Prescription Drugs

CLINICAL PHARMACOLOGY Action And Clinical Pharmacology Mechanism of Action Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers induced by vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. Some studies of influenza infection, including human challenge studies following vaccination, have suggested that HI antibody titers ranging from 1:15 to 1:65 may be associated with protection from illness in 50% of subjects and protection from illness is increased with higher titers (CBER Guidance, May 2007). Antibody against one influenza virus type or subtype may confer limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains (typically two type A and one type B), representing the influenza viruses likely to be circulating in Canada during the upcoming flu season, on the basis of the recommendations from the World Health Organization (WHO) and the National Advisory Committee on Immunization (NACI). Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year (MMWR). Pharmacodynamics The antibody response to FLUAD® is increased when compared to the response to vaccines without adjuvant, and is most pronounced for A/H3N2 and B influenza antigens. Seroprotection is generally obtained within 2 to 3 weeks after vaccination. Similarly, development of antibody levels associated with protection against disease is generally obtained within 2 to 3 weeks after a single dose in children who have been previously vaccinated against influenza. Children who have not been previously vaccinated against influenza develop protective antibody responses within 2 to 3 weeks after the second vaccine dose. This increased response is seen particularly in elderly subjects with low pre-immunization titre and/or with underlying diseases (diabetes, cardiovascular and respiratory diseases) who are at increased risk of complications of influenza infection. A similar immunogenicity profile has been noted after a second and third immunization with FLUAD®. Consistent higher antibody titers after immunization with FLUAD Pediatric™/FLUAD* have also been observed against homologous and heterologous strains. The difference in antibody responses with FLUAD® administered in the elderly population was statistically significant for some strains and/or some endpoints compared with the comparator. Duration Of Effect The duration of post-vaccination immunity to homologous strains or to strains closely related to the vaccine strains varies, but it is usually 6-12 months. Clinical Trials Study Demographics And Trial Design Pediatric Population The immunogenicity of FLUAD Pediatric™ was assessed in a randomized, controlled, observer-blinded, multicenter trial in which 6100 subjects were randomly assigned to receive two doses (4 weeks apart) of FLUAD Pediatric™ (3136 subjects) or TIV 1 (Sanofi licensed split vaccine; 1478 subjects) or TIV 2 (Novartis licensed subunit vaccine; 1485 subjects). Elderly Population Five randomized, comparator controlled, observer blind clinical studies, were selected as pivotal studies to support the immunogenicity of FLUAD®, compared with conventional non adjuvanted influenza vaccines. Additionally, immunogenicity results of one study have been presented to support the cross reactivity to heterologous influenza strains conferred by FLUAD®. Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days after administration of the single dose of FLUAD®. In the five pivotal studies and the one study investigating heterologous immune response, 212, 204, 154, 150, 448, and 46 subjects 65 years and older were enrolled to receive FLUAD®. The demographic and baseline characteristics were well balanced both between vaccine groups in each study as well as across studies. In these studies the mean age ranged from 72 to 79.1 years, sex ratio was mostly balanced except for a prevalence (72%-75%) of females in one study, and Caucasians were the most represented ethnic group across studies. As expected in a population with a high percentage of subjects with previous influenza vaccinations (63% to 97% across studies and vaccine groups), the percentage of subjects with seroprotection at baseline was relatively high. Study Results Pediatric Population In the pivotal trial, antibody responses three weeks after a second dose of FLUAD Pediatric™, given to children 6 months to < 6 years of age, were non-inferior to two other licensed influenza vaccines. The antibody responses as measured by geometric mean antibody titres (GMTs) and seroconversion rates against all three homologous influenza virus antigens included in the FLUAD Pediatric™ vaccine were higher than for the comparator vaccines 3 weeks after administration of the second vaccine dose (Day 50). Percentages of children with HI titres ≥ 40 against all three homologous influenza strains were equal to or higher for the FLUAD Pediatric™ vaccine than for the comparator vaccines 3 weeks after the second dose (Table 5). The difference in antibody responses with FLUAD® administered in the elderly population was statistically significant for some strains and/or some endpoints, compared with the comparator. Table 5 : Immunogenicity (Homologous Strains) of FLUAD Pediatric™ in Children 6 months to < 2 years of age at Day 50 FLUAD Pediatric™ (aTIV) N = 266 TIV 1 N = 387 TIV 2 N = 389 Ratios or differences between vaccine groups A/H1N1 GMRa (95% CI) 96 (78-118) 18 (15-21) 28 (24-34) aTIV: TIV 1= 5.3 (4.07-6.91) aTIV: TIV 2= 3.37 (2.59-4.39) % ≥ 40b(95% CI) 99.25 (97.31-99.91) 82.43 (78.26-86.09) 87.4 (83.69-90.53) aTIV- TIV 1 = 16.82% (13.10-21.00) aTIV- TIV 2 = 11.84% (8.60-15.60) % SCc(95% CI) 95.49 (92.25-97.65) 77.78 (73.30-81.82) 85.09 (81.16-88.48) aTIV- TIV 1= 17.71% (12.87-22.55)aTIV- TIV2= 10.40% (6.07-14.73) A/H3N2 GMRa(95% CI) 112 (93-134) 33 (29-39) 50 (43-58) aTIV: TIV 1 = 3.35 (2.65-4.24) aTIV: TIV 2 = 2.25 (1.78-2.84) % ≥ 40b (95% CI) 99.62 (97.92-99.99) 99.22 (97.75-99.84) 99.74 (98.58-99.99) aTIV- TIV 1 = 0.40% (-1.30-1.90) aTIV- TIV 2 = -0.12% (-1.80-1.10) % SCc(95% CI) 98.12 (95.67-99.39) 92.51 (89.42-94.92) 95.63 (93.09-97.43) aTIV- TIV 1 = 5.61% (2.52-8.70) aTIV- TIV 2= 2.49% (-0.12-5.10) B GMRa (95% CI) 78 (67-90) 14 (13-16) 17 (15-19) aTIV: TIV 1 = 5.52 (4.56-6.68) aTIV: TIV 2 = 4.72 (3.9-5.71) % ≥ 40b(95% CI) 98.87 (96.74-99.77) 81.4 (77.15-85.15) 87.92 (84.26-90.99) aTIV- TIV 1 = 17.48% (13.60-21.70) aTIV- TIV 2 = 10.95% (7.60-14.70) % SCc(95% CI) 98.12 (95.67-99.39) 79.33 (74.95-83.25) 85.35 (81.44-88.71) aTIV- TIV 1= 18.79% (14.44-23.14) aTIV- TIV 2 = 12.77% (8.90-16.65) aGMR = geometric mean ratio = Ratio of Day 50:Day 1 GMTs; b ≥ 40 = percentage of subjects with HI titre ≥ 40; cSC = percentage of subjects with seroconversion or significant increase = the percentage of subjects achieving ≥ 4-fold increase in HI titre from a seropositive pre-vaccination titre ( ≥ 10), or, an HI titre ≥ 40 from a seronegative ( < 10) pre-vaccination titre. Vaccine group ratios adjusted for baseline titre. Bold indicates a higher antibody response in favour