tissue Disorders Pruritus, urticaria, and rash General Disorders And Administration Site Conditions Cellulitis and large injection site swelling Influenza-like illness Adverse Reactions Associated With Influenza Vaccination Anaphylaxis has been reported after administration of AFLURIA. Egg protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, asthma, and systemic anaphylaxis (see CONTRAINDICATIONS). Neurological disorders temporally associated with influenza vaccination, such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy, have been reported. Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination. DRUG INTERACTIONS Concurrent Use With Other Vaccines There are no data to assess the concomitant administration of AFLURIA with other vaccines. If AFLURIA is given at the same time as another injectable vaccine(s), the vaccine(s) should be administered in separate syringes and a separate arm should be used. AFLURIA should not be mixed with any other vaccine in the same syringe or vial.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Guillain-Barré Syndrome If Guillain-Barré syndrome (GBS) has occurred within 6 weeks following previous influenza vaccination, the decision to give Fluzone High-Dose should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. (See REFERENCES 1 and 2.) Preventing And Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Altered Immunocompetence If Fluzone High-Dose is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained. Limitations Of Vaccine Effectiveness Vaccination with Fluzone High-Dose may not protect all recipients. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). Inform the patient or caregiver that Fluzone High-Dose contains killed viruses and cannot cause influenza. Among persons aged 65 years and older, Fluzone High-Dose stimulates the immune system to produce antibodies that help protect against influenza. Among persons aged 65 years and older, Fluzone High-Dose offers better protection against influenza as compared to Fluzone. Annual influenza vaccination is recommended. Instruct vaccine recipients and caregivers to report adverse reactions to their healthcare provider and/or to Vaccine Adverse Event Reporting System (VAERS). Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Fluzone High-Dose 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 Fluzone High-Dose. It is also not known whether Fluzone High-Dose can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fluzone High-Dose should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness of Fluzone High-Dose in persons <65 years of age have not been established. Geriatric Use Safety, immunogenicity, and efficacy of Fluzone High-Dose have been evaluated in adults 65 years of age and older. [See ADVERSE REACTIONS and Clinical Studies] REFERENCES 1.Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797-802. 2.Baxter, R, et al. Lack of Association of Guillain-Barré Syndrome with Vaccinations. Clin Infect Dis 2013;57(2):197-204.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barré Syndrome If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUVIRIN® should be based on careful consideration of the potential benefits and risks. Altered Immunocompetence If FLUVIRIN® is administered to immunocompromised persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained. Preventing And Managing Allergic Reactions Prior to administration of any dose of FLUVIRIN®, the healthcare provider should review the patient's prior immunization history for possible adverse events, to determine the existence of any contraindication to immunization with FLUVIRIN® and to allow an assessment of benefits and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. The tip caps of the FLUVIRIN® prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals. Limitations Of Vaccine Effectiveness Vaccination with FLUVIRIN® may not protect all individuals. Syncope Syncope (fainting) can occur in association with administration of injectable vaccines, including Fluvirin. 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 by maintaining a supine or Trendelenburg position. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility FLUVIRIN® has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. Use In Specific Populations Pregnancy Pregnancy Category B A reproductive and developmental toxicity study has been performed in rabbits at a dose level that was approximately 15 times the human dose based on body weight. The study revealed no evidence of impaired fertility or harm to the fetus due to FLUVIRIN®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this vaccine should be used during pregnancy only if clearly needed. In a reproductive and developmental toxicity study, the effect of FLUVIRIN® on embryo-fetal and postnatal development was evaluated in pregnant rabbits. Animals were administered FLUVIRIN® by intramuscular injection twice prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (approximately 15-fold excess relative to the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, embryo-fetal development, or post-natal development were observed. There were no vaccine related fetal malformations or other evidence of teratogenicity. Nursing Mothers It is not known whether FLUVIRIN® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUVIRIN® is administered to a nursing woman. Pediatric Use The safety and immunogenicity of FLUVIRIN® have not been established in children under 4 years of age. The safety and immunogenicity of FLUVIRIN® have been established in the age group 4 years to 16 years. The use of FLUVIRIN® in these age groups is supported by evidence from adequate and well controlled studies of FLUVIRIN® in adults that demonstrate the immunogenicity of FLUVIRIN® [see ADVERSE REACTIONS and Clinical Studies]. Geriatric Use Since 1997, of the total number of geriatric subjects (n = 397) in clinical studies of FLUVIRIN®, 29% were 65 years and over, while 2.1% were 75 years and over. Antibody responses were lower in the geriatric population than in younger subjects. Adverse events occurred less frequently in geriatric subjects (≥65 years) than in younger adults. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. [See ADVERSE REACTION and Clinical Studies].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Risks Of Hospitalization And Wheezing In Children Younger Than 24 Months Of Age In clinical trials, risks of hospitalization and wheezing were increased in children younger than 2 years of age who received FluMist (trivalent Influenza Vaccine Live, Intranasal) [see ADVERSE REACTIONS]. This observation with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see DESCRIPTION]. Asthma, Recurrent Wheezing, And Active Wheezing Children younger than 5 years of age with recurrent wheezing and persons of any age with asthma may be at increased risk of wheezing following administration of FluMist Quadrivalent. FluMist Quadrivalent has not been studied in persons with severe asthma or active wheezing. Guillain-Barré Syndrome The 1976 swine influenza vaccine (inactivated) was associated with an elevated risk of Guillain-Barré syndrome (GBS). Evidence for causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, based on data for inactivated influenza vaccines, it is probably slightly more than 1 additional case per 1 million persons vaccinated [1]. If GBS has occurred within 6 weeks of any prior influenza vaccination, the decision to give FluMist Quadrivalent should be based on careful consideration of the potential benefits and potential risks. Altered Immunocompetence FluMist Quadrivalent has not been studied in immunocompromised persons. The effectiveness of FluMist has not been studied in immunocompromised persons. Data on safety and shedding of vaccine virus after administration of FluMist in immunocompromised persons are limited to 173 persons with HIV infection and 10 mild to moderately immunocompromised children and adolescents with cancer [see CLINICAL PHARMACOLOGY]. Medical Conditions Predisposing To Influenza Complications The safety of FluMist Quadrivalent in individuals with underlying medical conditions that may predispose them to complications following wild-type influenza infection has not been established. Management Of Acute Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine [see CONTRAINDICATIONS]. Limitations Of Vaccine Effectiveness FluMist Quadrivalent may not protect all individuals receiving the vaccine. Patient Counseling Information Advise the vaccine recipient or caregiver to read the FDA-approved patient labeling (Information for Patients and Their Caregivers). Inform vaccine recipients or their parents/guardians of the need for two doses at least 1 month apart in children 2 through 8 years of age, depending on vaccination history. Provide the Vaccine Information Statements (VIS) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. Asthma And Recurrent Wheezing Ask the vaccinee or their parent/guardian if the vaccinee has asthma. For children younger than 5 years of age, also ask if the vaccinee has recurrent wheezing since this may be an asthma equivalent in this age group. Inform the vaccinee or their parent/guardian that there may be an increased risk of wheezing associated with FluMist Quadrivalent in persons younger than 5 years of age with recurrent wheezing and persons of any age with asthma [see WARNINGS AND PRECAUTIONS]. Vaccination With A Live Virus Vaccine Inform vaccine recipients or their parents/guardians that FluMist Quadrivalent is an attenuated live virus vaccine and has the potential for transmission to immunocompromised household contacts. Adverse Event Reporting Instruct the vaccine recipient or their parent/guardian to report adverse reactions to their healthcare provider. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility FluMist Quadrivalent has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility. Use In Specific Populations Pregnancy Pregnancy Category B A developmental and reproductive toxicity study has been performed in female rats administered FluMist Quadrivalent either three times (during the period of organogenesis) or six times (prior to gestation and during the period of organogenesis), 200 microliter/rat/occasion (approximately 150 human dose equivalents), by intranasal instillation and has revealed no evidence of impaired fertility or harm to the fetus due to FluMist Quadrivalent. There are however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human response FluMist Quadrivalent should be administered during pregnancy only if clearly needed. Nursing Mothers It is not known whether FluMist Quadrivalent is excreted in human milk. Because some viruses are excreted in human milk, caution should be exercised when FluMist Quadrivalent is administered to a nursing woman. Pediatric Use Safety and effectiveness of FluMist Quadrivalent in children 24 months of age and older is based on data from FluMist clinical studies and a comparison of post-vaccination antibody titers between persons who received FluMist Quadrivalent and those who received FluMist [see Clinical Studies]. FluMist Quadrivalent is not approved for use in children younger than 24 months of age because use of FluMist in children 6 through 23 months has been associated with increased risks of hospitalization and wheezing in clinical trials [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Geriatric Use FluMist Quadrivalent is not approved for use in persons 65 years of age and older because in a clinical study (AV009), effectiveness of FluMist to prevent febrile illness was not demonstrated in adults 50 through 64 years of age [see Clinical Studies]. In this study, solicited events among individuals 50 through 64 years of age were similar in type and frequency to those reported in younger adults. In a clinical study of FluMist in persons 65 years of age and older, subjects with underlying high-risk medical conditions (N = 200) were studied for safety. Compared to controls, FluMist recipients had a higher rate of sore throat.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barré Syndrome If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLULAVAL QUADRIVALENT should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than one additional case/one million persons vaccinated. Syncope Syncope (fainting) can occur in association with administration of injectable vaccines, including FLULAVAL QUADRIVALENT. 