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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. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have cocirculated worldwide. Protection from influenza virus infection has not been correlated with a specific level of hemagglutination inhibition (HI) antibody titer post-vaccination. However, in some human studies, antibody titers ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects. (See ref. 2) (See ref. 3) 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 influenza 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 The effectiveness of Fluzone Quadrivalent was demonstrated based on clinical endpoint efficacy data for Fluzone (trivalent influenza vaccine) and on an evaluation of serum HI antibody responses to Fluzone Quadrivalent. Fluzone Quadrivalent, an inactivated influenza vaccine that contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, is manufactured according to the same process as Fluzone. Efficacy Of Fluzone (Trivalent Influenza Vaccine) In Children 6 Through 24 Months Of Age A randomized, double-blind, placebo-controlled study was conducted at a single US center during the 1999-2000 (Year 1) and 2000-2001 (Year 2) influenza seasons. The intent-totreat analysis set included a total of 786 children 6 through 24 months of age. Participants received two doses of either Fluzone (N = 525) or a placebo (N = 261). Among all randomized participants in both years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were Black, and 7.2% were of other racial groups. Cases of influenza were identified through active and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary endpoint and is presented in Table 7. Table 7: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Culture- Confirmed Influenza in Children Aged 6 through 24 Months during the 1999-2000 and 2000-2001 Influenza Seasons - Intent-to-Treat Analysis Seta Year Fluzoneb Placeboc Fluzone vs. Placebo nd Ne Rate (n/N)f (95% CI) nd Ne Rate (n/N)f (95% CI) Relative Risk (95% CI) Percent Relative Reductions (95% CI) Year 1h (1999-2000) 15 273 5.5 (3.1; 8.9) 22 138 15.9 (10.3; 23.1) 0.34 (0.18; 0.64) 66 (36; 82) Year 2i(2000-2001) 9 252 3.6 (1.6; 6.7) 4 123 3.3 (0.9; 8.1) 1.10 (0.34; 3.50) -10 (-250; 66) aThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated bFluzone: 1999-2000 formulation containing A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) and 2000-2001 formulation containing A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) cPlacebo: 0.4% NaCl dn is the number of participants with culture-confirmed influenza for the given year of study as listed in the first column eN is the number of participants randomly assigned to receive Fluzone or placebo for the given year of study as listed in the column headers (intent-to-treat analysis set) fRate (%) = (n/N) * 100 gRelative reduction in vaccine efficacy was defined as (1-relative risk) x 100 hIncludes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up) iIncludes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up) Efficacy Of Fluzone (Trivalent Influenza Vaccine) In Adults A randomized, double-blind, placebo-controlled study was conducted in a single US center during the 2007-2008 influenza season. Participants received one dose of either Fluzone vaccine (N=813), an active comparator (N = 814), or placebo (N = 325). The intent-to-treat analysis set included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% were of other racial/ethnic groups. Cases of influenza were identified through active and passive surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR). Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 8. Table 8: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Influenza in Adults Aged 18 through 49 Years during the 2007-2008 Influenza Season - Intent-to-Treat Analysis Setab Laboratory-Confirmed Symptomatic Influenza Fluzonec (N=813)e Placebod (N=325)e Fluzone vs. Placebo nf Rate (%)g (95% CI) nf Rate (%)g (95% CI) Relative Risk (95% CI) Percent Relative Reductionh(95% CI) Positive culture 21 2.6 (1.6; 3.9) 31 9.5 (6.6; 13.3) 0.27 (0.16; 0.46) 73 (54; 84) 28 3.4 (2.3; 4.9) 35 10.8 (7.6: 14.7) 0.32 (0.20; 0.52) 68 (48; 80) Positive culture, positive PCR, or both 28 3.4 (2.3; 4.9) 35 10.8 (7.6; 14.7) 0.32 (0.20; 0.52) 68 (48; 80) aNCT00538512 bThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated cFluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (Victoria lineage) dPlacebo: 0.9% NaCl eN is the number of participants randomly assigned to receive Fluzone or placebo fn is the number of participants satisfying the criteria listed in the first column gRate (%) = (n/N) * 100 hRelative reduction in vaccine efficacy was defined as (1 - relative risk) x 100 Immunogenicity Of Fluzone Quadrivalent In Children 6 Months Through 8 Years Of Age In Study 1 (NCT01240746) [see ADVERSE REACTIONS], 1419 children 6 months through 35 months of age and 2101 children 3 years through 8 years of age were included in the per-protocol immunogenicity analysis. Participants received one or two 0.25 mL doses or one or two 0.5 mL doses, respectively of Fluzone Quadrivalent, TIV-1, or TIV-2. For participants who received two doses, the doses were administered approximately 4 weeks apart. The distribution of demographic characteristics was similar to that of the safety analysis [see ADVERSE REACTIONS]. HI antibody geometric mean titers (GMTs) and seroconversion rates 28 days following vaccination with Fluzone Quadrivalent were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (see Table 9 and Table 10). Table 9: Study 1a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of Age (Per-protocol Analysis Set)b Antigen Strain Fluzone Quadrivalentc Nd=2339 Pooled TIVe Nd=1181 GMT Ratio (95% CI)f GMT GMT A (H1N1) 1124 1096 1.03 (0.93; 1.14) A (H3N2) 822 828 0.99 (0.91; 1.08) Fluzone Quadrivalentc Nd=2339 TIV-1 g (B Victoria) Nd=582 TIV-2h (B Yamagata) Nd=599 GMT Ratio (95% CI)f GMT GMT GMT B/Brisbane/60/2008 (B Victoria) 86.1 64.3 (19.5)1 1.34 (1.20; 1.50) B/Florida/04/2006 (B Yamagata) 61.5 (16.3)i 58.3 1.06 (0.94; 1.18) aNCT01240746 bPer-protocol analysis set included all persons who had no study protocol deviations cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/ Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) dN is the number of participants in the per-protocol analysis set ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was > 0.66 g2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed hInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), andB/Florida/04/2006 (Yamagata lineage), non-licensed iTIV-2 did not contain B/Brisbane/60/2008 jTIV-1 did not contain B/Florida/04/2006 Table 10: Study 1a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by Seroconversion Rates at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of Age (Per-protocol Analysis Set)b Antigen Strain Fluzone Quadrivalentc Nd=2339 Pooled TIVe Nd=1181 Difference of Seroconversion Rates (95% CI)g Seroconversionf (%) A (H1N1) 92.4 91.4 0.9 (-0.9; 3.0) A (H3N2) 88.0 84.2 0.9 (-0.9; 3.0) Fluzone Quadrivalentc Nd=2339 TIV-1h (B Victoria) Nd=582 TIV-2i (B Yamagata) Nd=599 Difference of Seroconversion Rates (95% CI)g Seroconversionf(%) B/Brisbane/60/2008 (B Victoria) 71.8 61.1 (20.0)j 10.7 (6.4; 15.1) B/Florida/04/2006 (B Yamagata) 66.1 (17.9)k 64.0 2.0 (-2.2; 6.4) aNCT01240746 bPer-protocol analysis set included all persons who had no study protocol deviations cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) dN is the number of participants in the per-protocol analysis set ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 fSeroconversion: Paired samples with pre-vaccination HI titer < 1:10 and post-vaccination titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10 gNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was > -10% h2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed iInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/ Florida/04/2006 (Yamagata lineage), non-licensed jTIV-2 did not contain B/Brisbane/60/2008 kTIV-1 did not contain B/Florida/04/2006 Non-inferiority immunogenicity criteria based on HI antibody GMTs and seroconversion rates were also met when age subgroups (6 months to < 36 months and 3 years to < 9 years) were examined. In addition, HI antibody GMTs and seroconversion rates following Fluzone Quadrivalent were higher than those following TIV for the B strain not contained in each respective TIV based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by TIV] > 1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV and the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone Quadrivalent minus TIV] > 10% for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV). Immunogenicity Of Fluzone Quadrivalent In Adults ≥ 18 Years Of Age In Study 2 (NCT00988143) [see ADVERSE REACTIONS], 565 adults 18 years of age and older who had received one dose of Fluzone Quadrivalent, TIV-1, or TIV-2 were included in the perprotocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis [see ADVERSE REACTIONS]. HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (see Table 11). Table 11: Study 2a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 18 Years of Age and Older (Per-protocol Analysis Set)b Antigen Strain Fluzone Quadrivalentc Nd=190 Pooled TIVe Nd=375 GMT Ratio (95% CI)f GMT GMT A (H1N1) 161 151 1.06 (0.87; 1.31) A (H3N2) 304 339 0.90 (0.70; 1.15) Fluzone Quadrivalentc Nd=190 TIV-1g (B Victoria) Nd=187 TIV-2h (B Yamagata) Nd=188 GMT Ratio (95% CI)f GMT GMT GMT B/Brisbane/60/2008 (B Victoria) 101 114 (44.0)1 0.89 (0.70; 1.12) B/Florida/04/2006 (B Yamagata) 155 (78.1)j 135 1.15 (0.93; 1.42) aNCT00988143 bPer-protocol analysis set included all persons who had no study protocol deviations cFluzone Quadrivalent containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) dN is the number of participants in the per-protocol analysis set ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was > 2/3 g2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed h2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed iTIV-2 did not contain B/Brisbane/60/2008 jTIV-1 did not contain B/Florida/04/2006 Immunogenicity Of Fluzone Quadrivalent In Geriatric Adults ≥ 65 Years Of Age In Study 3 (NCT01218646) [see ADVERSE REACTIONS], 660 adults 65 years of age and older were included in the per-protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis [see ADVERSE REACTIONS]. HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to those following TIV for all four strains, based on pre-specified criteria (see Table 12). Seroconversion rates 21 days following Fluzone Quadrivalent were non-inferior to those following TIV for H3N2, B/Brisbane, and B/Florida, but not for H1N1 (see Table 13). The HI antibody GMT following Fluzone Quadrivalent was higher than that following TIV-1 for B/Florida but not higher than that following TIV-2 for B/Brisbane, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by TIV] > 1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV). Seroconversion rates following Fluzone Quadrivalent were higher than those following TIV for the B strain not contained in each respective TIV, based on pre-specified criteria (the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone Quadrivalent minus TIV] > 10% for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV). Table 12: Study 3a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-protocol