of the Fluad Pediatric group. TIV 1 = Novartis licensed subunit vaccine; TIV 2= Sanofi licensed split vaccine. The percentage of children 6 months to < 2 years of age with increasingly higher HI titres at approximately 3 weeks after the second vaccine dose were higher for FLUAD Pediatric™ than for the comparator influenza vaccines (Table 6). However, the HI antibody thresholds associated with protection against influenza in children have not been established. After six months, GMTs and percentages of children with HI titre ≥ 40 to homologous influenza strains remained higher for the FLUAD Pediatric™ vaccine in subjects 6 months to < 2 years of age than for the comparator vaccines. Table 6 : Percentages (95% CI) of Children 6 months to < 2 years of Age with HI Titres ≥ 40, ≥ 110, ≥ 330, ≥ 629 at Day 50 (approximately 3 weeks after the second vaccine dose) FLUAD Pediatric (aTIV) N = 266 TIV 1 N = 387 TIV 2 N = 389 Difference between vaccine groups (aTIV - TIV 1) Difference between vaccine groups (aTIV - TIV 2) Titre ≥ 40 A/H1N1 99.25% (97.31-99.91) 82.43% (78.26-86.09) 87.40% (83.69-90.53) 16.82% (13.10-21.00) 11.84% (8.60-15.60) A/H3N2 99.62% (97.92-99.99) 99.22% (97.75-99.84) 99.74 % (98.58-99.99) 0.40% (-1.30-1.90) -0.12% (-1.80-1.10) B 98.87% (96.74-99.77) 81.40% (77.15-85.15) 87.92% (84.26-90.99) 17.48% (13.60-21.70) 10.95% (7.60-14.70) Titre ≥ 110 A/H1N1 99.25% (97.31-99.91) 72.87% (68.15-77.24) 80.21% (75.89-84.05) 26.38% (22.00-31.10) 19.04% (15.20-23.30) A/H3N2 99.25% (97.31-99.91) 92.51% (89.42-94.92) 96.66% (94.35-98.21) 6.74% (4.10-9.90) 2.59% (0.40-4.90) B 96.62% (93.67-98.44) 45.99% (40.95-51.10) 52.19% (47.09-57.24) 50.62% (45.10-55.80) 44.43% (39.00-49.70) Titre ≥ 330 A/H1N1 84.59% (79.68-88.71) 38.24% (33.38-43.29) 41.90% (36.95-46.98) 46.34% (39.60-52.50) 42.68% (35.90-48.90) A/H3N2 93.23% (89.52-95.94) 52.20% (47.09-57.27) 63.75% (58.76-68.54) 41.04% (35.10-46.70) 29.48% (23.80-35.00) B 62.78% (56.67-68.61) 20.16% (16.27-24.50) 19.02% (15.24-23.28) 42.63% (35.40-49.40) 43.76% (36.60-50.50) Titre ≥ 629 A/H1N1 78.95% (73.55 - 83.69) 35.92% (31.13 - 40.92) 38.05% (33.20 - 43.08) 43.03% (36.00-49.50) 40.90% (33.80-47.40) A/H3N2 93.23% (89.52 - 95.94) 51.68% (46.58 - 56.76) 63.24% (58.23 - 68.04) 41.55% (35.60-47.20) 29.99% (24.30-35.50) B 60.15% (53.99 - 66.08) 19.64% (15.80 - 23.95) 18.77% (15.01 - 23.01) 40.51% (33.30-47.30) 41.38% (34.20-48.20) TIV1= Novartis licensed subunit vaccine; TIV 2= Sanofi licensed split vaccine Immunogenicity Against Heterologous Strains (Variants From Those Included In The Vaccine) The antibody responses, as measured by Geometric Mean Ratios (GMRs), against all three heterologous influenza strains were higher for FLUAD Pediatric™ than those for the comparator vaccines 3 weeks and six months after administration of the second vaccine dose (Day 50 and Day 209, respectively; Table 7 and Table 8). Seroconversion (SC) rates against all three heterologous influenza strains were also higher for FLUAD Pediatric™ than for the comparator vaccines 3 weeks after administration of the second vaccine dose (Day 50; Table 7). Table 7 : Immunogenicity (Heterologous Strains) of FLUAD* Pediatric in Children 6 months to < 2 years of age at Day 50 Day 50 (3 weeks after second dose) FLUAD Pediatric™ (aTIV) N = 132 TIV 1 N = 216 TIV 2 N = 214 Ratios or Differences between vaccine groups H1N1 GMRa (95% CI) 3.08 (2.54-3.75) 1.83 (1.57-2.14 ) 1.64 (1.41-1.92) aTIV:TIV1 = 1.68 (1.31-2.16) aTIV:TIV2 = 1.88 (1.46-2.41) % SCb (95% CI) 32 (24-40) 21 (16-27) 20 (15-26) aTIV - TIV1 = 11 (1.1-20.3) aTIV - TIV2 = 12 (2.8-21.9) H3N2 GMRa (95% CI) 13 (10-15) 3.42 (2.93-4) 4.55 (3.9-5.32) aTIV:TIV1 = 3.69 (2.87-4.74) aTIV:TIV2 = 2.78 (2.16-3.57) % SCb (95% CI) 90 (84-95) 38 (32-45) 47 (40-54) aTIV - TIV1 = 52 (42.9-59.4) aTIV - TIV2 = 43 (34-50.9) B GMRa (95% CI) 22 (18-26) 4.64 (4.03-5.34) 5.34 (4.63-6.15) aTIV:TIV1 = 4.71 (3.75-5.93) aTIV:TIV2 = 4.1 (3.26-5.16) % SCb (95% CI) 96 (91-99) 44 (38-51) 46 (39-53) aTIV - TIV1 = 52 (44.2-59) aTIV - TIV2 = 50 (42.1-57.1) a GMR = geometric mean ratio = Ratio of Day 50:Day 1 geometric mean titres; b SC = seroconversion or significant increase = the percentage of subjects achieving ≥ 4-fold increase in HI titre from a seropositive pre-vaccination titre ( ≥ 10), or, an HI titre ≥ 40 from a seronegative ( < 10) pre-vaccination titre. Vaccine group ratios adjusted for baseline titre. Bold indicates higher HI antibody response in favour of the Fluad Pediatric group. TIV 1= Novartis licensed subunit vaccine, TIV 2= Sanofi licensed split vaccine. Table 8 : Immunogenicity (Heterologous Strains) of FLUAD Pediatric™ in Children 6 months to < 2 years of age at Day 209 Day 209 (6 months after second dose) FLUAD™ Pediatric (aTIV) N = 132 TIV 1 N = 216 TIV 2 N = 214 Ratios or Differences between vaccine groups H1N1 GMRa (95% CI) 1.48 (1.31-1.67) 1.33 (1.21-1.46) 1.24 (1.13-1.37) aTIV:TIV1 = 1.11 (0.95-1.3) aTIV:TIV2 = 1.19 (1.02-1.39) % SCb (95% CI) 16 (10-23) 11 (7-16) 6 (3-10) aTIV - TIV1 = 5 (-1.9-13.3) aTIV - TIV2 = 10 (3.3-17.5) H3N2 GMRa (95% CI) 2.36 (1.97-2.83) 1.45 (1.26-1.67) 1.67 (1.44-1.92) aTIV:TIV1 = 1.63 (1.29-2.05) aTIV:TIV2 = 1.42 (1.12-1.79) % SCb (95% CI) 24 (17-32) 13 (9-19) 16 (12-22) aTIV - TIV1 = 11 (2.5-19.8) aTIV - TIV2 = 8 (-1-17.1) B GMRa (95% CI) 3.64 (3.18-4.17) 1.47 (1.32-1.63) 1.59 (1.43-1.77) aTIV:TIV1 = 2.48 (2.09-2.95) aTIV:TIV2 = 2.28 (1.92-2.71) % SCb (95% CI) 27 (19-35) 10 (6-15) 10 (6-15) aTIV - TIV1 = 16 (8.2-25.3) aTIV - TIV2 = 17 (8.5-25.6) a GMR = geometric mean ratio = Ratio of Day 50:Day 1 geometric mean titres; b SC = seroconversion or significant increase = the percentage of subjects achieving ≥ 4-fold increase in HI titre from a seropositive pre-vaccination titre ( ≥ 10), or, an HI titre ≥ 40 from a seronegative ( < 10) pre-vaccination titre. Bold indicates higher HI antibody response in favour of the Fluad Pediatric group. TIV 1= Novartis licensed subunit vaccine, TIV 2= Sanofi licensed split vaccine. Elderly Population Evaluation of vaccine immunogenicity was originally based on the CHMP criteria defined in the CPMP/BWP/214/96 guideline. Generally all 3 CHMP criteria were met with FLUAD® for each strain (see Table 9 below). When not all 3 criteria were met, the GMR and seroconversion/significant increase CHMP criteria were more frequently achieved with FLUAD® than with the comparator vaccine. Table 9 : CHMP Criteria Fulfilled Against Homologous Influenza Strains After One Vaccinationa - HI assay (PP-Population) V7P5 V7P8 V7P17 V7P24 V7P34 FLUAD® (w) N=94 AGRIFLU* N=97 FLUAD® (w) N=100 AGRIFLU* N=99 FLUAD® (w) N=147 AGRIFLU* N=150 FLUAD® (c) N=140 Flushield N=140 FLUAD® (c) N=211 AGRIFLU* N=106 H3N2 3/3 3/3 3/3 2/3 3/3 3/3 3/3 3/3 1/3 1/3 H1N1 3/3 2/3 1/3 1/3 3/3 2/3 2/3 2/3 3/3 2/3 B 3/3 2/3 3/3 2/3 3/3 3/3 3/3 2/3 3/3 2/3 Source: FLUAD*(w) = 'water' formulation (FLUAD*/MF59W.1); FLUAD*(c) = 'citrate' formulation (FLUAD*/MF59C.1); Note: for all studies only results with FLUAD* (single