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 Prior to administration, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of FLULAVAL QUADRIVALENT. Altered Immunocompetence If FLULAVAL QUADRIVALENT is administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the immune response may be lower than in immunocompetent persons. Limitations Of Vaccine Effectiveness Vaccination with FLULAVAL QUADRIVALENT may not protect all susceptible individuals. Persons At Risk Of Bleeding As with other intramuscular injections, FLULAVAL QUADRIVALENT should be given with caution in individuals with bleeding disorders such as hemophilia or on anticoagulant therapy to avoid the risk of hematoma following the injection. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility FLULAVAL QUADRIVALENT has not been evaluated for carcinogenic, mutagenic potential, or male infertility in animals. Vaccination of female rats with FLULAVAL QUADRIVALENT had no effect on fertility [see Use In Specific Populations]. Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FLULAVAL QUADRIVALENT during pregnancy. Healthcare providers are encouraged to register women by calling 1-888-452-9622. Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are insufficient data on FLULAVAL QUADRIVALENT in pregnant women to inform vaccineassociated risks. A developmental toxicity study was performed in female rats administered FLULAVAL QUADRIVALENT prior to mating and during gestation and lactation periods. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to FLULAVAL QUADRIVALENT [see Data]. Clinical Considerations Disease-Associated Maternal And/Or Embryo/Fetal Risk Pregnant women infected with seasonal influenza are at increased risk of severe illness associated with influenza infection compared with non-pregnant women. Pregnant women with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery. Data Animal Data In a developmental toxicity study, female rats were administered FLULAVAL QUADRIVALENT by intramuscular injection 4 and 2 weeks prior to mating, on gestation Days 3, 8, 11, and 15, and on lactation Day 7. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to post-natal Day 25 were observed. There were no vaccine-related fetal malformations or variations. Lactation Risk Summary It is not known whether FLULAVAL QUADRIVALENT is excreted in human milk. Data are not available to assess the effects of FLULAVAL QUADRIVALENT on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FLULAVAL QUADRIVALENT and any potential adverse effects on the breastfed child from FLULAVAL QUADRIVALENT or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine. Pediatric Use Safety and effectiveness of FLULAVAL QUADRIVALENT in children younger than 6 months have not been established. Geriatric Use In a randomized, double-blind, active-controlled trial, immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who received FLULAVAL QUADRIVALENT (n = 397); approximately one-third of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 to 64 years) and the frequencies of solicited and unsolicited adverse events were generally lower than in younger subjects [see ADVERSE REACTIONS, Clinical Studies].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barré Syndrome If GuillainBarré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLUARIX QUADRIVALENT should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is inconclusive. If influenza vaccine does pose a risk, it is probably slightly more than one additional case/one million persons vaccinated. Syncope Syncope (fainting) can occur in association with administration of injectable vaccines, including FLUARIX QUADRIVALENT. 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 Prior to administration, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccinationrelated adverse reactions. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of FLUARIX QUADRIVALENT. Altered Immunocompetence If FLUARIX QUADRIVALENT is administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the immune response may be lower than in immunocompetent persons. Limitations Of Vaccine Effectiveness Vaccination with FLUARIX QUADRIVALENT may not protect all susceptible individuals. Persons At Risk Of Bleeding As with other intramuscular injections, FLUARIX QUADRIVALENT should be given with caution in individuals with bleeding disorders, such as hemophilia or on anticoagulant therapy, to avoid the risk of hematoma following the injection. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility FLUARIX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential or male infertility in animals. Vaccination of female rats with FLUARIX QUADRIVALENT had no effect on fertility [see Use In Specific Populations]. Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FLUARIX QUADRIVALENT during pregnancy. Healthcare providers are encouraged to register women by calling 1-888-452-9622. Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are insufficient data on FLUARIX QUADRIVALENT in pregnant women to inform vaccineassociated risks. A developmental toxicity study was performed in female rats administered FLUARIX QUADRIVALENT prior to mating and during gestation and lactation periods. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to FLUARIX QUADRIVALENT [see Data]. Clinical Considerations Disease-Associated Maternal And/Or Embryo/Fetal Risk Pregnant women infected with seasonal influenza are at increased risk of severe illness associated with influenza infection compared with non-pregnant women. Pregnant women with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery. Data Animal Data In a developmental toxicity study, female rats were administered FLUARIX QUADRIVALENT by intramuscular injection 4 and 2 weeks prior to mating, on gestation Days 3, 8, 11, and 15, and on lactation Day 7. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to post-natal Day 25 were observed. There were no vaccine-related fetal malformations or variations. Lactation Risk Summary It is not known whether FLUARIX QUADRIVALENT is excreted in human milk. Data are not available to assess the effects of FLUARIX QUADRIVALENT on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FLUARIX QUADRIVALENT and any potential adverse effects on the breastfed child from FLUARIX QUADRIVALENT or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine. Pediatric Use Safety and effectiveness of FLUARIX QUADRIVALENT in children younger than 3 years have not been established. Safety and immunogenicity of FLUARIX QUADRIVALENT in children aged 3 through 17 years have been evaluated [see ADVERSE REACTIONS, Clinical Studies]. Geriatric Use In a randomized, double-blind (2 arms) and open-label (one arm), active-controlled trial, immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who received FLUARIX QUADRIVALENT (n = 1,517); 469 of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 through 64 years) and the frequencies of solicited and unsolicited adverse events were generally lower than in younger subjects.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Fever And Febrile Seizures Administration of CSL’s 2010 Southern Hemisphere influenza vaccine was associated with postmarketing reports of increased rates of fever and febrile seizures in children predominantly below the age of 5 years as compared to previous years; these increased rates were confirmed by postmarketing studies. Febrile events were also observed in children 5 through 8 years of age. Guillain-Barré Syndrome If Guillain-Barré Syndrome (GBS) has occurred within 6 weeks of previous influenza vaccination, the decision to give AFLURIA should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than one additional case per 1 million persons vaccinated. Preventing And Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Altered Iimmuocompetence If AFLURIA is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the immune response may be diminished. Limitations Of Vaccine Effectiveness Vaccination with AFLURIA may not protect all individuals. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility AFLURIA has not been evaluated for carcinogenic or mutagenic potential, or male infertility in animals. A reproductive study of female rats vaccinated with AFLURIA revealed no impairment of fertility (see Pregnancy). Use In Specific Populations Pregnancy Pregnancy Category B A reproductive and developmental toxicity study has been performed in female rats at a dose approximately 265 times the human dose (on a mg/kg basis) and revealed no evidence of impaired female fertility or harm to the fetus due to AFLURIA. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, AFLURIA should be given to a pregnant woman only if clearly needed. In the reproductive and developmental toxicity study, the effect of AFLURIA on embryo-fetal and pre-weaning development was evaluated in pregnant rats. Animals were administered AFLURIA by intramuscular injection twice prior to gestation, once during the period of organogenesis (gestation day 6), and once later in pregnancy (gestation day 20), 0.5 mL/rat/occasion (approximately a 265-fold excess relative to the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis. Pregnancy exposure and safety surveillance An exposure and surveillance study which monitors pregnancy outcomes in women exposed to AFLURIA during pregnancy has been established. Women who are vaccinated with AFLURIA during pregnancy should be encouraged to contact the pregnancy study center by calling 1-877-311-8972 or visit the website http://www.pregnancystudies.org. Nursing Mothers AFLURIA has not been evaluated in nursing mothers. It is not known whether AFLURIA is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AFLURIA is administered to a nursing woman. Pediatric Use AFLURIA is not approved for use in children less than 5 years of age. In a clinical study in which children received AFLURIA or a US-licensed comparator vaccine (Study 1, see Clinical Trials Experience), the incidence of fever in children 6 months through 35 months of age following the first and second doses of AFLURIA were 37% and 15%, respectively, as compared to 14% following each dose in the comparator group. Among children 3 years through 4 years of age, the incidence of fever following the first and second doses of AFLURIA were 32% and 14%, respectively, as compared to 11% and 16% in the comparator. In an open-label study (Study 2), fever, irritability, loss of appetite, and vomiting/ diarrhea occurred more frequently in children 6 months through 35 months of age as compared to older children. Across three pediatric studies of AFLURIA (Studies 1, 2, and 3), 1.2% of eligible children (n=1,764) were discontinued from the second vaccination because of severe fever (≥ 104°F) within 48 hours of the first vaccination. Across the three pediatric studies, two children, a 7-month old and a 3-year old, experienced vaccine-related febrile seizures (rate of 0.07% across studies), one of which was serious. Administration of CSL’s 2010 Southern Hemisphere influenza vaccine was associated with increased rates of fever and febrile seizures, predominantly in children below the age of 5 years as compared to previous years, in postmarketing reports confirmed by postmarketing studies (see WARNINGS AND PRECAUTIONS). The PharmaJet Stratis Needle-Free Injection System is not approved as a method of administering AFLURIA to children and adolescents less than 18 years of age due to lack of adequate data supporting safety and effectiveness in this population. Geriatric Use In clinical studies, AFLURIA has been administered to, and safety information collected for, 836 subjects ages 65 years and older (see Clinical Trials Experience). After administration of AFLURIA, hemagglutination-inhibiting antibody responses in persons 65 years of age and older were lower as compared to younger adult subjects (see Clinical Studies). The PharmaJet Stratis Needle-Free Injection System is not approved as a method of administering AFLURIA to adults 65 years of age and older due to lack of adequate data supporting safety and effectiveness in this population.