Analysis Set)b Antigen Strain Fluzone Quadrivalentc Nd=220 Pooled TIVe Nd=440 GMT Ratio (95% CI)f GMT GMT A (H1N1) 231 270 0.85 (0.67; 1.09) A (H3N2) 501 324 1.55 (1.25; 1.92) Fluzone Quadrivalentc Nd=220 TIV-19 (B Victoria) Nd=219 TIV-2h (B Yamagata) Nd=221 GMT Ratio (95% CI)f GMT GMT GMT B/Brisbane/60/2008 (B Victoria) 73.8 57.9 (42.2)i 1.27 (1.05; 1.55) B/Florida/04/2006 (B Yamagata) 61.1 (28.5)j 54.8 1.11 (0.90; 1.37) aNCT01218646 bPer-protocol analysis set included all persons who had no study protocol deviations cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) dN is the number of participants in the per-protocol analysis set ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was > 0.66 g2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed hInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed iTIV-2 did not contain B/Brisbane/60/2008 jTIV-1 did not contain B/Florida/04/2006 Table 13: Study 3a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by Seroconversion Rates at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-protocol Analysis Set)b Antigen Strain Fluzone Quadrivalentc Nd=220 Pooled TIVe Nd=440 Difference of Seroconversion Rate (95% CI)f Seroconversiong(%) A (H1N1) 65.91 69.77 -3.86 (-11.50; 3.56) A (H3N2) 69.09 59.32 9.77 (1.96; 17.20) Fluzone Quadrivalentc Nd=220 TIV-1h (B Victoria) Nd=219 TIV-2i(B Yamagata) Nd=221 Difference of Seroconversion Rate (95% CI)f SeroconversionS(%) B/Brisbane/60/2008 (B Victoria) 28.64 18.72 (8.60)j 9.91 (1.96; 17.70) B/Florida/04/2006 (B Yamagata) 33.18 (9.13)k 31.22 1.96 (-6.73; 10.60) aNCT01218646 bPer-protocol analysis set included all persons who had no study protocol deviations cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) dN is the number of participants in the per-protocol analysis set ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was > -10% gSeroconversion: Paired samples with pre-vaccination HI titer < 1:10 and post-vaccination titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10 h2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed iInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/ Florida/04/2006 (Yamagata lineage), non-licensed jTIV-2 did not contain B/Brisbane/60/2008 kTIV-1 did not contain B/Florida/04/2006 REFERENCES 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, 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. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have cocirculated worldwide. Protection from influenza virus infection has not been correlated with a specific level of hemagglutination inhibition (HAI) antibody titer post-vaccination. However, in some human studies, antibody titers ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects (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 Intradermal Quadrivalent In Adults 18 Through 64 Years Of Age In Study 1 (NCT01712984), study participants were randomized to receive one dose of Fluzone Intradermal Quadrivalent, TIV-ID1, or TIV-ID2. Of the 2249 participants randomized to provide blood samples for immunogenicity analyses, 2113 adults 18 through 64 years of age were included in the per-protocol analysis set. The distribution of demographics was similar to that of the safety analysis set [see Clinical Trials Experience]. HAI antibody geometric mean titers (GMTs) and seroconversion rates 28 days following vaccination with Fluzone Intradermal Quadrivalent were non-inferior to those following each TIV-ID for all four strains, based on pre-specified criteria (see Table 4 and Table 5). Table 4: Study 1a: Non-inferiority of Fluzone Intradermal Quadrivalent Relative to TIV-ID for Each Strain by HAI Antibody GMTs at 28 Days Post-Vaccination, Adults 18 Through 64 Years of Age (Per-protocol Analysis Set)b Antigen Strain Fluzone Intradermal Quadrivalent Pooled TIV-IDc GMT Ratio (95% CI)d Me GMT Me GMT A (H1N1) 1041 589 1072 680 0.87 (0.78; 0.97) A (H3N2) 1041 368 1071 430 0.86 (0.77; 0.96) Fluzone Intradermal Quadrivalent TIV-ID1f(B Yamagata) TIV-ID2g(B Victoria) GMT Ratio (95% CI)d Me GMT Me GMT Me GMT B/Texas/6/2011 (B Yamagata) 1041 105 539 93.5 533 O (5 1.13 (1.02; 1.25) B/Brisbane/60/2008 (B Victoria) 1041 136 538 (66.7)i 533 130 1.05 (0.94; 1.16) aNCT01712984 b Per-protocol analysis set included all persons who underwent serologic testing and had no study protocol deviations cPooled TIV-ID group includes participants vaccinated with either TIV-ID1 or TIV-ID2 d Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Intradermal Quadrivalent divided by pooled TIV-ID for the A strains, or the TIV-ID containing the corresponding B strain) was > 2/3 e M is the number of participants in the per-protocol analysis set with available data for the considered endpoint f TIV-ID1: 2012-2013 Fluzone Intradermal TIV containing A/California/7/2009 (H1N1), A/ Victoria/361/2011 (H3N2), and B/Texas/6/2011 (Yamagata lineage), licensed g TIV-ID2: Investigational Intradermal TIV containing A/California/7/2009 (H1N1), A/ Victoria/361/2011 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), non-licensed hTIV-ID2 did not contain B/Texas/6/2011 iTIV-ID1 did not contain B/Brisbane/60/2008 Table 5: Study 1a: Non-inferiority of Fluzone Intradermal Quadrivalent Relative to TIV-ID for Each Strain by Seroconversion Rates at 28 Days Post-Vaccination, Adults 18 Through 64 Years of Age (Per-protocol Analysis Set)b Antigen Strain Fluzone Intradermal Quadrivalent Pooled TIV-IDc Difference of Seroconversion Rates (95% CI)f Md Sero- conversione (%) Md Sero-conversione (%) A (H1N1) 1041 57.6 1072 60.4 -2.72 (-6.90; 1.47) A (H3N2) 1040 58.5 1071 59.8 -1.30 (-5.48; 2.89) Fluzone Intradermal Quadrivalent TIV-ID1g (B Yamagata) TIV-ID2h (B Victoria) Difference of Seroconversion Rates (95% CI)f Md Sero- conversione(%) Md Sero- conversione (%) Md Sero- conversione (%) B/Texas/6/2011 (B Yamagata) 1041 55.7 539 46.9 533 (24.6)i 8.78 (3.58; 13.9) B/Brisbane/60/2008 (B Victoria) 1041 50.4 538 (22.1)j 533 44.1 6.34 (1.13; 11.5) aNCT01712984 b Per-protocol analysis set included all persons who underwent serologic testing and had no study protocol deviations cPooled TIV group includes participants vaccinated with either TIV-ID1 or TIV-ID2 d M is the number of participants in the per-protocol analysis set with available data for the considered endpoint e Seroconversion: Paired samples with pre-vaccination HAI titer < 1:10 and post-vaccination titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10 f Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (Fluzone Intradermal Quadrivalent minus pooled TIV-ID for the A strains, or the TIV-ID containing the corresponding B strain) was > -10% g TIV-ID1: 2012-2013 Fluzone Intradermal TIV containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Texas/6/2011 (Yamagata lineage), licensed h TIV-ID2: Investigational Intradermal TIV containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), non-licensed iTIV-ID2 did not contain B/Texas/6/2011 jTIV-ID1 did not contain B/Brisbane/60/2008 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 and analysis of influenza virus isolates permits identification of yearly antigenic variants. 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 induced by vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some studies, HI antibody titers of ≥ 1:40 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 little 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 strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains representing the influenza viruses likely to circulate in the United States in the upcoming winter. Annual influenza vaccination is recommended by the Advisory Committee on Immunization Practices because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.4 Clinical Studies Efficacy Against Culture-Confirmed Influenza The efficacy experience with FLUCELVAX is relevant to FLUCELVAX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions. A multinational (US, Finland, and Poland), randomized, observer-blind, placebo-controlled trial was performed to assess clinical efficacy and safety of FLUCELVAX during the 2007-2008 influenza season in adults aged 18 through 49 years. A total of 11,404 subjects were enrolled to receive FLUCELVAX (N=3828), AGRIFLU (N=3676) or placebo (N=3900) in a 1:1:1 ratio. Among the overall study population enrolled, the mean age was 33 years, 55% were female, 84% were Caucasian, 7% were Black, 7% were Hispanic, and 2% were of other ethnic origin. FLUCELVAX efficacy was assessed by the prevention of culture-confirmed symptomatic influenza illness caused by viruses antigenically matched to those in the vaccine and prevention of influenza illness caused by all influenza viruses compared to placebo. Influenza cases were identified by active and passive surveillance of influenza-like illness (ILI). ILI was defined as a fever (oral temperature ≥ 100.0°F / 38°C) and cough or sore throat. Nose and throat swab samples were collected for analysis within 120 hours of onset of an influenza-like illness in the period from 21 days to 6 months after vaccination. Overall vaccine efficacy against all influenza viral subtypes and vaccine efficacy against individual influenza viral subtypes were calculated (Tables 5 and 6, respectively). Table 5: Vaccine Efficacy against Culture-Confirmed Influenza Number of subjects per protocol Number of subjects with influenza Attack Rate (%) Vaccine Efficacy (VE)1,2 % Lower Limit of OneSided 97.5% CI of VE2,3 Antigenically Matched Strains FLUCELVAX 3776 7 0.19 83.8 61.0 Placebo 3843 44 1.14 -- -- All Culture-Confirmed Influenza FLUCELVAX 3776 42 1.11 69.5 55.0 Placebo 3843 140 3.64 -- -- 1Efficacy against influenza was evaluated over a 9 month period in 2007/2008 2Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100% 3VE success criterion: the lower limit of the one-sided 97.5% CI for the estimate of the VE relative to placebo is > 40% Study: NCT00630331 Table 6: Efficacy of FLUCELVAX against Culture-Confirmed Influenza by Influenza Viral Subtype FLUCELVAX (N=3776) Placebo (N=3843) Vaccine Efficacy (VE)2 Attack Rate (%) Number of Subjects with Influenza Attack Rate (%) Number of Subjects with Influenza % Lower Limit of One-Sided 97.5% CI of VE1,2 Antigenically Matched Strains A/H3N23 0.05 2 0 0 -- -- A/H1N1 0.13 5 1.12 43 88.2 67.4 B3 0 0 0.03 1 -- -- All Culture-Confirmed Influenza A/H3N2 0.16 6 0.65 25 75.6 35.1 A/H1N1 0.16 6 1.48 57 89.3 73.0 B 0.79 30 1.59 61 49.9 18.2 1No VE success criterion was prespecified in the protocol for each individual influenza virus subtype. 