syringe) are presented; ai.e., on day 28. In all five pivotal clinical trials consistent numerically higher HI antibody titers (i.e., day 28 GMT FLUAD®/comparator ratio > 1) and greater percentages of subjects achieving seroconversion or significant increase in HI titres (i.e., vaccine group difference for the seroconversion rate of FLUAD®/comparator > 0) for homologous strains were observed for FLUAD®. The differences were statistically significant for some strains and/or some endpoints (see Table 10 and Table 11). However, clinical relevance of the difference is unknown. Table 10: Postvaccination GMTs and Vaccine Group Ratios - HI assay (PP-Population) Study Antigen FLUAD® Comparator N GMT (95% CI) N GMT (95% CI) Vaccine Group Ratio (99.17% CI)# V7P5 H3N2 94 331 (271-406) 97 161 (132-196) 2.06 (1.4-3.03) § H1N1 94 252 (214-297) 97 179 (152-211) 1.41 (1.03-1.92) § B 94 137 (115-162) 97 85 (71-100) 1.62 (1.17-2.24) § V7P8 H3N2 100 121 (69-210) 99 62 (37-104) 1.94 (1.25-3.01) § H1N1 100 179 (121-265) 99 153 (106-220) 1.17 (0.86-1.6) B 100 77 (52-115) 99 60 (41-86) 1.3 (0.95-1.78) V7P17 H3N2 147 276 (228-335) 150 153 (127-185) 1.81 (1.25-2.61) § H1N1 147 367 (314-429) 150 266 (228-311) 1.38 (1.03-1.85) § B 147 289 (250-335) 150 206 (178-238) 1.41 (1.07-1.86) § V7P24 H3N2 140 251 (213-295) 140 204 (173-240) 1.23 (0.9-1.68) H1N1 140 223 (183-272) 140 217 (178-266) 1.03 (0.7-1.5) B 140 182 (149-222) 140 133 (109-162) 1.37 (0.94-2.0) V7P34 H3N2 211 243 (220-267) 106 203 (177-233) 1.19 (0.95-1.5) H1N1 211 203 (175-235) 106 155 (126-190) 1.31 (0.93-1.85) B 211 168 (147-191) 106 140 (116-168) 1.2 (0.89-1.63) # 2-sided 99.17% Bonferroni adjusted CI within each study for 6 comparisons (3 strains by 2 endpoints). §indicate that if CI does not contain 1, i.e. statistically significant difference. Table 11: Postvaccination SC and Vaccine Group Differences - HI assay (PP-Population) Study Antigen FLUAD® Comparator N SC (95% CI) N SC (95% CI) Vaccine Group Difference (99.17% CI)# V7P5 H3N2 94 83 (74-90) 97 61 (50-71) 22 (5-38) § H1N1 94 32 (23-42) 97 23 (15-32) 9 (-8-26) B 94 52 (42-63) 97 30 (21-40) 22 (4-40) § V7P8 H3N2 100 54 (44-64) 99 28 (20-38) 26 (7-42) § H1N1 100 23 (15-32) 99 11 (6-19) 12 (-2-26) B 100 35 (26-45) 99 27 (19-37) 8 (-10-25) V7P17 H3N2 147 55 (47-63) 150 36 (28-44) 19 (4-33) § H1N1 147 35 (27-43) 150 23 (17-31) 11 (-3-25) B 147 48 (40-57) 150 33 (25-41) 16 (1-30) § V7P24 H3N2 140 56 (48-65) 140 35 (27-44) 21 (6-36) § H1N1 140 26 (19-35) 140 24 (17-32) 2 (-12-16) B 140 41 (32-49) 140 27 (20-35) 14 (-1-28) V7P34 H3N2 211 23(18-30) 106 18(11-27) 5 (-8-17) H1N1 211 40 (33-47) 106 30 (22-40) 10 (-6-24) B 211 41 (34-48) 106 25 (17-34) 16 (1-30) § SC = seroconversion or significant increase. # 2-sided 99.17% Bonferroni adjusted CI within each study, for 6 comparisons (3 strains by 2 endpoints). § indicate that if CI does not contain 0, i.e. statistically significant difference. Postvaccination GMTs and seroconversion rates for heterologous strains were observed to be consistently higher for FLUAD® than for AGRIFLU®. The difference was statistically significant for some strains and/or some endpoints (see Table 12). Table 12 : GMT and Seroconversion Response to Heterologous Influenza Strains After One Vaccination a - Study V7P3 - HI assay (PP-Population) FLUAD® N=39 AGRIFLU* N=35 Vaccine Group Comparisons (99.17% CI)# H3N2 GMT (95% CI) % SC (95% CI) 173 (117-256) 79 (64-91) 99 (65-150) 46 (29-63) 1.75 (0.81-3.8) 34 (4-58) § H1N1 GMT (95% CI) % SC (95% CI) 270 (200-365) 74 (58-87) 133 (97-183) 37 (21-55) 2.03 (1.12-3.67) § 37 (7-61) § B GMT (95% CI) 200 (153-261) 105 (79-139) 1.9 (1.12-3.24) § % SC (95% CI) 92 (79-98) 69 (51-83) 24 (0-48) SC= seroconversion or significant increase, i.e., ≥ 4-fold increase in HI titer from a pre-vaccination titer ≥ 1:10 or a rise from < 1:10 to ≥ 1:40 in those who were serum-negative at baseline; a i.e., on day 28. # 2-sided 99.17% Bonferroni adjusted CI within each study, for 6 comparisons (3 strains by 2 endpoints). § indicate statistically significant difference/ratio. Seroprotection GMR and rates for heterologous strains were observed to be consistently higher for FLUAD® than for AGRIFLU* (see Table 13). Table 13 : Seroprotection and GMR Immune Response to Heterologous Influenza Strains After One Vaccinationa - Study V7P3 - HI assay (PP-Population) FLUAD® N=39 AGRIFLU* N=35 H3N2 % SP (95% CI) 100 (91-100) 83 (66-93) GMR (95% CI) 7.86 (5.41-11) 4.08 (2.75-6.06) H1N1 % SP (95% CI) 100 (91-100) 94 (81-99) GMR (95% CI) 5.32 (3.84-7.36) 2.54 (1.8-3.57) B % SP (95% CI) 100 (91-100) 97 (85-100) GMR (95% CI) 9.06 (7.08-12) 3.84 (2.96-4.99) SP= seroprotection, i.e., HI titer ≥ 1:40, GMR= day 28/day 0 geometric mean titer ratio. a i.e., on day 28. Toxicology Nonclinical Toxicology Studies Study type, gender, and species Route and regimena Results Repeat dose toxicity - male and female rabbits Two or three 0.5 mL intramuscular doses of FLUAD® two weeks apart There were no systemic adverse effects, and FLUAD® was well tolerated locally. Delayed contact hypersensitivity - female Guinea pigs Intradermal 0.1 mL and topical 0.5 mL doses of FLUAD® during induction phase, and topical 0.5 mL dose of FLUAD® during challenge phase. FLUAD® was not a skin sensitiser in Guinea pigs in this study. aOn a body weight basis, each dose administered to rabbits was approximately 15 times the human dose FLUAD® has not been evaluated for reproductive and developmental toxicity, carcinogenic or mutagenic potential. REFERENCES 1. Advisory Committee on Immunization Practices (ACIP) 2013. Prevention and Control of Influenza with Vaccines. MMWR 2013; 62 (RR-07): 1-48. 2. Canada Communicable Disease Report (CCDR), November 15, 2001; V.27. 3. Colombo et al., Rev. Epidemiol. Santé Publique 2001 April; 49 (2): 157-16. 4. Glathe H., Lange W. Influenza Vaccination in Older Patients Drugs Aging 1995; 6 (5): 368-387. 5. Gross P.A., Hermogenes A.W., Sacks H.S., et.al. The Efficacy of Influenza Vaccine in Elderly Persons - A Meta-analysis and Review of the Literature. Ann Intern Med .1995; 123 (7): 518-527. 6. FDA Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. CBER, May 2007. 7. Hamdy RC, Micklewright M, Beecham VF, Moore SW. Influenza vaccine may enhance theophylline toxicity. A case report and review of the literature. Journal of the Tennessee Medical Association 1995;88:463-4. 8. Monto S.A. Influenza: Quantifying Morbidity and Mortality. Am J Med Jun 1987; 82 (6A): 20-25. 9. National Advisory Committee on Immunization (NACI). Statement on seasonal trivalent inactivated influenza vaccine (TIV) for 2013-2014. CCDR 2013;39(ACS-4):1-37. 10. Spila-Alegiani et al., Reactogenicity in the elderly of nine commercial influenza vaccines: results from the Italian SVEVA study, Vaccine 17 (1999) 1898-1904. 11. Souto JC, Oliver A, Montserrat I, Mateo J, Sureda A, Fontcuberta J. Influenza immunization is a safe procedure in patients undergoing long-term anticoagulation. Arch Intern Med 1996;156:1589-92.

FLUAD Pediatric™ and FLUAD® (Influenza Virus Vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1) SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients Intramuscular injection Parenteral / Each 0.25 mL dose contains 7.5 ^g of influenza virus haemagglutinin surface antigens from each of the three virus strains, types A and B (see DESCRIPTION) Polysorbate 80 For a complete listing see Dosage Forms, Composition and Packaging Section. Parenteral / Each 0.5 mL dose contains 15 μg of influenza virus haemagglutinin surface antigens from each of the three virus strains, types A and B (see DESCRIPTION) DESCRIPTION FLUAD Pediatric™/FLUAD® is a trivalent, surface antigen, inactivated influenza virus vaccine adjuvanted with MF59C.1. The influenza virus strains are individually grown in the allantoic cavity of embryonated hens' eggs inoculated with a specific type of influenza virus suspension containing kanamycin and neomycin sulphate. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with formaldehyde. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of cetyltrimethylammonium bromide (CTAB), a process which removes most of the internal proteins. The CTAB is removed from the surface antigen preparation. The MF59C.1 adjuvant contained in FLUAD Pediatric™/FLUAD® is an oil-in-water emulsion composed of squalene as the oil phase, stabilised with the surfactants polysorbate 80 and sorbitan trioleate, in citrate buffer. FLUAD Pediatric™/FLUAD® is presented as a sterile, milky-white suspension for intramuscular injection in a prefilled syringe. It has been formulated to contain at least 7.5 mcg HA/0.25 mL dose or 15 mcg HA/0.5 mL dose of each of the following three influenza strains recommended for the 2015/2016 influenza season: A/California/7/2009 (H1N1)pdm09-like virus (A/California/7/2009 NYMC X-181 (H1N1)); A/Switzerland/9715293/2013 (H3N2)-like virus (A/Switzerland/9715293/2013 NIB-88 (H3N2)); and B/Phuket/3073/2013-like virus (B/Brisbane/9/2014), as recommended annually for immunization by the World Health Organisation (WHO) and the National Advisory Committee on Immunization (NACI). Drug Substance Proper name: Purified haemagglutinin (HA) and neuraminidase (NA) surface antigens from each of the three influenza virus strains, types A and B, recommended annually for immunization by the World Health Organisation (WHO) and the National Advisory Committee on Immunization (NACI). Chemical name: As above Product Characteristics FLUAD Pediatric™/FLUAD® is a trivalent, surface antigen, inactivated influenza vaccine adjuvanted with MF59C.1. The influenza virus strains are individually grown in the allantoic cavity of embryonated hens' eggs inoculated with a specific type of influenza virus suspension containing kanamycin and neomycin sulphate. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with formaldehyde. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of cetyltrimethylammonium bromide (CTAB), a process which removes most of the internal proteins. The CTAB is removed from the surface antigen preparation. The MF59C.1 adjuvant contained in FLUAD Pediatric™/FLUAD® is an oil-in-water emulsion composed of squalene as the oil phase, stabilised with the surfactants polysorbate 80 and sorbitan trioleate, in citrate buffer. FLUAD Pediatric™/FLUAD® appears as a sterile, milky-white suspension for intramuscular injection in a prefilled syringe. It has been formulated to contain at least 7.5 mcg HA/0.25 mL dose or 15 mcg HA/0.5 mL dose of each of the following three influenza strains recommended for the 2015/2016 influenza season: A/California/7/2009 (H1N1)pdm09-like virus (A/California/7/2009 NYMC X-181 (H1N1)); A/Switzerland/9715293/2013 (H3N2)-like virus (A/Switzerland/9715293/2013 NIB-88 (H3N2)); and B/Phuket/3073/2013-like virus (B/Brisbane/9/2014), as recommended annually for immunization by the World Health Organisation (WHO) and the National Advisory Committee on Immunization (NACI). FLUAD Pediatric™ is intended for use in the pediatric population of 6 months to less than 2 years of age. It is administered as a 0.25 mL injection. FLUAD® is intended for use in the elderly population of 65 years of age and older and is administered as a 0.5 mL injection. See DOSAGE AND ADMINISTRATION for further information.