2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100%; 3 There were too few cases of influenza due to vaccine-matched influenza A/H3N2 or B to adequately assess vaccine efficacy. Study: NCT00630331 There are no data demonstrating prevention of influenza disease after vaccination with FLUCELVAX in the pediatric age group. Immunogenicity Of FLUCELVAX QUADRIVALENT In Adults 18 Years Of Age And Above Immunogenicity of FLUCELVAX QUADRIVALENT was evaluated in adults 18 years of age and older in a randomized, double-blind, controlled study conducted in the US (Study 1). In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (FLUCELVAX QUADRIVALENT (N=1334), TIV1c, N=677 or TIV2c N= 669). In the per protocol set, the mean age of subjects who received FLUCELVAX QUADRIVALENT was 57.5 years; 55.1% of subjects were female and 76.1% of subjects were Caucasian, 13% were black and 9% were Hispanics. The immune response to each of the vaccine antigens was assessed, 21 days after vaccination. The immunogenicity endpoints were geometric mean antibody titers (GMTs) of hemagglutination inhibition (HI) antibodies response and percentage of subjects who achieved seroconversions, defined as a pre-vaccination HI titer of < 1:10 with a post-vaccination titer ≥ 1:40 or a pre-vaccination HI titer > 1:10 and at least 4-fold increase in serum HI antibody titer. FLUCELVAX QUADRIVALENT was noninferior to TIVc. Noninferiority was established for all 4 influenza strains included in the QIVc, as assessed by ratios of GMTs and the differences in the percentages of subjects achieving seroconversion at 3 weeks following vaccination. The antibody response to influenza B strains contained in FLUCELVAX QUADRIVALENT was superior to the antibody response after vaccination with TIVc containing an influenza B strain from the alternate lineage. There was no evidence that the addition of the second influenza B strain resulted in immune interference to other strains included in the vaccine. (See Table 7) Table 7: Noninferiority of FLUCELVAX QUADRIVALENT relative to TIVc in adults 18 Years of Age and Above - Per Protocol Analysis Set [Study 1] FLUCELVAX QUADRIVALENT N = 1250 TIV1c/TIV2c1 N = 635/N = 639 Vaccine Group Ratio (95% CI) Vaccine Group Difference (95% CI) A/H1N1 GMT (95% CI) 302.8 (281.8-325.5) 298.9 (270.3-330.5) 1.0 (0.9-1.1) - Seroconversion Rate2 (95% CI) 49.2% (46.4-52.0) 48.7% (44.7-52.6) - -0.5% (-5.3-4.2) A/H3N2 GMT (95% CI) 372.3 (349.2-396.9) 378.4 (345.1-414.8) 1.0 (0.9-1.1) - Seroconversion Rate2 (95% CI) 38.3% (35.6-41.1) 35.6% (31.9-39.5) - -2.7% (-7.2-1.9) B1 GMT (95% CI) 133.2 (125.3-141.7) 115.6 (106.4-125.6) 0.9 (0.8-1.0) - Seroconversion Rate2 (95% CI) 36.6% (33.9-39.3) 34.8% (31.1-38.7) - -1.8% (-6.2-2.8) B2 GMT (95% CI) 177.2 (167.6-187.5) 164.0 (151.4-177.7) 0.9 (0.9-1.0) - Seroconversion Rate2 (95% CI) 39.8% (37.0-42.5) 35.4% (31.7-39.2) - -4.4% (-8.9-0.2) Abbreviations: HI = hemagglutination inhibition. PPS = per protocol set. GMT = geometric mean titer. CI = confidence interval. 1Per protocol set: All subjects in Full Analysis Set, immunogenicity population, who has correctly received the assigned vaccine, have no major protocol deviations leading to exclusion as defined prior to unblinding/analysis and are not excluded due to other reasons defined prior to unblinding or analysis. 2The comparator vaccine for noninferiority comparisons for A/H1N1, A/H3N2 and B1 is TIV1c, for B2 it is TIV2c. 3Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10 and postvaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold increase in post-vaccination HI antibody titer. Study 1: NCT01992094 Immunogenicity In Children And Adolescents 4 Through 17 Years Of Age Immunogenicity of FLUCELVAX QUADRIVALENT was evaluated in children 4 through 17 years of age in a randomized, double-blind, controlled study conducted in the US (Study 2). (See ADVERSE REACTIONS) In this study, 1159 subjects received FLUCELVAX QUADRIVALENT. In the per protocol set, the mean age of subjects who received FLUCELVAX QUADRIVALENT was 9.8 years; 47% of subjects were female and 54% of subjects were Caucasian, 22% were black and 19% were Hispanics. The immune response to each of the vaccine antigens was assessed, 21 days after vaccination. The immunogenicity endpoints were the percentage of subjects who achieved seroconversion, defined as a pre-vaccination hemagglutination inhibition (HI) titer of < 1:10 with a post-vaccination HI titer ≥ 1:40 or at least a 4-fold increase in serum HI titer; and percentage of subjects with a post-vaccination HI titer ≥ 1:40. In subjects receiving FLUCELVAX QUADRIVALENT, for all four influenza strains, the 95% LBCI seroconversion rates were ≥ 40% and the percentage of subjects who achieved HI titer ≥ 1:40 post vaccination were ≥ 70% (95% LBCI). (See Table 8) Table 8: The Percentage of Children and Adolescents 4 through 17 years of Age with Seroconversion2 and HI Titers ≥ 1:40 post vaccination with FLUCELVAX QUADRIVALENT - Per-Protocol Analysis Set3 [Study 2] FLUCELVAX QUADRIVALENT A/H1N1 N = 1014 Seroconversion Rate3 (95% CI) 72% (69-75) HI titer ≥ 1:40 99% (98-100) A/H3N2 N = 1013 Seroconversion Rate3 (95% CI) 47% (44-50) HI titer ≥ 1:40 100% (99-100) B1 N = 1013 Seroconversion Rate3 (95% CI) 66% (63-69) HI titer ≥ 1:40 92% (91-94) B2 N = 1009 Seroconversion Rate3 (95% CI) 73% (70-76) HI titer ≥ 1:40 91% (89-93) Abbreviations: HI = hemagglutinin inhibition. CI = confidence interval. 1Analyses are performed on data for day 22 for previously vaccinated subjects and day 50 for not previously vaccinated subjects. 2Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10 and postvaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold increase in post-vaccination HI titer. Immunogenicity success criteria were met if the lower limit of the 95% confidence interval (CI) of the percentage of subjects with HI titer ≥ 1:40 is ≥ 70%; and the lower limit of the 95% CI of the percentage of subjects with seroconversion is ≥ 40%. 3Per protocol set: All subjects in Full Analysis Set, immunogenicity population, who has correctly received the assigned vaccine, have no major protocol deviations leading to exclusion as defined prior to unblinding/analysis and are not excluded due to other reasons defined prior to unblinding or analysis. Study 2: NCT 01992107 REFERENCES 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 A, et al. The role of serum hemagglutinininhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777. 4. 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.

Fluzone Quadrivalent (Influenza Vaccine) for Intramuscular Injection DESCRIPTION Fluzone Quadrivalent (Influenza Vaccine) for intramuscular injection is an inactivated influenza vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The viruscontaining 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 phosphate-buffered isotonic sodium chloride solution. The Fluzone Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. Antigens from the four strains included in the vaccine are produced separately and then combined to make the quadrivalent formulation. Fluzone Quadrivalent suspension for injection is clear and slightly opalescent in color. Antibiotics are not used in the manufacture of Fluzone Quadrivalent. The Fluzone Quadrivalent prefilled syringe and vial presentations are not made with natural rubber latex. Fluzone Quadrivalent is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following four influenza strains recommended for the 2016-2017 influenza season: A/California/07/2009 X-179A (H1N1), A/Hong Kong/4801/2014 X-263B (H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and B/Brisbane/60/2008 (B Victoria lineage). The amounts of HA and other ingredients per dose of vaccine are listed in Table 6. The single-dose, pre-filled syringe (0.25 mL and 0.5 mL) and the single-dose vial (0.5 mL) are manufactured and formulated without thimerosal or any other preservative. The 5 mL multi-dose vial presentation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury. Each 0.25 mL dose from the multi-dose vial contains 12.5 mcg mercury. Table 6: Fluzone Quadrivalent Ingredients Ingredient Quantity (per dose) Fluzone Quadrivalent 0.25 mL Dose Fluzone Quadrivalent 0.5 mL Dose Active Substance: Split influenza virus, inactivated strainsa: 30 mcg HA total 60 mcg HA total A (H1N1) 7.5 mcg HA 15 mcg HA A (H3N2) 7.5 mcg HA 15 mcg HA B/(Victoria lineage) 7.5 mcg HA 15 mcg HA B/(Yamagata lineage) 7.5 mcg HA 15 mcg HA Other: Sodium phosphate-buffered isotonic QSb to appropriate QSb to appropriate sodium chloride solution volume volume Formaldehyde ≤ 50 mcg ≤ 100 mcg Octylphenol ethoxylate ≤ 125 mcg ≤ 250 mcg Preservative Single-dose presentations - - Multi-dose presentation (thimerosal) 12.5 mcg mercury 25 mcg mercury aper United States Public Health Service (USPHS) requirement bQuantity Sufficient “-” Indicates information is not applicable

Fluzone Intradermal Quadrivalent (Influenza Vaccine) for Intradermal Injection DESCRIPTION Fluzone Intradermal Quadrivalent (Influenza Vaccine) for intradermal 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 phosphate-buffered isotonic sodium chloride solution. The Fluzone Intradermal Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. Antigens from the four strains included in the vaccine are produced separately and then combined to make the quadrivalent formulation. Fluzone Intradermal Quadrivalent suspension for injection is clear and slightly opalescent in color. Neither antibiotics nor preservative are used in the manufacture of Fluzone Intradermal Quadrivalent. The Fluzone Intradermal Quadrivalent microinjection system is not made with natural rubber latex. Fluzone Intradermal Quadrivalent is standardized according to United States Public Health Service requirements and is formulated to contain the following four influenza strains recommended for the 2016-2017 influenza season: A/California/07/2009 X-179A (H1N1), A/ Hong Kong/4801/2014 X-263B(H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and B/ Brisbane/60/2008 (B Victoria lineage). The amounts of HA and other ingredients per dose of vaccine are listed in Table 3. Table 3: Fluzone Intradermal Quadrivalent Ingredients aper United States Public Health Service (USPHS) requirement Ingredient Quantity per 0.1 mL Dose Active Substance: Split influenza virus, inactivated strainsa: 36 mcq HA total A (H1N1) 9 mcq HA A (H3N2) 9 mcq HA B/(Victoria lineaqe) 9 mcq HA B/(Yamaqata lineaqe) 9 mcq HA Other: Sodium phosphate-buffered isotonic sodium chloride solution QSb to appropriate volume Formaldehyde ≤ 20 mcq Octylphenol ethoxylate ≤ 55 mcq aper United States Public Health Service (USPHS) requirement bQuantity Sufficient

FLUCELVAX QUADRIVALENT (Influenza Vaccine) for Intramuscular Injection DESCRIPTION FLUCELVAX QUADRIVALENT (Influenza Vaccine), a vaccine for intramuscular injection, is a subunit influenza vaccine prepared from virus propagated in Madin Darby Canine Kidney (MDCK) cells, a continuous cell line. These cells were adapted to grow freely in suspension in culture medium. The virus is inactivated with ß-propiolactone, disrupted by the detergent cetyltrimethylammonium bromide and purified through several process steps. Each of the 4 virus strains is produced and purified separately then pooled to formulate the quadrivalent vaccine. FLUCELVAX QUADRIVALENT is a sterile, slightly opalescent suspension in phosphate buffered saline. FLUCELVAX QUADRIVALENT is standardized according to United States Public Health Service requirements for the 2016-2017 influenza season and is formulated to contain a total of 60 micrograms (mcg) hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following four influenza strains: A/Brisbane/10/2010 (H1N1) (an A/California/7/2009-like virus); A/Hong Kong/4801/2014 (H3N2); B/Utah/9/14 (a B/Phuket/3073/2013-like virus); B/Hong Kong/259/2010 (a B/Brisbane/60/08-like virus). Each dose of FLUCELVAX QUADRIVALENT may contain residual amounts of MDCK cell protein ( ≤ 8.4 mcg), protein other than HA ( ≤ 160 mcg), MDCK cell DNA ( ≤ 10 ng), polysorbate 80 ( ≤ 1500 mcg), cetyltrimethlyammonium bromide ( ≤ 18 mcg), and β-propiolactone ( < 0.5 mcg), which are used in the manufacturing process. FLUCELVAX QUADRIVALENT contains no preservative or antibiotics. The tip caps and plungers of the prefilled syringes are not made with natural rubber latex.