INDICATIONS Indications And Clinical Use FLUAD Pediatric™/FLUAD® is an inactivated influenza virus vaccine indicated for active immunization against influenza in the pediatric population (6 months to less than 2 years of age) and the elderly (65 years of age and older) (see Clinical Trials). FLUAD Pediatric™ is intended for use in the pediatric population of 6 months to less than 2 years of age. It is administered as a 0.25 mL injection. FLUAD® is intended for use in the elderly population of 65 years of age and older and is administered as a 0.5 mL injection. See DOSAGE AND ADMINISTRATION for further information. Consistently higher immune responses to tested heterologous (antigenically mismatched) and homologous (antigenically matched) strains were observed for FLUAD Pediatric™/FLUAD® in the pediatric and elderly populations noted above. The difference in antibody responses with FLUAD® administered in the elderly population was statistically significant for some strains and/or some endpoints compared with the comparator. The National Advisory Committee on Immunization (NACI) encourages annual vaccination for all Canadians who have no contraindication (CCDR 2009). The vaccine should be offered to the pediatric and elderly populations up to and even after influenza virus activity is documented in a community. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment Pediatric Population (Children 6 Months To Less Than 2 Years Of Age) Pediatric subjects who are being vaccinated for the first time against seasonal influenza or Pediatric Subjects who were vaccinated for the first time last season with only one dose of influenza vaccine Pediatric subjects who have been previously vaccinated with two doses of any seasonal influenza vaccine in a previous season Infants and children from 6 months to less than 2 years: Two 0.25 mL doses 4 weeks apart. One 0.25 mL dose When FLUAD Pediatric™ is to be given as two doses, it is recommended that the same vaccine and dose is given for both vaccinations. There are no data to support the use of FLUAD Pediatric™ as the first dose, and another influenza vaccine as the second dose. If FLUAD Pediatric™ is not available at the time of the second dose, the clinician should use best judgment to complete the vaccination. As is with other influenza vaccines, children who have received the appropriate course of FLUAD Pediatric™ or another seasonal influenza vaccine are considered to be primed. These children may receive a single age-appropriate dose of influenza vaccine prior to the next influenza season. There are limited data to study the usage of FLUAD Pediatric™ in children in more than 1 influenza season. These data indicate that FLUAD Pediatric™ may be given to children in more than 1 influenza season. Elderly Population (Adults 65 Years Of Age And Older) A single 0.5 mL dose administered once a year. FLUAD® should under no circumstances be administered by any other route than intramuscularly. Administration Gently shake the contents of each syringe to aid inspection for the presence of particulate matter. After shaking, the normal appearance of FLUAD Pediatric™/FLUAD® is a milky-white suspension. If there are visible particles, allow the vaccine to come to room temperature and shake before use (FLUAD Pediatric™/FLUAD® can be kept at room temperature (20º-25ºC) for up to 2 hours as a holding time before injection). Do not use the vaccine if particles remain, if it is discoloured, or if it has been frozen. Before immunization, the skin over the site to be injected should be cleansed with a suitable germicide. FLUAD Pediatric™/FLUAD® should be administered as a single intramuscular injection preferably in the region of the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal region or areas where there may be a major nerve trunk. FLUAD Pediatric™/FLUAD® should under no circumstances be administered by any other route than intramuscularly. Administration With Other Vaccines FLUAD Pediatric™/FLUAD® should not be mixed with other vaccines in the same syringe. Separate injection limbs should be used if more than one vaccine is being administered during the same visit. HOW SUPPLIED Storage And Stability Store FLUAD Pediatric™/FLUAD® between 2°C and 8°C. Do not freeze. Do not use if vaccine has been frozen. Protect from light. Do not use vaccine after expiration date. FLUAD Pediatric™/FLUAD® can be administered following a 2 hour exposure at temperatures between 8° and 25°C. This is not, however, a recommendation for storage. Dosage Forms, Composition And Packaging Dosage Forms FLUAD Pediatric™ is a sterile milky-white suspension for intramuscular injection in 1 mL prefilled syringes containing a 0.25 mL dose. FLUAD® is a sterile milky-white suspension for intramuscular injection in 1 mL prefilled syringes containing a 0.5 mL dose. Composition Active Ingredients: -influenza virus haemagglutinin (HA) and neuraminidase (NA) from each of the following 3 strains: 0.25 mL dose 0.5 mL dose A/California/7/2009 (H1N1)pdm09-like virus (A/California/7/2009 NYMC X-181 (H1N1)) 7.5 μg (HA) 15 μg (HA) A/Switzerland/9715293/2013 (H3N2)-like virus (A/Switzerland/9715293/2013 NIB-88 (H3N2)) 7.5 μg (HA) 15 μg (HA) B/Phuket/3073/2013-like virus (B/Brisbane/9/2014) 7.5 μg (HA) 15 μg (HA) Other Ingredients: Adjuvant: MF59C.1 0.25 mL dose 0.5 mL dose squalene 4.875 mg 9.75 mg polysorbate 80 0.5875 mg 1.175 mg sorbitan trioleate 0.5875 mg 1.175 mg sodium citrate 0.33 mg 0.66 mg citric acid water for injection 0.02 mg 0.04 mg - Excipients: sodium chloride 2.00 mg 4.00 mg potassium chloride 0.05 mg 0.10 mg potassium dihydrogen phosphate 0.05 mg 0.10 mg disodium phosphate dehydrate 0.335 mg 0.67 mg magnesium chloride hexahydrate 0.025 mg 0.05 mg calcium chloride dihydrate water for injection 0.03 mg to volume 0.06 mg to volume − Manufacturing Process Residuals: The vaccine may contain trace amounts of the following: neomycin (trace) kanamycin (trace) ovalbumin (egg protein, residual) formaldehyde (residual) cetyltrimethylammonium bromide (CTAB) (residual) barium (residual) The syringe plunger does not contain latex and FLUAD Pediatric™/FLUAD® is considered safe for use in persons with latex allergies. Packaging FLUAD Pediatric™/FLUAD® is supplied in packages containing one or ten single dose prefilled glass syringes (Type I), without needles. Not all pack sizes may be marketed. Distributed by: Novartis Pharmaceuticals Canada Inc. 385 Bouchard Blvd. Dorval, QC H9S 1A9. Revised: June 9, 2015

PATIENT INFORMATION FLUAD Pediatric™ and FLUAD® (Influenza Virus Vaccine, surface antigen, inactivated, Adjuvanted with MF59C.1) This leaflet is part III of a three-part “Product Monograph” published when FLUAD Pediatric™/FLUAD®was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about FLUAD Pediatric™/FLUAD®. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS VACCINE What the vaccine is used for: FLUAD Pediatric™/FLUAD® is an inactivated influenza virus vaccine against influenza subtypes A and B contained in the vaccine, indicated in children 6 months to less than 2 years of age and adults 65 years of age and older. What it does: FLUAD Pediatric™/FLUAD® provides active immunization of persons 6 months to less than 2 years of age and persons 65 years of age and older against influenza disease, used to prevent people from developing influenza (the flu), or reduce flu symptoms. Like other influenza vaccines FLUADPediatric™/FLUAD® causes the body to produce antibodies against the virus. This means that when your body is exposed to the flu virus, your body is able to defend itself. The antibodies stop the attacking virus. You cannot catch influenza from the vaccine, since it only contains portions of the virus, and not the whole live virus. Your body takes 2 to 3 weeks to produce antibodies after vaccination. Therefore, if you are exposed to influenza immediately before or after your vaccination, you could still develop the illness. The vaccine will not protect you against the common cold, even though some of the symptoms are similar to influenza. Influenza viruses change all the time, so different vaccines are made every year. To stay protected against influenza, you need to be re-vaccinated every year before the winter season. It is particularly important for some groups of people to be vaccinated. These include people with certain medical conditions, elderly people, people who are likely to be exposed to the infection and people on certain medications. If you are in doubt as to whether you should be vaccinated, talk to your local health professionals. FLUAD Pediatric™/FLUAD® follows the World Health Organisation (WHO) and National Advisory Committee on Immunization (NACI) recommendation for vaccination for the northern hemisphere for the 2015/2016 season. When it should not be used: FLUAD Pediatric™/FLUAD® should not be used where there is a history of hypersensitivity to egg proteins or other components of the vaccine, any of the excipients or in people who have had a life-threatening reaction to previous influenza vaccination. (For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph). What the medicinal ingredients are: Influenza virus vaccine (surface antigen, inactivated) subtypes A and B (2015/2016 season). Influenza virus surface antigens (haemagglutinin and neuraminidase), of the following strains: A/California/7/2009 (H1N1)pdm09-like virus (A/California/7/2009 NYMC X-181 (H1N1)); 15 micrograms HA§ for the 0.5 mL dose and 7.5 micrograms for the 0.25 ml dose. A/Switzerland/9715293/2013 (H3N2)-like virus (A/Switzerland/9715293/2013 NIB-88 (H3N2)); 15 micrograms HA§ for the 0.5 mL dose and 7.5 micrograms for the 0.25 ml dose. B/Phuket/3073/2013-like virus (B/Brisbane/9/2014); 15 micrograms HA§ for the 0.5 mL dose and 7.5 micrograms for the 0.25 ml dose. § haemagglutinin This vaccine complies with the WHO recommendations (northern hemisphere) for the 2015/2016 season. What the important nonmedicinal ingredients are: Sodium chloride, Potassium chloride, Potassium dihydrogen phosphate, Disodium phosphate dihydrate, Magnesium chloride hexahydrate, Calcium chloride dihydrate, Squalene, Polysorbate 80, Sorbitan trioleate, Sodium citrate, Citric acid and Water for Injections. May also contain trace amounts of: Neomycin, kanamycin, egg proteins, formaldehyde, or cetyltrimethylammonium bromide (CTAB), barium (residual). For a full listing of nonmedicinal ingredients see Part 1 of the product monograph. What dosage forms it comes in: Each 0.5 mL dose contains 15 micrograms of influenza virus haemagglutinin (HA) and each 0.25 mL dose contains 7.5 micrograms of influenza virus HA from each of the following 3 strains: A/California/7/2009 (H1N1)pdm09-like virus (A/California/7/2009 NYMC X-181 (H1N1)); A/Switzerland/9715293/2013 (H3N2)-like virus (A/Switzerland/9715293/2013 NIB-88 (H3N2)); and B/Phuket/3073/2013-like virus (B/Brisbane/9/2014). Sterile suspension for intramuscular injection provided as one or ten single dose prefilled glass syringes (Type I), without needles. FLUAD Pediatric™/FLUAD® does not contain thimerosal or any other preservative. The syringe plunger does not contain latex and FLUAD® is considered safe for use in persons with latex allergies WARNINGS AND PRECAUTIONS FLUAD* should not be administered to anyone with known allergies to eggs or egg products, or any other constituent of the vaccine or to anyone who has had a life-threatening reaction to previous influenza vaccination. If Guillain-Barré Syndrome (GBS) has occurred within six weeks of previous influenza vaccination, the decision to give FLUAD® should be based on careful consideration of the potential benefits and risks. Immunocompromised patients may have a diminished immune response to FLUAD Pediatric™/FLUAD®. BEFORE you or your child receives FLUAD Pediatric™/FLUAD®, talk to your doctor or pharmacist if: You or your child are/is allergic to eggs or egg-products You or your child are/is allergic to any of the following: kanamycin and neomycin sulphate, formaldehyde, cetyltrimethylammonium bromide, or polysorbate 80 You or your child have/has a fever, or you think you may be getting a fever You or your child had a serious reaction to any flu vaccine in the past You or your child have/has any known allergies You or your child have/has experienced any health problems You are pregnant: ask your doctor for advice You or your child are/is currently on any medication (i.e. immunosuppressant, theophylline, anticoagulants such as warfarin) FLUAD® may be given at the same time as other vaccines. There are no data to assess the concomitant administration of FLUAD Pediatric™ with other vaccines. Do not mix with any other vaccine in the same syringe. As with any vaccine, immunization with FLUAD® may not protect 100% of individuals against influenza disease. Immunosuppressive therapies may reduce immune response to FLUAD Pediatric™/FLUAD®. Use In Specific Populations Safety and effectiveness of FLUAD® has not been established in pregnant women and nursing mothers. Safety and effectiveness in children over 2 years of age and adolescents has not been established. Antibody responses were lower in the geriatric population than in younger adult subjects. INTERACTIONS WITH THIS VACCINE Overview No interaction between FLUAD Pediatric™/FLUAD® and other vaccines or medication is known. Drug-Drug Interactions FLUAD® may be given at the same time as other vaccines. There are no data to assess the concomitant administration of FLUADPediatric™ with other vaccines. FLUAD Pediatric™/FLUAD® should not be mixed with any other vaccine in the same syringe. Immunization should be carried out on separate limbs. It should be noted that the systemic adverse reactions may be intensified. The immunological response may be diminished if the patient is undergoing immunosuppressant treatment. Although a possible interaction has been suggested in the literature between influenza vaccination and the use of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. There were no studies designed to evaluate the drug interactions with FLUAD Pediatric™/FLUAD®. PROPER USE OF THIS VACCINE Usual dose: Children 6 months to < 2 years of age: A single dose of 0.25 mL. Children 6 months to < 2 years of age who have not been previously vaccinated against influenza, should receive a second dose after at least 4 weeks. Adults aged 65 years and over: A single dose of 0.5 mL. Immunization should be carried out by intramuscular injection only. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. Overdose: In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms. No data are available. Missed Dose: Not applicable SIDE EFFECTS AND WHAT TO DO ABOUT THEM Vaccination with FLUAD Pediatric™/FLUAD® (influenza vaccine, surface antigen, inactivated) cannot cause influenza because the vaccine does not contain live virus. Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination. Occasionally people have side effects with influenza vaccines. The most common of these are fever, feeling unwell, shivering, tiredness, headache, sweating, muscle joint pain, and warmth. Skin reactions include redness, swelling, pain, ecchymosis (blue/black staining of the skin) and a hardening of the skin at the injection site and itching. These reactions will normally disappear without treatment in a day or two. Rarely, neuralgia (nerve pain), paresthesia (numbness and tingling), convulsions (seizures), thrombocytopenia (a blood disorder), lymphadenopathy (swelling of the glands in the neck, armpit or groin), muscular weakness, and allergic reactions (this might include but is not limited to breathing or swallowing difficulties, or swelling in the face or skin) have been reported with influenza vaccination. In rare cases, allergic reactions may lead to shock. Very rarely, vasculitis (inflammation of blood vessels) temporarily affecting the kidneys, exudative erythema multiforme (severe skin rash), neurological disorders (affecting the nerves and brain), such as encephalomyelitis, and neuritis, injection-site cellulitis-like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week) and extensive swelling of injected limb lasting more than one week have been reported. The most common ( ≥ 10%) local adverse reactions observed in clinical studies for FLUAD® in the elderly population were injection site pain, induration, swelling, and erythema. The most common ( ≥ 10%) systemic adverse reactions observed in clinical studies for FLUAD® in the elderly population were headache, myalgia, and malaise. The most common ( ≥ 10%) local adverse reactions (after any vaccination) observed in clinical studies for FLUAD Pediatric™ in children 6 months to < 2 years of age were erythema, tenderness, and induration. The most common ( ≥ 10%) systemic adverse reactions (after any vaccination) observed in clinical studies for FLUAD Pediatric™ in children 6 months to < 2 years of age were irritability, fever, vomiting , sleepiness, change in eating habits, diarrhea, and persistent crying. This is not a complete list of side effects. For any unexpected effects while taking FLUAD Pediatric™/FLUAD®, contact your doctor or pharmacist. HOW TO STORE IT This product should be stored at 2°C to 8°C (in a refrigerator), not frozen. The syringe should be kept in the outer carton, thus protecting it from light. FLUAD Pediatric™/FLUAD® can be administered following a 2 hour exposure at temperatures between 8° and 25°C. This is not, however, a recommendation for storage. Do not use vaccine after the expiration date. MORE INFORMATION REPORTING SUSPECTED SIDE EFFECTS To monitor vaccine safety, the Public Health Agency of Canada collects case reports on adverse events following immunization. For health care professionals: If a patient experiences an adverse event following immunization, please complete the appropriate Adverse Events following Immunization (AEFI) Form and send it to your local Health Unit in your province/territory. For the General Public: Should you experience an adverse event following immunization, please ask your doctor, nurse, or pharmacist to complete the Adverse Events following Immunization (AEFI) Form. If you have any questions or have difficulties contacting your local health unit, please contact Vaccine Safety Section at Public Health Agency of Canada : By toll-free telephone: 866-844-0018 By toll-free fax: 866-844-5931 Email: caefi@phac-aspc.gc.ca Web: http://www.phac-aspc.gc.ca/im/vs-sv/index-eng.php Mail: The Public Health Agency of Canada, Vaccine Safety Section, 130 Colonnade Road, A/L 6502A, Ottawa, ON K1A 0K9 NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying the Public Health Agency of Canada. The Public Health Agency of Canada does not provide medical advice This leaflet was prepared by Novartis Vaccines and Diagnostics, S.r.l., Siena, Italy, an affiliate of: Novartis Vaccines and Diagnostics, Inc., 350 Massachusetts Avenue, Cambridge, MA USA 02139 This document plus the full product monograph, prepared for health professionals can be found at: http://www.novartis.ca or by contacting the sponsor, Novartis Vaccines and Diagnostics at 1-800-363-8883

OVERDOSE For management of a suspected drug overdose, contact your regional Poison Control Centre. No data are available. CONTRAINDICATIONS FLUAD Pediatric™/FLUAD® is contraindicated in persons with a known hypersensitivity to the active substances, to any of the excipients and to eggs, chicken proteins, kanamycin and neomycin sulphate, formaldehyde, and cetyltrimethylammonium bromide (CTAB), or in anyone who has had a life-threatening reaction to previous influenza vaccination. For a complete listing of ingredients in the formulation and components of the container, see the Dosage Forms, Composition and Packaging section of the product monograph.