INDICATIONS Fluzone® 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. Fluzone Quadrivalent is approved for use in persons 6 months of age and older. DOSAGE AND ADMINISTRATION For intramuscular use only Dose And Schedule The dose and schedule for Fluzone Quadrivalent are presented in Table 1. Table 1: Dose and Schedule for Fluzone Quadrivalent Age Dose Schedule 6 months through 35 months One or two dosesa , 0.25 mL each If 2 doses, administer at least 4 weeks apart 36 months through 8 years One or two dosesa , 0.5 mL each If 2 doses, administer at least 4 weeks apart 9 years and older One dose, 0.5 mL - a1 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 Administration Parenteral drug products should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit. If any of these defects or conditions exist, Fluzone Quadrivalent should not be administered. Before administering a dose of vaccine, shake the prefilled syringe or vial. Withdraw one dose of vaccine from the single-dose vial using a sterile needle and syringe. Use a separate sterile needle and syringe for each dose withdrawn from the multi-dose vial. The preferred sites for intramuscular injection are the anterolateral aspect of the thigh in infants 6 months through 11 months of age, the anterolateral aspect of the thigh (or the deltoid muscle if muscle mass is adequate) in persons 12 months through 35 months of age, or the deltoid muscle in persons ≥ 36 months of age. 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, intradermally, or subcutaneously. Fluzone Quadrivalent should not be combined through reconstitution or mixed with any other vaccine. HOW SUPPLIED Dosage Forms And Strengths Fluzone Quadrivalent is a suspension for injection. Fluzone Quadrivalent is supplied in 4 presentations: Prefilled single-dose syringe (pink syringe plunger rod), 0.25 mL, for persons 6 months through 35 months of age. Prefilled single-dose syringe (clear syringe plunger rod), 0.5 mL, for persons 36 months of age and older. Single-dose vial, 0.5 mL, for persons 36 months of age and older. Multi-dose vial, 5 mL, for persons 6 months of age and older. Single-dose, prefilled syringe (pink plunger rod), without needle, 0.25 mL (NDC 49281-516-00) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281- 516-25). Single-dose, prefilled syringe (clear plunger rod), without needle, 0.5 mL (NDC 49281-416-88 ) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-416-50 Single-dose vial, 0.5 mL (NDC 49281-416-58) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-416-10). Multi-dose vial, 5 mL (NDC 49281-625-78) (not made with natural rubber latex). Supplied as package of 1 (NDC 49281- 625-15). A maximum of ten doses can be withdrawn from the multidose vial. Storage And Handling Store all Fluzone Quadrivalent presentations 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: Jun 2016

INDICATIONS Fluzone® Intradermal Quadrivalent is indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. Fluzone Intradermal Quadrivalent is approved for use in persons 18 through 64 years of age. DOSAGE AND ADMINISTRATION For intradermal use only Dose And Schedule Fluzone Intradermal Quadrivalent should be administered as a single 0.1 mL injection by the intradermal route in adults 18 through 64 years of age. Administration Inspect Fluzone Intradermal Quadrivalent visually for particulate matter and/or discoloration prior to administration. If either of these conditions exist, the vaccine should not be administered. The preferred site of injection is the skin in the region of the deltoid. Note: A potential way to make vaccination more efficient is to have the patient place the hand of the arm being immunized on his/her hip, so the arm bends at the elbow. This can help create a more accessible angle to the skin in the deltoid region. Fluzone Intradermal Quadrivalent should not be combined through reconstitution or mixed with any other vaccine. 1. Gently shake the device and remove needle cap To prepare for vaccination, gently shake the device and remove needle cap before administering the vaccine. 2. Position the device in your hand between the thumb and middle finger, keeping the index finger free Hold the device by placing the thumb and middle finger on the finger pads above device window. Keep the index finger free. 3. Gently pierce the skin over the deltoid region Using light pressure, gently pierce the skin perpendicular to the deltoid region. 4. Press the plunger to inject the vaccine Using index finger, gently press the plunger to inject the vaccine. Do not aspirate. When the plunger stops, vaccination is complete. Note: Excessive pressure on the plunger may prematurely activate the needle shield on the patient's arm. Because the vaccine is injected into the skin, a wheal (superficial bump) and/or redness may be visible at the injection site. 5. Activate the needle shield and dispose Remove the needle from the skin. Direct the needle away from you and others. Push very firmly with the thumb on the plunger to activate the needle shield. You will hear a click when the shield extends to cover the needle. Dispose the device in an appropriate container. HOW SUPPLIED Dosage Forms And Strengths Fluzone Intradermal Quadrivalent is a suspension for injection. Fluzone Intradermal Quadrivalent is supplied in a single-dose prefilled microinjection system, 0.1 mL, for adults 18 through 64 years of age. Single-dose prefilled microinjection system, 0.1 mL (NDC 49281-710-48) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-710-40). Storage And Handling Store Fluzone Intradermal Quadrivalent 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: Jun 2016

INDICATIONS FLUCELVAX QUADRIVALENT is an inactivated vaccine indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLUCELVAX QUADRIVALENT is approved for use in persons 4 years of age and older. For children and adolescents 4 through 17 years of age, approval is based on the immune response elicited by FLUCELVAX QUADRIVALENT. Data demonstrating a decrease in influenza disease after vaccination of this age group with FLUCELVAX QUADRIVALENT are not available. [see Clinical Studies] DOSAGE AND ADMINISTRATION For intramuscular injection only. Dosage And Schedule Administer FLUCELVAX QUADRIVALENT as a single 0.5 mL intramuscular injection preferably in the region of the deltoid muscle of the upper arm. Do not inject the vaccine in the gluteal region or areas where there may be a major nerve trunk. Table 1: Dosage and Schedule Age Dose Schedule 4 through 8 years of age One or two doses,1 0.5 mL each If 2 doses, administer at least 4 weeks apart 9 years of age and older One dose, 0.5 mL Not Applicable 1 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. Administration Shake the syringe vigorously before administering. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. [see DESCRIPTION] If either condition exists, do not administer the vaccine. Do not use the vaccine if the contents have been frozen. Attach a sterile needle to the pre-filled syringe and administer intramuscularly only. Do not administer this product intravenously, intradermally or subcutaneously. HOW SUPPLIED Dosage Forms And Strengths FLUCELVAX QUADRIVALENT is a suspension for injection supplied in a 0.5 mL single-dose pre-filled Luer Lock syringe. Storage And Handling FLUCELVAX QUADRIVALENT is supplied in a carton containing ten 0.5 mL single-dose syringes without needles: Carton NDC number: 70461-200-01 Pre-filled syringe NDC number: 70461-200-11 Store this product refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light. Do not use after the expiration date. Manufactured by: Seqirus, Inc. 475 Green Oaks Parkway, Holly Springs, North Carolina (NC) 27540, United States (USA) 1-919-577-5000. Revised: May 2016.

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

PATIENT INFORMATION Inform vaccine recipients of the potential benefits and risks of immunization with FLUCELVAX QUADRIVALENT. Educate vaccine recipients regarding the potential side effects; clinicians should emphasize that (1) FLUCELVAX QUADRIVALENT contains non-infectious particles and cannot cause influenza and (2) FLUCELVAX QUADRIVALENT is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against other respiratory illnesses. Instruct vaccine recipients to report adverse reactions to their healthcare provider. Provide vaccine recipients with the Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines). Inform vaccine recipients that annual vaccination is recommended.

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer Fluzone Quadrivalent to anyone with a history of 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.

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer Fluzone Intradermal Quadrivalent to anyone with a history of 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.

OVERDOSE No information provided. CONTRAINDICATIONS Do not administer FLUCELVAX QUADRIVALENT to anyone with a history of severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see DESCRIPTION].