SIDE EFFECTS Adverse Drug Reaction Overview Adverse event information is derived from both controlled and uncontrolled clinical trials and worldwide post-marketing experience. Vaccination with FLUAD Pediatric™/FLUAD® cannot cause influenza because the vaccine does not contain live virus. Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination. Allergic-type responses, such as urticarial rash, allergic bronchospasm, or systemic anaphylaxis occur extremely rarely. The most common local adverse drug reactions in the pediatric population are erythema and tenderness. The incidence of pediatric subjects reporting any solicited systemic reactions was generally slightly higher in the FLUAD Pediatric™ group than in the comparator group (42% vs. 38%). The most common FLUAD® local adverse drug reactions in the elderly are pain at the injection site, temperature at the injection site, and erythema. The incidence of elderly subjects reporting any solicited systemic reactions was generally slightly higher in the FLUAD® group than in the comparator group (17% vs. 12%). Reactions are generally mild or moderate and of limited duration. Prophylactic acetaminophen may decrease the frequency of some side effects in adults. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Children 6 Months To Less Than 2 Years Of Age The safety of FLUAD Pediatric™ was assessed in six randomized clinical trials that involved 4091 infants and children 6 months to less than 2 years of age (FLUAD Pediatric™: 1800; conventional non-adjuvanted trivalent and investigational quadrivalent influenza comparator vaccines: 2083; other non-influenza control vaccines: 208). The most frequently reported solicited local reaction after each vaccination was erythema, followed by tenderness. Most local reactions were mild or moderate, and 1% or fewer subjects experienced severe reactions. The most frequently reported solicited systemic reaction after each vaccination was irritability, followed by sleepiness and body temperature ≥ 38°C. Most systemic reactions were mild or moderate, and < 1% of subjects experienced severe reactions. After the first vaccination with FLUAD Pediatric™, 17% of subjects experienced fever (body temperature ≥ 38°C) compared with 12% to 16% after the first vaccination with the non-adjuvanted influenza comparator. Pooled reactogenicity data are provided in Table 1. Table 1 : Any Solicited Reactions After First and Second Vaccinations in Children 6 Months to < 2 Years of Age Percentages of Subjects with Anya Solicited Reactionb After First Vaccination After Second Vaccination FLUAD Pediatric™ N=1799 Comp. 1 N=1457 Comp. 2 N=622 FLUAD Pediatric™ N=1704 Comp. 1 N=1379 Comp. 2 N=606 Solicited Local Reactions Erythema 19% 17% 13% 21% 17% 11% Tenderness 13% 11% 5% 11% 9% 4% Induration 7% 5% 3% 9% 5% 2% Ecchymosis 5% 5% 4% 5% 5% 2% Swelling 3% 3% 1% 4% 3% < 1% Solicited Systemic Reactionsc Irritability 23% 22% 16% 18% 17% 9% Body Temp. ( > 38C) 17% N=1798 16% 12% 19% 16% 13% Sleepiness 19% 16% 14% 14% 12% 6% Change in eating habits 15% 16% 12% 12% 10% 6% Diarrhea 15% 15% 14% 12% 9% 12% Persistent 11% 11% 10% 7% 6% 5% crying N=829 N=560 N=557 N=809 N=539 N=545 Vomiting 7% 7% 5% 5% 4% 5% a Severe reactions were reported in zero to less than 1% of subjects b N represents the total number of subjects exposed during the observation period (30 minutes to 7 days) post-vaccination c After first vaccination: FLUAD Pediatric™ N = 1800, Comp. 1 N= 1458, and Comp. 2 N = 622. After second vaccination: FLUAD Pediatric™ N = 1704, Comp. 1 N= 1379, and Comp. 2 N = 606 Comp. = Comparator; Comp. 1 = Agrippal, Influsplit, Fluzone and Vaxigrip; Comp. 2 = AGRIFLU* and Quadrivalent vaccine comparator During clinical trials of FLUAD Pediatric™, rhinitis, cough, upper respiratory tract inflammation, and nasopharyngitis were reported as temporally related unsolicited adverse events in both pediatric age groups. In addition, the following unsolicited adverse events of note were reported within 3 weeks of vaccination as at least possibly related: 1 case of febrile convulsion, 13 cases of rash, and 1 case of anaphylactic reaction. Adults 65 Years of Age and Older The safety profile of FLUAD® in adults 65 years and older is based on data from 39 studies. Overall 12,889 subjects were exposed to at least one dose with FLUAD®. Of these 492 received a second consecutive vaccination one year later, and 150 a third FLUAD*vaccine dose the following year. In one study, two doses of FLUAD® were administered 4 weeks apart. In 38 studies solicited local (injection site) and systemic reactions were collected from subjects who completed a symptom diary card for at least four days following vaccination. Safety data after first vaccination for subjects 65 years of age and older were pooled from 31 trials, safety data after second consecutive vaccination were pooled from five studies and after third consecutive vaccination from two studies. Pooled Reactogenicity data are provided in Table 2, Table 3 and Table 4. The most frequently reported solicited local adverse events within 4 days of vaccination were injection site pain, followed by temperature at the injection site (“warm” or “hot”) and erythema. Local injection-site reactions (pain and temperature at the injection site) were more frequent in subjects who received the MF59 adjuvanted vaccine than in those who received nonadjuvanted vaccine. The frequency of pain was 26% in the FLUAD®group vs. 14% in the comparator group. Temperature at the injection site was 18% in the FLUAD® group vs 11% in the comparator group. Solicited local reactions were generally of mild or moderate intensity, and generally resolved within 2-3 days with 3% or less of subjects reporting a severe local reaction. The most frequently reported solicited systemic adverse events were headache, fatigue, malaise and myalgia. Most reports of systemic reactions were mild to moderate in severity and generally transient, with 1% or less of subjects reporting a severe systemic reaction across all studies. In the subset of subjects who received second and third consecutive vaccinations, for both the FLUAD® and the comparator vaccines groups, there was a trend for an increase in the percentage of subjects reporting each local reaction during the 3 days after the second vaccination, compared to the first vaccination, but no further increase after the third vaccination. Overall, systemic reactions were reported by similar percentages of subjects after the first, second, and third vaccinations in both the FLUAD® and comparator vaccines groups. Table 2 : Any (Severea) Local and Systemic Reactions in Elderly Subjects ≥ 65 Years (Days 0-3) After One Vaccination - Pooled Studies Percentages of Subjects with Any (Severea) Solicited Reaction FLUAD® N = 3713 Comparator N = 1656 Subjects with Any Solicited Local Reaction 37% 30% Pain at injection site 26% ( < 1%) 26% ( < 1%) N = 3712 14% ( < 1%) Temperature at injection site 18% (1%) 11% (1%) N = 2265 N = 1438 Ecchymosis 3% ( < 1%) 2% (0) N = 1272 N = 44 Induration 11% (1%) 9% (1%) N = 3712 N = 1655 Erythema 14% (1%) 14% (1%) N = 3712 N = 1655 Swelling 5% (1%) 6% (1%) N = 1447 N = 218 Subjects with Any Solicited Systemic Reaction 17% 12% Chills 3% ( < 1%) 2% ( < 1%) N = 3712 N = 1655 Fatigue 6% ( < 1%) 7% (1%) N = 1493 N = 264 Headache 6% ( < 1%) 5% (1%) N = 3712 N = 