SIDE EFFECTS In children 6 months through 35 months of age, the most common ( ≥ 10%) injection-site reactions were pain (57%)a or tenderness (54%)b, erythema (37%), and swelling (22%); the most common solicited systemic adverse reactions were irritability (54%)b, abnormal crying (41%)b, malaise (38%)a, drowsiness (38%)b, appetite loss (32%)b, myalgia (27%)a, vomiting (15%)b, and fever (14%). In children 3 years through 8 years of age, the most common ( ≥ 10%) injection-site reactions were pain (67%), erythema (34%), and swelling (25%); the most common solicited systemic adverse reactions were myalgia (39%), malaise (32%), and headache (23%). In adults 18 years and older, the most common ( ≥ 10%) injection-site reaction was pain (47%); the most common solicited systemic adverse reactions were myalgia (24%),  headache (16%), and malaise (11%). In adults 65 years of age and older, the most common ( ≥ 10%) injection-site reaction was pain (33%); the most common solicited systemic adverse reactions were myalgia (18%), headache (13%), and malaise (11%). 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. Children 6 Months Through 8 Years of Age Study 1 (NCT01240746, see http://clinicaltrials.gov) was a single-blind, randomized, activecontrolled multi-center safety and immunogenicity study conducted in the US. In this study, children 6 months through 35 months of age received one or two 0.25 mL doses of either Fluzone Quadrivalent or one of two formulations of a comparator trivalent influenza vaccine (TIV-1 or TIV-2), and children 3 years through 8 years of age received one or two 0.5 mL doses of either Fluzone Quadrivalent, TIV-1, or TIV-2. Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). For participants who received two doses, the doses were administered approximately 4 weeks apart. The safety analysis set included 1841 children 6 months through 35 months of age and 2506 children 3 years through 8 years of age. Among participants 6 months through 8 years of age in the three vaccine groups combined, 49.3% were female (Fluzone Quadrivalent, 49.2%; TIV-1, 49.8%; TIV-2, 49.4%), 58.4% Caucasian (Fluzone Quadrivalent, 58.4%; TIV-1, 58.9%; TIV-2, 57.8%), 20.2% Black (Fluzone Quadrivalent, 20.5%; TIV-1, 19.9%; TIV-2, 19.1%), 14.1% Hispanic (Fluzone Quadrivalent, 14.3%; TIV-1, 13.2%; TIV-2, 14.7%), and 7.3% were of other racial/ethnic groups (Fluzone Quadrivalent, 6.8%; TIV-1, 8.0%; TIV-2, 8.5%). Table 2 and Table 3 summarize solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events for 28 days after each dose and serious adverse events (SAEs) during the 6 months following the last dose. Table 2: Study 1a: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Children 6 Months Through 35 Months of Age (Safety Analysis Set)b Fluzone Quadrivalentc (Nf=1223) TIV-1d (B Victoria) (Nf=310) TIV-2e (B Yamagata) (Nf=308) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Injection-site adverse reactions Paini 57.0 10.2 1.0 52.3 11.5 0.8 50.3 5.4 2.7 Tendernessj 54.1 11.3 1.9 48.4 8.2 1.9 49.7 10.3 0.0 Erythema 37.3 1.5 0.2 32.9 1.0 0.0 33.3 1.0 0.0 Swelling 21.6 0.8 0.2 19.7 1.0 0.0 17.3 0.0 0.0 Systemic adverse reactions Fever ( ≥ 100.4°F)k 14.3 5.5 2.1 16.0 6.6 1.7 13.0 4.1 2.0 Malaisei 38.1 14.5 4.6 35.2 14.8 4.7 32.4 12.8 6.8 Myalgiai 26.7 6.6 1.9 26.6 9.4 1.6 25.0 6.8 2.7 Headachei 8.9 2.5 0.6 9.4 3.9 0.0 12.2 4.7 0.0 Irritabilitvi 54.0 26.4 3.2 52.8 20.1 3.1 53.5 22.9 2.8 Crying abnormalj 41.2 12.3 3.3 36.5 8.2 1.9 29.9 10.4 2.1 Drowsinessj 37.7 8.4 1.3 32.1 3.8 0.6 31.9 5.6 0.7 Appetite lossj 32.3 9.1 1.8 33.3 5.7 1.9 25.0 8.3 0.7 Vomitingj 14.8 6.2 1.0 11.3 4.4 0.6 13.9 6.3 0.0 aNCT01240746 bThe safety analysis set includes all persons who received at least one dose of study vaccine cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed fN is the number of participants in the safety analysis set gGrade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site tenderness: cries and protests when injection-site is touched; Injectionsite erythema, Injection-site swelling: ≥ 2.5 cm to < 5 cm; Fever: > 101.3°F to ≤ 103.1°F (6 months through 23 months); ≥ 101.2°F to ≤ 102.0°F (24 months through 35 months); Malaise, Myalgia, and Headache: some interference with activity; Irritability: requiring increased attention; Crying abnormal: 1 to 3 hours; Drowsiness: not interested in surroundings or did not wake up for a feed/meal; Appetite loss: missed 1 or 2 feeds/meals completely; Vomiting: 2 to 5 episodes per 24 hours hGrade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site tenderness: cries when injected limb is moved, or the movement of the injected limb is reduced; Injection-site erythema, Injection-site swelling: ≥ 5 cm; Fever: > 103.1°F (6 months through 23 months); ≥ 102.1°F (24 months through 35 months); Malaise, Myalgia, and Headache: Significant; prevents daily activity; Irritability: inconsolable; Crying abnormal: > 3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite loss: refuses ≥ 3 feeds/ meals or refuses most feeds/meals; Vomiting: ≥ 6 episodes per 24 hours or requiring parenteral hydration iAssessed in children 24 months through 35 months of age jAssessed in children 6 months through 23 months of age kFever measured by any route Table 3: Study 1a: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Children 3 Years Through 8 Years of Age (Safety Analysis Set)b Fluzone Quadrivalentc (Nf=1669) TIV-1d (B Victoria) (Nf=424) TIV-2e (B Yamagata) (Nf=413) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Injection-site adverse reactions Pain 66.6 15.8 2.1 64.6 9.5 2.0 63.8 11.6 2.8 Erythema 34.1 2.9 1.8 36.8 3.4 1.2 35.2 2.5 1.8 Swelling 24.8 2.8 1.4 25.4 1.5 1.2 25.9 2.5 1.8 Systemic adverse reactions Fever ( ≥ 100.4°F)i 7.0 2.1 2.1 7.1 2.2 1.2 7.6 2.8 0.8 Headache 23.1 6.8 2.2 21.2 5.1 2.7 24.4 7.5 2.0 Malaise 31.9 11.2 5.5 32.8 11.4 5.6 33.4 10.8 5.0 Myalgia 38.6 12.2 3.3 34.1 9.0 2.7 38.4 11.1 2.8 aNCT01240746 bThe safety analysis set includes all persons who received at least one dose of study vaccine cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/ Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed fN is the number of participants in the safety analysis set gGrade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site erythema, Injection-site swelling: ≥ 2.5 cm to < 5 cm; Fever: ≥ 101.2°F to ≤ 102.0°F; Headache, Malaise, and Myalgia: some interference with activity hGrade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema, Injection-site swelling: ≥ 5 cm; Fever: ≥ 102.1°F; Headache, Malaise, and Myalgia: Significant; prevents daily activity iFever measured by any route Among children 6 months through 8 years of age, unsolicited non-serious adverse events were reported in 1360 (47.0%) recipients in the Fluzone Quadrivalent group, 352 (48.0%) recipients in the TIV-1 group, and 346 (48.0%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were cough, vomiting, and pyrexia. During the 28 days following vaccination, a total of 16 (0.6%) recipients in the Fluzone Quadrivalent group, 4 (0.5%) recipients in the TIV-1 group, and 4 (0.6%) recipients in the TIV-2 group, experienced at least one SAE; no deaths occurred. Throughout the study period, a total of 41 (1.4%) recipients in the Fluzone Quadrivalent group, 7 (1.0%) recipients in the TIV-1 group, and 14 (1.9%) recipients in the TIV-2 group, experienced at least one SAE. Three SAEs were considered to be possibly related to vaccination: croup in a Fluzone Quadrivalent recipient and 2 episodes of febrile seizure, 1 each in a TIV-1 recipient and a TIV-2 recipient. One death occurred in the TIV-1 group (a drowning 43 days post-vaccination). Adults In study 2 (NCT00988143, see http://clinicaltrials.gov), a multi-centered randomized, open-label trial conducted in the US, adults 18 years of age and older received one dose of either Fluzone Quadrivalent or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or TIV-2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The safety analysis set included 570 recipients, half aged 18-60 years and half aged 61 years or older. Among participants in the three vaccine groups combined, 67.2% were female (Fluzone Quadrivalent, 68.4%; TIV-1, 67.9%; TIV-2, 65.3%), 88.4% Caucasian (Fluzone Quadrivalent, 91.1%; TIV-1, 86.8%; TIV-2, 87.4%), 9.6% Black (Fluzone Quadrivalent, 6.8%; TIV-1, 12.1%; TIV-2, 10.0%), 0.4% Hispanic (Fluzone Quadrivalent, 0.0%; TIV-1, 0.5%; TIV-2, 0.5%), and 1.7% were of other racial/ethnic groups (Fluzone Quadrivalent, 2.1%; TIV-1, 0.5%; TIV-2, 2.2%). Table 4 summarizes solicited injection-site and systemic adverse reactions reported within 3 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events and SAEs during the 21 days following vaccination. Table 4: Study 2a: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 3 Days After Vaccination in Adults 18 Years of Age and Older (Safety Analysis Set)b Fluzone Quadrivalentc (Nf=190) TIV-1d (B Victoria) (Nf=190) TIV-2e (B Yamagata) (Nf=190) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Injection-site adverse reactions Pain 47.4 6.8 0.5 52.1 7.9 0.5 43.2 6.3 0.0 Erythema 1.1 0.0 0.0 1.6 0.5 0.0 1.6 0.5 0.0 Swelling 0.5 0.0 0.0 3.2 0.5 0.0 1.1 0.0 0.0 Induration 0.5 0.0 0.0 1.6 0.5 0.0 0.5 0.0 0.0 Ecchymosis 0.5 0.0 0.0 0.5 0.0 0.0 0.5 0.0 0.0 Systemic adverse reactions Myalgia 23.7 5.8 0.0 25.3 5.8 0.0 16.8 5.8 0.0 Headache 15.8 3.2 0.5 18.4 6.3 0.5 18.0 4.2 0.0 Malaise 10.5 1.6 1.1 14.7 3.2 1.1 12.1 4.7 0.5 Shivering 2.6 0.5 0.0 5.3 1.1 0.0 3.2 0.5 0.0 Fever ( ≥ 100.4°F)i 0.0 0.0 0.0 0.5 0.5 0.0 0.5 0.5 0.0 aNCT00988143 bThe safety analysis set includes all persons who received study vaccine cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) d2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed e2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed fN is the number of participants in the safety analysis set gGrade 2 - Injection-site pain: Some interference with activity; Injection-site erythema, Injectionsite swelling, Injection-site induration, and Injection-site ecchymosis: ≥ 5.1 to ≤ 10 cm; Fever: ≥ 101.2°F to ≤ 102.0°F; Myalgia, Headache, Malaise, and Shivering: some interference with activity hGrade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: > 10 cm; Fever: ≥ 102.1°F; Myalgia, Headache, Malaise, and Shivering: Significant; prevents daily activity iFever measured by any route Unsolicited non-serious adverse events were reported in 33 (17.4%) recipients in the Fluzone Quadrivalent group, 45 (23.7%) recipients in the TIV-1 group, and 45 (23.7%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were headache, cough, and oropharyngeal pain. In the follow-up period, there were two SAEs, 1 (0.5%) in the Fluzone Quadrivalent group and 1 (0.5%) in the TIV-2 group. No deaths were reported during the trial period. Geriatric Adults In Study 3 (NCT01218646, see http://clinicaltrials.gov), a multi-center, randomized, double-blind trial conducted in the US, adults 65 years of age and older received one dose of either Fluzone Quadrivalent, or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or TIV- 2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The safety analysis set included 675 recipients. Among participants in the three vaccine groups combined, 55.7% were female (Fluzone Quadrivalent, 57.3%; TIV-1, 56.0%; TIV-2, 53.8%), 89.5% Caucasian (Fluzone Quadrivalent, 87.6%; TIV-1, 89.8%; TIV-2, 91.1%), 2.2% Black (Fluzone Quadrivalent, 4.0%; TIV-1, 1.8%; TIV-2, 0.9%), 7.4% Hispanic (Fluzone Quadrivalent, 8.4%; TIV-1, 7.6%; TIV-2, 6.2%) and 0.9% were of other racial/ ethnic groups (Fluzone Quadrivalent, 0.0%; TIV-1, 0.9%; TIV-2, 1.8%). Table 5 summarizes solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events and SAEs during the 21 days following vaccination. Table 5: Study 3a: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Adults 65 Years of Age and Older (Safety Analysis Set)b Fluzone Quadrivalentc (Nf=225) TIV-1d (B Victoria) (Nf=225) TIV-2e (B Yamagata) (Nf=225) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Any (%) Grade 2g (%) Grade 3h (%) Injection-site adverse reactions Pain 32.6 1.3 0.9 28.6 2.7 0.0 23.1 0.9 0.0 Erythema 2.7 0.9 0.0 1.3 0.0 0.0 1.3 0.4 0.0 Swelling 1.8 0.4 0.0 1.3 0.0 0.0 0.0 0.0 0.0 Systemic adverse reactions Myalgia 18.3 4.0 0.4 18.3 4.0 0.0 14.2 2.7 0.4 Headache 13.4 1.3 0.4 11.6 1.3 0.0 11.6 1.8 0.4 Malaise 10.7 4.5 0.4 6.3 0.4 0.0 11.6 2.7 0.9 Fever ( ≥ 100.4°F)i 1.3 0.0 0.4 0.0 0.0 0.0 0.9 0.4 0.4 aNCT01218646 bThe safety analysis set includes all persons who received study vaccine cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed fN is the number of participants in the safety analysis set gGrade 2 - Injection-site pain: some interference with activity; Injection-site erythema and Injection-site swelling: ≥ 5.1 to ≤ 10 cm; Fever: ≥ 101.2°F to ≤ 102.0°F; Myalgia, Headache, and Malaise: some interference with activity hGrade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema and Injection-site swelling: > 10 cm; Fever: ≥ 102.1°F; Myalgia, Headache, and Malaise: Significant; prevents daily activity iFever measured by any route Unsolicited non-serious adverse events were reported in 28 (12.4%) recipients in the Fluzone Quadrivalent group, 22 (9.8%) recipients in the TIV-1 group, and 22 (9.8%) recipients in the TIV- 2 group. The most commonly reported adverse events were oropharyngeal pain, rhinorrhea, injection-site induration, and headache. Three SAEs were reported during the follow-up period, 2 (0.9%) in the TIV-1 group and 1 (0.4%) in the TIV-2 group. No deaths were reported during the trial period. Post-Marketing Experience Currently, there are no post-marketing data available for Fluzone Quadrivalent vaccine. The following events have been spontaneously reported during the post-approval use of the trivalent formulation of Fluzone. 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. 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 tightnes 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 DRUG INTERACTIONS No information provided. a Assessed in children 24 months through 35 months of age b Assessed in children 6 months through 23 months of age

SIDE EFFECTS In adults 18 through 64 years of age, the most common ( ≥ 10%) injection-site reactions were pain (53.3%), pruritus (52.1%), erythema (36.7%), swelling (19.5%), and induration (17.0%); the most common solicited systemic adverse reactions were myalgia (34.1%), headache (33.1%), malaise (27.7%), and shivering (12.1%). 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. Fluzone Intradermal Quadrivalent In Adults 18 Through 64 Years Of Age Study 1 (NCT01712984, see http://clinicaltrials.gov) was a randomized, double-blind, active-controlled, multi-center safety and immunogenicity study conducted in the US. In this study, adults 18 through 64 years of age received a single injection of either Fluzone Intradermal Quadrivalent or one of two formulations of a comparator trivalent influenza vaccine by the intradermal route (TIV-ID1 or TIV-ID2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Intradermal Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The safety analysis set, comprised of all participants who received a study vaccine, included 3355 recipients. Among participants in the three vaccine groups combined, 61.3% were female, 84.9% White, 11.9% Black, 1.1% Asian, and 2.1% were of other racial/ethnic groups. Table 1 summarizes solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events for 28 days after vaccination and serious adverse events (SAEs) for 6 months after vaccination. Table 1: Study 1a: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Adults 18 Through 64 Years of Age (Safety Analysis Set)b * Fluzone Intradermal Quadrivalent (Ne=1649-1656) TIV-ID1 c (B Yamagata) (Ne=819-820) TIV-ID2d (B Victoria) (Ne=836-838) Any (%) Grade 2f (%) Grade 3g (%) Any (%) Grade 2f (%) Grade 3g (%) Any (%) Grade 2f (%) Grade 3g (%) Injection-site adverse reactions Pain 53.3 9.7 1.4 48.2 7.9 1.2 50.1 7.5 1.4 Pruritis 52.1 9.4 2.8 45.4 9.0 1.8 44.6 7.5 2.3 Erythema 36.7 10.9 0.4 34.0 9.8 0.1 32.1 6.3 0.4 Swelling 19.5 4.8 0.1 14.8 3.9 0.0 14.7 2.0 0.0 Induration 17.0 2.8 < 0.1 13.5 1.8 0.0 11.2 2.2 0.0 Ecchymosis 2.6 0.4 0.0 1.8 0.4 0.0 1.8 0.1 0.0 Systemic adverse reactions Myalgia 34.1 8.1 2.6 29.0 8.2 1.5 31.1 7.4 2.5 Headache 33.1 9.1 3.2 31.3 9.6 2.4 33.2 8.9 1.8 Malaise 27.7 9.2 3.0 26.3 6.6 1.8 30.4 8.4 2.5 Shivering 12.1 2.0 1.4 10.4 2.2 0.6 11.2 3.3 1.6 Fever ( ≥ 100.4°F)h 0.8 0.2 0.2 0.7 0.2 0.1 0.5 0.0 0.0 a NCT01712984 b The safety analysis set includes all persons who received study vaccine c TIV-ID1: 2012-2013 Fluzone Intradermal TIV containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Texas/6/2011 (Yamagata lineage), licensed d TIV-ID2: Investigational Intradermal TIV containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), non-licensed e N is the number of vaccinated participants with available data for the events listed f Grade 2 - Injection-site pain and injection-site pruritus: Some interference with activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: ≥ 51 to ≤ 100 mm; Fever: ≥ 101.2°F to ≤ 102.0°F; Myalgia, Headache, Malaise, and Shivering: Some interference with activity g Grade 3 - Injection-site pain and injection-site pruritus: Significant - prevents daily activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: > 100 mm; Fever: ≥ 102.1°F; Myalgia, Headache, Malaise, and Shivering: Significant - prevents daily activity h Fever measured by any route Unsolicited non-serious adverse events were reported in 382 (22.8%) recipients in the Fluzone Intradermal Quadrivalent group, 169 (20.2%) recipients in the TIV-ID1 group, and 212 (25.1%) recipients in the TIV-ID2 group. The most commonly reported unsolicited non-serious adverse events were cough, headache, and oropharyngeal pain. During the 28 days following vaccination, a total of 6 (0.4%) recipients in the Fluzone Intradermal Quadrivalent group, 2 (0.2%) recipients in the TIV-ID1 group, and 3 (0.4%) recipients in the TIV-ID2 group experienced at least one SAE; no deaths occurred. Throughout the study period (6 months post-vaccination), a total of 20 (1.2%) recipients in the Fluzone Intradermal Quadrivalent group, 14 (1.7%) recipients in the TIV-ID1 group, and 11 (1.3%) recipients in the TIV-ID2 group experienced at least one SAE. One death (177 days post-vaccination due to acute coronary myocardial infarction) occurred in the Fluzone Intradermal Quadrivalent group. This death was considered not related to the study vaccine by the Investigator. Fluzone Intradermal (Trivalent Influenza Vaccine) In Adults 18 Through 64 Years Of Age The safety experience with Fluzone Intradermal (trivalent influenza vaccine) is relevant to Fluzone Intradermal Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions. In a study of adults 18 through 64 years of age (NCT00772109), safety was evaluated in 2855 Fluzone Intradermal recipients compared to 1421 Fluzone (trivalent influenza vaccine) recipients. Rates of solicited injection-site reactions and systemic adverse events in adults are shown in Table 2. Table 2: Frequency of Solicited Injection-Site Reactions and Systemic Adverse Events Within 7 Days After Vaccine Injection, Adults 18 Through 64 Years of Age Fluzone Intradermal (Na=2798-2802) Percentage Fluzone (Na=1392-1394) Percentage Any Grade 2b Grade 3c Any Grade 2b Grade 3c Iniection-Site Erythema 76.4 28.8 13.0 13.2 2.1 0.9 Injection-Site Induration 58.4 13.0 3.4 10.0 2.3 0.5 Iniection-Site Swelling 56.8 13.4 5.4 8.4 2.1 0.9 Iniection-Site Pain 51.0 4.4 0.6 53.7 5.8 0.8 Iniection-Site Pruritus 46.9 4.1 1.1 9.3 0.4 0.0 Iniection-Site Ecchymosis 9.3 1.4 0.4 6.2 1.1 0.4 Headache 31.2 6.4 1.5 30.3 6.5 1.6 Myalgia 26.5 4.6 1.5 30.8 5.5 1.4 Malaise 23.3 5.5 2.2 22.2 5.5 1.8 Shivering 7.3 1.5 0.7 6.2 1.1 0.6 Feverd ( ≥ 99.5°F) 3.9 0.6 0.1 2.6 0.4 0.2 a N is the number of vaccinated subjects with available data for the events listed b Grade 2 - Injection-site erythema, Injection-site induration, Injection-site swelling, and Injection-site ecchymosis: ≥ 2.5 cm to < 5 cm; Injection-site pain and Injection-site pruritus: sufficiently discomforting to interfere with normal behavior or activities; Fever: > 100.4°F to ≤ 102.2°F; Headache, Myalgia, Malaise, and Shivering: interferes with daily activities c Grade 3 - Injection-site erythema, Injection-site induration, Injection-site swelling, and Injection-site ecchymosis: ≥ 5 cm; Injection-site pain: incapacitating, unable to perform usual activities; Injection-site pruritus: incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism; Fever: > 102.2°F; Headache, Myalgia, Malaise, and Shivering: prevents daily activities d Fever - The percentage of temperature measurements that were taken by oral or axillary routes, or not recorded were 99.9%, < 0.1%, and 0.1%, respectively, for Fluzone Intradermal; and 99.6%, 0.0%, and 0.4%, respectively, for Fluzone Post-Marketing Experience The following events have been spontaneously reported during the post-approval use of the trivalent formulation of Fluzone. 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. 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-Barr 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, vasodilation/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 DRUG INTERACTIONS No information provided.