1655 Malaise 6% ( < 1%) 5% ( < 1%) N = 3712 N = 1655 Myalgia 7% ( < 1%) 3% ( < 1%) N = 3712 N = 1655 Nausea 2% ( < 1%) 2% ( < 1%) N = 2581 N = 1655 Rash < 1% ( < 1%) < 1% ( < 1%) N = 2230 N = 1365 Sweating 3% (0) 3% ( < 1%) N = 1447 N = 218 Arthralgia 4% ( < 1%) 2% ( < 1%) N = 3666 N = 1609 Fever ( ≥ 38°C/ ≥ 40°C) 1% (0) < 1% (0) N = 3675 N = 1652 a Defined as ecchymosis, erythema, induration, and swelling > 50mm; temperature at injection site “hot”; rash “urticaria” Table 3 : Any (Severea) Local and Systemic Reactions in Elderly Subjects ≥ 65 Years (Days 0-3) Who Received Two Consecutive FLUAD* Vaccinations One Year Apart, by Vaccination Percentages of Subjects with Any (Severea) Solicited Reaction 1st Vaccination 2nd Vaccination FLUAD® N=487 Comparator N=329 FLUAD® N=487 Comparator N=329 Solicited Local Reactions Pain at injection site 19% (1%) 7% (0) 27% (1%) 21% ( < 1%) Temperature at injection site 6% (2%) 4% (1%) 15% (3%) 12% (2%) Induration 9% (1%) 6% (1%) 13% (1%) 10% ( < 1%) Erythema 9% (1%) 6% (0) 23% (2%) 20% (3%) Solicited Systemic Reactions Chills 4% ( < 1%) 4% ( < 1%) 3% (0) 2% (0) Fatigue 15% (0) N=39 0 N=35 0 N=39 3% (0) N=35 Headache 5% ( < 1%) 5% ( < 1%) 8% (0) 5% (0) Malaise 7% ( < 1%) 6% (0) 8% (0) 6% ( < 1%) Myalgia 4% ( < 1%) 2% ( < 1%) 3% (0) 2% (0) Nausea 3% (0) 2% (0) 2% (0) 3% ( < 1%) Rash < 1% ( < 1%) N=306 < 1% (0) N=222 < 1% ( < 1%) < 1% (0) Arthralgia 2% ( < 1%) N=448 1% ( < 1%) N=294 1% (0) 2% (0) Fever ( ≥ 38°C/ ≥ 40°C) 1% (0) 0 1% (0) 1% (0) aSevere defined as: induration, erythema and swelling > 50mm; temperature at injection site “hot”; rash “urticaria” Table 4 : Any (Severea) Solicited Local and Systemic Reaction in Elderly Subjects ≥ 65 Years (Days 0-3) Who Received Three Consecutive FLUAD* Vaccinations One Year Apart, by Vaccination 1st Vaccination 2nd Vaccination 3rd Vaccination FLUAD® N=149 Comp. N=87 FLUAD® N=150 Comp. N=87 FLUAD® N=150 Comp. N=87 Solicited Local Reactions Pain at injection site 28% (1%) 5% (0) 29% (1%) 15% (0) 28% (1%) 16% (0) Temperature at injection site 4% (1%) 5% (0) 7% (1%) 2% (1%) 12% (1%) 7% (0) Induration 8% (0) 5% (0) 12% (1%) 6% (0) 13% (1%) 6% (0) Erythema 9% (0) 6% (0) 14% (1%) 7% (1%) 22% (3%) 9% (0) Solicited Systemic Reactions Chills 4% (0) 6% (1%) 1% (0) 2% (0) 3% (0) 0 Fatigue 17% (0) 0 0 (N=35) 3%(N=32) #NAME? #NAME? Headache 4% (0) 2% (0) 8% (0) 5% (0) 4% (1%) 3% (0) Malaise 7% (0) 3% (0) 5% (0) 3% (0) 7% (0) 3% (0) Myalgia 3% (0) 1% (1%) 5% (0) 2% (0) 1% (0) 2% (0) Nausea 2% (0) 0 3% (0) 2% (0) 3% (0) 2% (0) Rash - (N=0) - (N=0) 0 (N=115) 0 (N=55) 0 0 Arthralgia 2% (0) 2% (2%) 1% (0) 3% (0) 1% (0) 3% (0) Fever ( ≥ 38°C/ ≥ 40°C) 0 0 1% (0) 0 1% (0) 0 aSevere defined as: induration, erythema and swelling > 50mm; temperature at injection site “hot”; rash “urticaria”; Comp.= comparator vaccine Post-Market Adverse Drug Reactions FLUAD® was first licensed in Italy in 1997. The authorization was extended to other European Union countries through a Mutual Recognition Procedure that concluded in 2000 and currently FLUAD® is registered for marketing authorization in many countries worldwide. The initial formulation contained the preservative thimerosal, and thimerosal was also used in the manufacturing process. Since 2003 FLUAD® has been thimerosal-free (see Pharmaceutical Information section). The post-marketing experience with FLUAD® in the elderly is extensive. Because post-marketing reporting is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. The adverse events described below have been included because: a) they represent reactions that are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) of the frequency of reporting. The following additional adverse reactions have been the subject of spontaneous reports during post-approval use of FLUAD® since 2003. General Disorders And Administration Site Conditions Local injection site reactions including redness, swelling, pain at the injection site, ecchymosis, induration. Injection-site cellulitis-like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week). Extensive swelling of injected limb lasting more than one week. Immune System Disorders Allergic reactions in rare cases leading to shock, angioedema. Vascular Disorders Vasculitis (in rare cases associated with transient renal involvement), exudative erythema multiforme. Blood and Lymphatic System Disorders Thrombocytopenia (including very rare severe cases, < 0.01%, with platelet counts less than 5,000 per mm³), lymphadenopathy. Musculoskeletal And Connective Tissue Disorders Muscular weakness Nervous System Disorders Neuralgia, paraesthesia, convulsion, myelitis (including encephalomyelitis and transverse myelitis), neuritis and Guillain-Barré Syndrome. Skin And Subcutaneous Tissue Disorders Generalized skin reactions including pruritus, urticaria, and non-specific rash. There is no post-marketing experience with FLUAD Pediatric™ in infants and children. DRUG INTERACTIONS Overview No interaction between FLUAD Pediatric™/FLUAD® and other vaccines or medication are known. Drug-Drug Interactions FLUAD® may be given at the same time as other vaccines. There are no data to assess the concomitant administration of FLUAD Pediatric™ with other vaccines. FLUAD Pediatric™/FLUAD® should not be mixed with any other vaccine in the same syringe. Immunization should be carried out on separate limbs. It should be noted that any adverse reactions may be intensified. Although a possible interaction has been suggested in the literature between influenza vaccination and the use of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. There were no studies designed to evaluate the drug interactions with FLUAD Pediatric™/FLUAD®. The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General FLUAD Pediatric™/FLUAD® should under no circumstances be administered by any other route than intramuscularly. Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. Prior to administration of any dose of FLUAD Pediatric™/FLUAD®, the vaccine recipient should be asked about personal medical history, family medical history, recent and current health status, including immunization history, main allergies and any adverse events associated with previous immunizations. Before the injection of any biological product, such as vaccines, the person responsible for administration should take all precautions known for the prevention of allergic or any other reactions. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event occurs following administration of the vaccine. Immunization with FLUAD Pediatric™/FLUAD® should be postponed in patients with febrile illness or acute infections. Hematologic As with other intramuscular injections, administration of FLUAD Pediatric™/FLUAD® requires careful consideration in patients with clinically significant bleeding disorders. Immune The immune response to FLUAD Pediatric™/FLUAD® in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. Neurologic If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD Pediatric™/FLUAD® should be based on careful consideration of the potential benefits and risks. Monitoring And Laboratory Tests Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, hepatitis C and, especially HTLV1 have been observed. The Western Blot technique disproves the results. The transient false positive reactions could be due to the IgM response by the vaccine.