SIDE EFFECTS Clinical Trials Experience The most common ( ≥ 10%) local and systemic reactions in adults 18-64 years of age were injection site pain (45.4%) headache (18.7%), fatigue (17.8%) and myalgia (15.4%), injection site erythema (13.4%), and induration (11.6%). The most common ( ≥ 10%) local and systemic reactions in adults ≥ 65 years of age were injection site pain (21.6%), and injection site erythema (11.9%). The most common ( ≥ 10%) local and systemic reactions in children 4 to < 6 years of age after first dose of vaccine were tenderness at the injection site (46%), injection site erythema (18%), sleepiness (19%), irritability (16%), injection site induration (13%) and change in eating habits (10%). The most common ( ≥ 10%) local and systemic reactions in children 6 through 8 years of age after first dose of vaccine were pain at the injection site (54%), injection site erythema (22%), injection site induration (16%), headache (14%), fatigue (13%) and myalgia (12%). The most common ( ≥ 10%) local and systemic reactions in children and adolescents 9 through 17 years of age were pain at the injection site (58%), headache (22%), injection site erythema (19%), fatigue (18%), myalgia (16%), and injection site induration (15%). 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 clinical studies of another vaccine, and may not reflect rates observed in clinical practice. Adults 18 Years Of Age And Older The safety of FLUCELVAX QUADRIVALENT in adults was evaluated in a randomized, double-blind, controlled study conducted in the US (Study 1). The safety population included a total of 2680 adults 18 years of age and older; 1340 adults 18 through 64 years of age and 1340 adults 65 years of age and older. In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (TIV1c and TIV2c) (FLUCELVAX QUADRIVALENT (n=1335), TIV1c, n=676 or TIV2c n= 669). The mean age of subjects who received FLUCELVAX QUADRIVALENT was 57.4 years of age; 54.8% of subjects were female and 75.6% were Caucasian, 13.4% were Black, 9.1% were Hispanics, 0.7% were American Indian and 0.3%, 0.1% and 0.7% were Asian, Native Hawaiian and others, respectively. The safety data observed are summarized in Table 2. In this study, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination. Solicited adverse reactions for FLUCELVAX QUADRIVALENT and comparator are summarized in Table 2. Table 2: Incidence of Solicited Adverse Reactions in the Safety Population1 Reported Within 7 Days of Vaccination (Study 1) 18 through 64 years of age ≥ 65 years of age Percentages (%)2 FLUCELVAX Trivalent Influenza Vaccine FLU- CELVAX Trivalent Influenza Vaccine VALENT N=663 TIVIc N=330 TIV2c N=327 RIVA- LENT N=656 TIV1c N=340 TIV2c N=336 Local Adverse Reactions Injection site induration 11.6 (0) 9.7 (0.3) 10.4 (0) 8.7 (0) 6.8 (0) 7.7(0) Injection site erythema 13.4 (0) 13.3 (0) 10.1 (0) 11.9 (0) 10.6 (0) 10.4 (0) Injection site ecchymosis 3.8 (0) 3.3 (0.3) 5.2 (0) 4.7 (0) 4.4 (0) 5.4 (0) Injection site pain 45.4 (0.5) 37.0 (0.3) 40.7 (0) 21.6 (0) 18.8 (0) 18.5 (0) Systemic Adverse Reactions Chills 6.2 (0.2) 6.4 (0.6) 6.4 (0) 4.4 (0.3) 4.1 (0.3) 4.5 (0.6) Nausea 9.7 (0.3) 7.3 (0.9) 8.9 (1.2) 3.8 (0.2) 4.1 (0) 4.2 (0.3) Myalgia 15.4 (0.8) 14.5 (0.9) 15.0 (1.2) 8.2 (0.2) 9.4 (0.3) 8.3 (0.6) Arthralgia 8.1 (0.5) 8.2 (0) 9.5 (0.9) 5.5 (0.5) 5.0 (0.3) 6.8 (0.9) Headache 18.7 (0.9) 18.5 (0.9) 18.7 (0.6) 9.3 (0.3) 8.5 (0.6) 8.3 (0.6) Fatigue 17.8 (0.6) 22.1 (0.3) 15.6 (1.5) 9.1 (0.8) 10.6 (0.3) 8.9 (0.6) Vomiting 2.6 (0) 1.5 (0.3) 0.9 (0) 0.9 (0.2) 0.3 (0) 0.6 (0) Diarrhea 7.4 (0.6) 7.6 (0) 7.6 (0.6) 4.3 (0.5) 5.0 (0.9) 5.1 (0.3) Loss of appetite 8.3 (0.3) 8.5 (0.3) 8.3 (0.9) 4.0 (0.2) 5.0 (0) 3.6 (0.3) Fever: ≥ 38.0 °C( ≥ 40.0 °C) 0.8 (0) 0.6 (0) 0.3 (0) 0.3 (0) 0.9 (0) 0.6 (0) 1Safety population: all subjects in the exposed population who provided post-vaccination safety data 2Percentage of severe adverse reactions are presented in parenthesis Study 1: NCT01992094 Unsolicited adverse events were collected for 21 days after vaccination. In adults 18 years of age and older, unsolicited adverse events were reported in 16.1% of subjects who received FLUCELVAX QUADRIVALENT, within 21 days after vaccination. In adults 18 years of age and older, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after vaccination) and were reported by 3.9%, of the subjects who received FLUCELVAX QUADRIVALENT. None of the SAEs were assessed as being related to study vaccine. Children And Adolescents 4 Through 17 Years Of Age The safety of FLUCELVAX QUADRIVALENT in children was evaluated in a randomized, double-blind, controlled study conducted in the US (Study 2). The safety population included a total of 2332 children 4 through 17 years of age; 1161 children 4 through 8 years of age and 1171 children 9 through 17 years of age. In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (FLUCELVAX QUADRIVALENT n=1159, TIV1c, n=593 or TIV2c n= 580). Children 9 through 17 years of age received a single dose of FLUCELVAX QUADRIVALENT or comparator vaccine. Children 4 through 8 years of age received one or two doses (separated by 4 weeks) of FLUCELVAX QUADRIVALENT or comparator vaccine based on determination of the subject’s prior influenza vaccination history. The mean age of subjects who received FLUCELVAX QUADRIVALENT was 9.6 years of age; 48% of subjects were female and 53% were Caucasian. The safety data observed are summarized in Table 3 and Table 4. In this study, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination. Solicited adverse reactions for FLUCELVAX QUADRIVALENT and comparator are summarized in Table 3 and Table 4. Table 3: Incidence of Solicited Adverse Reactions in the Safety Population1 (4 through 5 years of age) Reported Within 7 Days of the First dose of Vaccination (Study 2) Children 4 through 5 years Percentages (%)2 FLUCELVAX QUADRIVALENT N=182 Trivalent Influenza Vaccine TIV1c N=91 TIV2c N=93 Local Adverse Reactions Injection site induration 13 (1) 20 (2) 13 (0) Injection site erythema 18 (1) 23 (1) 17 (0) Injection site ecchymosis 9 (0) 11 (0) 8 (0) Injection site tenderness 46 (1) 45 (1) 43 (0) Systemic Adverse Reactions Change in eating habits 10 (1) 7 6 Sleepiness 19 (1) 12 (3) 10 (0) Irritability 16 (2) 10 (2) 10 (1) Chills 5 (1) 2 (0) 1 (0) Vomiting 4 (0) 2 (0) 2 (0) Diarrhea 4 (0) 2 (0) 2 (0) Fever: > 38.0 °C ( > 40.0 °C) 4 (0) 4 (0) 3 (0) 1Safety population: all subjects in the exposed population who provided post-vaccination safety data. 2Percentage of subjects with severe adverse reactions are presented in parenthesis. Study 2: NCT01992107 Table 4: Incidence of Solicited Adverse Reactions in the Safety Population1 (Children 6 through 17 years of age) Reported Within 7 Days of Vaccination (Study 2) Children 6 through 8 years (after first dose) Children 9 through 17 years Percentages (%)2 FLU- CELVAX QUADRI- VALENT N=371-372 Trivalent Influenza vaccine FLU- CELVAX QUADRI- VALENT N=579 Trivalent Influenza Vaccine TIVIc N=185 TIV2c N=186 TIV1c N=294 TIV2c N=281-282 Local Adverse Reactions Injection site induration 16 (0) 19 (1) 13 (0) 15 (0) 15 (0) 13 ( < 1) Injection site erythema 22 (0) 23 (1) 20 (0) 19 ( < 1) 17 (0) 15 ( < 1) Injection site ecchymosis 9 (0) 9 (0) 8 (0) 4 (0) 5 (0) 5 (0) Injection site pain 54 (1) 57 (1) 58 (2) 58 (1) 51 ( < 1) 50 (0) Systemic Adverse Events Chills 4 (1) 3 (0) 4 (0) 7 (0) 6 (1) 4 (1) Nausea 8 (1) 5 (0) 5 (1) 9 ( < 1) 8 (1) 7 (1) Myalgia 12 (1) 14 (0) 10 (0) 16 ( < 1) 17 ( < 1) 15 ( < 1) Arthralgia 4 (0) 5 (0) 4 (0) 6 (0) 6 (0) 8 ( < 1) Headache 14 (1) 13 (0) 12 (0) 22 (1) 23 (2) 18 (1) Fatigue 13 (2) 14 (0) 18 (0) 18 ( < 1) 16 (1) 16 ( < 1) Vomiting 3 (1) 3 (0) 3 (0) 2 (0) 1 (0) 2 (0) Diarrhea 3 ( < 1) 6 (1) 5 (0) 4 (0) 4 (0) 3 ( < 1) Loss of appetite 9 ( < 1) 5 (0) 8 (1) 9 (0) 9 ( < 1) 9 (0) Fever: ≥ 38.0 °C ( ≥ 40.0 °C) 4 (0) 3 (0) 2 (0) 1 ( < 1) 3 (0) 1 (0) 1Safety population: all subjects in the exposed population who provided post-vaccination safety data. 2Percentage of subjects with severe adverse reactions are presented in parenthesis. Study 2: NCT 01992107 In children who received a second dose of FLUCELVAX QUADRIVALENT, TIV1c, or TIV2c, the incidence of adverse reactions following the second dose of vaccine were similar to those observed with the first dose. Unsolicited adverse events were collected for 21 days after last vaccination. In children 4 through 17 years of age, unsolicited adverse events were reported in 24.3 of subjects who received FLUCELVAX QUADRIVALENT, within 3 weeks after last vaccination. In children 4 through 17 years of age, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after last vaccination) and were reported by 0.5%, of the subjects who received FLUCELVAX QUADRIVALENT. None of the SAEs were assessed as being related to study vaccine. Postmarketing Experience The safety experience with FLUCELVAX (trivalent influenza vaccine) is relevant to FLUCELVAX QUADRIVALENT, because both vaccines are manufactured using the same process and have overlapping compositions. The following additional adverse events have been identified during postapproval use of FLUCELVAX. 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. Immune system disorders: Anaphylactic reaction, angioedema. Skin and subcutaneous tissue disorders: Generalized skin reactions including pruritus, urticaria or non-specific rash. Nervous systems disorders: Syncope, Presyncope General disorders and administration site conditions: Extensive swelling of injected limb. DRUG INTERACTIONS Concomitant Use With Other Vaccines No data are available to assess the concomitant administration of FLUCELVAX QUADRIVALENT with other vaccines.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barré Syndrome The 1976 swine influenza vaccine was associated with an elevated risk of Guillain-Barré syndrome (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 ref. 1) If GBS has occurred within 6 weeks following previous influenza vaccination, the decision to give Fluzone Quadrivalent should be based on careful consideration of the potential benefits and risks. Preventing And Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of Fluzone Quadrivalent. Altered Immunocompetence If Fluzone Quadrivalent 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 Quadrivalent may not protect all recipients. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). Inform the vaccine recipient or guardian: Fluzone Quadrivalent contains killed viruses and cannot cause influenza. Fluzone Quadrivalent stimulates the immune system to protect against influenza, but does not prevent other respiratory infections. Annual influenza vaccination is recommended. Report adverse reactions to their healthcare provider and/or to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967. Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Fluzone Quadrivalent during pregnancy. Women who receive Fluzone Quadrivalent during pregnancy are encouraged to contact Sanofi Pasteur Inc. directly or have their healthcare provider contact Sanofi Pasteur Inc. at 1-800-822-2463. Vaccine Information Statements must be provided to vaccine recipients or their guardians, as required by the National Childhood Vaccine Injury Act of 1986 prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines). Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential. A reproductive study of female rabbits vaccinated with Fluzone Quadrivalent was performed and revealed no evidence of impaired female fertility [see Pregnancy]. Use In Specific Populations Pregnancy Pregnancy Category B: A developmental and reproductive toxicity study has been performed in female rabbits at a dose approximately 20 times the human dose (on a mg/kg basis) and has revealed no evidence of impaired female fertility or harm to the fetus due to Fluzone Quadrivalent. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Fluzone Quadrivalent should be given to a pregnant woman only if clearly needed. In the developmental and reproductive toxicity study, female rabbits were administered Fluzone Quadrivalent or control saline (each 0.5 mL/dose) by intramuscular injection 24 and 10 days before insemination, and on Days 6, 12, and 27 of gestation. The administration of Fluzone Quadrivalent did not result in systemic maternal toxicity (no adverse clinical signs and no change in body weight or food consumption). In addition, no adverse effects on pregnancy, parturition, lactation, or embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Fluzone Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive Fluzone Quadrivalent during pregnancy in Sanofi Pasteur Inc.'s vaccination pregnancy registry by calling 1-800-822-2463. Nursing Mothers It is not known whether Fluzone Quadrivalent is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fluzone Quadrivalent is administered to a nursing woman. Pediatric Use Safety and effectiveness of Fluzone Quadrivalent in children below the age of 6 months have not been established. Geriatric Use Safety and immunogenicity of Fluzone Quadrivalent were evaluated in adults 65 years of age and older. [See Clinical Studies] Antibody responses to Fluzone Quadrivalent are lower in persons ≥ 65 years of age than in younger adults. 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barr Syndrome If Guillain-Barr syndrome (GBS) has occurred within 6 weeks following previous influenza vaccination, the decision to give Fluzone Intradermal 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 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 Fluzone Intradermal Quadrivalent. Altered Immunocompetence If Fluzone Intradermal Quadrivalent 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 Intradermal Quadrivalent may not protect all recipients. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). Inform the vaccine recipient or guardian: Fluzone Intradermal Quadrivalent contains killed viruses and cannot cause influenza. Fluzone Intradermal Quadrivalent stimulates the immune system to protect against influenza, but does not prevent other respiratory infections. Annual influenza vaccination is recommended. Because the vaccine is injected into the skin, patients may experience visible reactions at the injection site, such as a wheal (superficial bump), redness, and swelling. Patients may also experience pain, itching, and induration at the injection site. Report adverse reactions to their healthcare provider and/or to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 or http://vaers.hhs.gov. Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Fluzone Intradermal Quadrivalent during pregnancy. Women who receive Fluzone Intradermal Quadrivalent during pregnancy are encouraged to contact Sanofi Pasteur Inc. directly or have their healthcare provider contact Sanofi Pasteur Inc. at 1-800-822-2463. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential. A reproductive study of female rabbits vaccinated with Fluzone Quadrivalent was performed and revealed no evidence of impaired female fertility [see Pregnancy]. Use In Specific Populations Pregnancy Pregnancy Category B: The developmental and reproductive toxicity study performed with the trivalent formulation of Fluzone Intradermal is relevant to Fluzone Intradermal Quadrivalent because both vaccines share the same manufacturing process and route of administration. The study, in which the trivalent formulation of Fluzone Intradermal (27 mcg) was administered to female rabbits at a dose approximately 20 times the human dose (on a mg/kg basis), revealed no evidence of impaired female fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Fluzone Intradermal Quadrivalent should be used during pregnancy only if clearly needed. Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Fluzone Intradermal Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive Fluzone Intradermal Quadrivalent during pregnancy in Sanofi Pasteur Inc.'s vaccination pregnancy registry by calling 1-800-822-2463. Nursing Mothers It is not known whether Fluzone Intradermal Quadrivalent is excreted in human milk. Because many drugs are excreted in human milk, the decision to give Fluzone Intradermal Quadrivalent to a nursing woman should be based on careful consideration of the potential benefits and risks. Pediatric Use Safety and effectiveness of Fluzone Intradermal Quadrivalent in persons < 18 years of age have not been established. In a clinical trial, 97 infants and toddlers 6 months through 35 months of age and 160 children 3 years through 8 years of age were enrolled to receive two injections of the trivalent formulation of Fluzone Intradermal. Infants and children in a control group received two injections of Fluzone. Fluzone Intradermal was associated with increased local reactogenicity relative to Fluzone. The size of the study was not adequate to reliably evaluate serious adverse events or the immune response elicited by Fluzone Intradermal relative to Fluzone. Geriatric Use Safety and effectiveness of Fluzone Intradermal Quadrivalent in persons 65 years of age and older have not been established. REFERENCES 1 Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barr 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-Barr Syndrome with Vaccinations. Clin Infect Dis 2013;57(2):197-204.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Guillain-Barré Syndrome The 1976 swine influenza vaccine was associated with an elevated risk of Guillain-Barré syndrome (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.1 If GBS has occurred after receipt of a prior influenza vaccine, the decision to give FLUCELVAX QUADRIVALENT should be based on careful consideration of the potential benefits and risks. Preventing And Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Syncope Syncope (fainting) can occur in association with administration of injectable vaccines, including Flucelvax. 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. Altered Immunocompetence After vaccination with FLUCELVAX QUADRIVALENT, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced immune response. Limitations Of Vaccine Effectiveness Vaccination with FLUCELVAX QUADRIVALENT may not protect all vaccine recipients against influenza disease. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility FLUCELVAX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Administration of Flucelvax vaccine (45 mcg HA/dose) did not affect female fertility in a rabbit reproductive and developmental toxicity study. Use In Specific Populations Pregnancy Pregnancy Category B: The developmental and reproductive toxicity study performed with the trivalent formulation of Flucelvax is relevant to Flucelvax Quadrivalent because both vaccines share the same manufacturing process and route of administration. A reproductive and developmental toxicity study has been performed in rabbits with Flucelvax, with a dose level that was approximately 11 times the human dose based on body weight. The study revealed no evidence of impaired female fertility or harm to the fetus. 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 Flucelvax containing 45 mcg HA/dose on embryo-fetal and post-natal development was evaluated in pregnant rabbits. Animals were administered vaccine by intramuscular injection 3 times prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (approximately 11-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 teratogenesis. Nursing Mothers FLUCELVAX QUADRIVALENT has not been evaluated in nursing mothers. It is not known whether FLUCELVAX QUADRIVALENT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUCELVAX QUADRIVALENT is administered to a nursing woman. Pediatric Use Safety and effectiveness have not been established in children less than 4 years of age. Geriatric Use Of the total number of subjects who received one dose of FLUCELVAX QUADRIVALENT in clinical studies and included in the safety population (2493), 26.47% (660) were 65 years of age and older and 7.7% (194) were 75 years of age or older. Antibody responses to FLUCELVAX QUADRIVALENT were lower in the geriatric (adults 65 years and older) population than in younger subjects. [see 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(25):1797-1802.