Influenza Vaccine STN BL 125254 Package insert -...

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Influenza Vaccine STN BL 125254

CSL Limited – Confidential 1 Version 47.1

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AFLURIA safely and effectively. See full prescribing information for AFLURIA. AFLURIA, Influenza Vaccine Suspension for Intramuscular Injection 2016-2017 Formula Initial U.S. Approval: 2007 ----------------------------INDICATIONS AND USAGE----------------------------- • AFLURIA is an inactivated influenza vaccine indicated for active

immunization against influenza disease caused by influenza virus subtypes A and type B present in the vaccine. (1)

• AFLURIA is approved for use in persons 5 years of age and older. (1) -------------------------DOSAGE AND ADMINISTRATION---------------------- For intramuscular (IM) injection only, by needle and syringe (5 years of age and older) or by PharmaJet® Stratis® Needle-Free Injection System (18 through 64 years of age). A single dose is 0.5 mL. (2)

Age Schedule 5 years through

8 years One dose or two doses at least 1 month aparta

9 years and older One dose 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. (2) ------------------------DOSAGE FORMS AND STRENGTHS--------------------- AFLURIA is a suspension for injection supplied in two presentations: • 0.5 mL pre-filled syringe (single dose) (3, 11) • 5 mL multi-dose vial (ten 0.5 mL doses) (3, 11)

-------------------------------CONTRAINDICATIONS------------------------------- • Severe allergic reaction (e.g., anaphylaxis) to any component of the

vaccine including egg protein, or to a previous dose of any influenza vaccine. (4, 11)

------------------------WARNINGS AND PRECAUTIONS------------------------- • Administration of CSL’s 2010 Southern Hemisphere influenza vaccine

was associated with increased rates of fever and febrile seizures in children predominantly below the age of 5 years as compared to previous years. Febrile events were also observed in children 5 through 8 years of age. (5.1)

• If Guillain-Barré Syndrome (GBS) has occurred within 6 weeks of previous influenza vaccination, the decision to give AFLURIA should be based on careful consideration of the potential benefits and risks. (5.2)

• Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. (5.3)

• Immunocompromised persons may have a diminished immune response to AFLURIA. (5.4)

------------------------------ADVERSE REACTIONS---------------------------- • In children 5 through 17 years of age, the most common injection-site

adverse reactions when administered by needle and syringe were pain (≥60%), redness (≥20%) and swelling (≥10%). The most common systemic adverse events were headache, myalgia (≥20%), irritability, malaise and fever (≥10%). (6.1)

• In adults 18 through 64 years of age, the most common injection-site adverse reactions when administered by needle and syringe were tenderness (≥60%), pain (≥40%), swelling (≥20%), and redness, itching (≥10%). The most common systemic adverse events were muscle aches (≥30%) and headache, malaise (≥20%). (6.1)

• In adults 18 through 64 years of age, the most common injection-site adverse reactions when administered by the PharmaJet Stratis Needle-Free Injection System up to 7 days post-vaccination were tenderness (≥80%), swelling, pain, redness (≥60%), itching (≥20%) and bruising (≥10%). The most common systemic adverse events within this period were myalgia, malaise (≥30%), and headache (≥20%). (6.1)

• In adults 65 years of age and older, when administered by needle and syringe the most common injection-site adverse reactions were tenderness (≥30%) and pain (≥10%). No systemic adverse events occurred in ≥10% of subjects in this age group (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Seqirus USA Inc. at 1-844-275-2461 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. -----------------------USE IN SPECIFIC POPULATIONS--------------------- • AFLURIA is not approved for use in children less than 5 years of age

because of increased rates of fever and febrile seizures. One comparator-controlled trial demonstrated higher rates of fever in recipients of AFLURIA as compared to a trivalent inactivated influenza vaccine control. (8.4)

• Antibody responses were lower in geriatric subjects than in younger subjects. (8.5)

See 17 for PATIENT COUNSELING INFORMATION. Revised: 04/2016

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FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Fever and Febrile Seizures 5.2 Guillain-Barré Syndrome 5.3 Preventing and Managing Allergic Reactions 5.4 Altered Immunocompetence 5.5 Limitations of Vaccine Effectiveness

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Adverse Reactions Associated With Influenza

Vaccination 7 DRUG INTERACTIONS

7.1 Concurrent Use With Other Vaccines

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES

14.1 Efficacy Against Laboratory-Confirmed Influenza 14.2 Immunogenicity in Children - Administration via Needle

and Syringe 14.3 Immunogenicity in Adults and Older Adults -

Administration via Needle and Syringe 14.4 Immunogenicity in Adults - Administration via PharmaJet

Stratis Needle-Free Injection System 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied 16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed

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FULL PRESCRIBING INFORMATION 1 2 3 1 INDICATIONS AND USAGE 4 5 AFLURIA® is an inactivated influenza vaccine indicated for active immunization against 6 influenza disease caused by influenza virus subtypes A and type B present in the vaccine. 7 AFLURIA is approved for use in persons 5 years of age and older. 8 9 10 2 DOSAGE AND ADMINISTRATION 11 12 For intramuscular (IM) injection only, by needle and syringe (5 years of age and older) or by 13 PharmaJet® Stratis® Needle-Free Injection System (18 through 64 years of age). A single dose 14 is 0.5 mL. 15 16 The dose and schedule for AFLURIA are presented in Table 1. 17

Table 1: AFLURIA Schedule 18

Age Schedule 5 years through

8 years One dose or two doses at least 1 month apart a

9 years and older One dose a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations 19

on prevention and control of influenza with vaccines. 20 21 Shake thoroughly and inspect visually before use. Parenteral drug products should be 22 inspected visually for particulate matter and discoloration prior to administration, whenever 23 suspension and container permit. If either of these conditions exists, the vaccine should not be 24 administered. 25 26 May be administered by needle and syringe (5 years of age and older) or PharmaJet Stratis 27 Needle-Free Injection System (18 through 64 years of age only). 28 29 When using the single-dose pre-filled syringe, shake the syringe thoroughly and administer the 30 dose immediately. 31 32 When using the multi-dose vial, shake the vial thoroughly before withdrawing each dose, and 33 administer the dose immediately. 34 • Needle and Syringe: Draw up the exact dose using a separate sterile needle and syringe for 35

each individual patient. It is recommended that small syringes (0.5 mL or 1 mL) be used to 36 minimize any product loss. 37

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• PharmaJet Stratis Needle-Free Injection System: For instructions on withdrawal of a 0.5 38 mL dose and use of the PharmaJet Stratis Needle-Free Injection System, refer to the 39 Instructions For Use for the PharmaJet Stratis Needle-Free Injection System. 40

41 The preferred site for intramuscular injection is the deltoid muscle of the upper arm. 42 43 Between uses, return the multi-dose vial to the recommended storage conditions between 44 2-8°C (36−46°F). Do not freeze. Discard if the vaccine has been frozen. 45 46 47 3 DOSAGE FORMS AND STRENGTHS 48 49 AFLURIA is a sterile suspension for intramuscular injection (see Description [11]). 50 51 AFLURIA is supplied in two presentations: 52 53

• 0.5 mL pre-filled syringe (single dose). 54 • 5 mL multi-dose vial (ten 0.5 mL doses). 55

56 57 4 CONTRAINDICATIONS 58 59 AFLURIA is contraindicated in individuals with known severe allergic reactions (e.g., 60 anaphylaxis) to any component of the vaccine including egg protein, or to a previous dose of 61 any influenza vaccine (see Description [11]). 62 63 64 5 WARNINGS AND PRECAUTIONS 65 66 5.1 Fever and Febrile Seizures 67 Administration of CSL’s 2010 Southern Hemisphere influenza vaccine was associated with 68 postmarketing reports of increased rates of fever and febrile seizures in children predominantly 69 below the age of 5 years as compared to previous years; these increased rates were confirmed 70 by postmarketing studies. Febrile events were also observed in children 5 through 8 years of 71 age. 72 73 5.2 Guillain-Barré Syndrome 74 If Guillain-Barré Syndrome (GBS) has occurred within 6 weeks of previous influenza 75 vaccination, the decision to give AFLURIA should be based on careful consideration of the 76 potential benefits and risks. 77 78 The 1976 swine influenza vaccine was associated with an increased frequency of GBS. 79

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Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza 80 viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than one 81 additional case per 1 million persons vaccinated. 82 83 5.3 Preventing and Managing Allergic Reactions 84 Appropriate medical treatment and supervision must be available to manage possible 85 anaphylactic reactions following administration of the vaccine. 86 87 5.4 Altered Immunocompetence 88 If AFLURIA is administered to immunocompromised persons, including those receiving 89 immunosuppressive therapy, the immune response may be diminished. 90 91 5.5 Limitations of Vaccine Effectiveness 92 Vaccination with AFLURIA may not protect all individuals. 93 94 95 6 ADVERSE REACTIONS 96 97 In children 5 through 17 years of age, the most common injection-site reactions observed in 98 clinical studies with AFLURIA administered by needle and syringe were pain (≥60%), redness 99 (≥20%) and swelling (≥10%). The most common systemic adverse events were headache, 100 myalgia (≥20%), irritability, malaise and fever (≥10%). 101 102 In adults 18 through 64 years of age, the most common injection-site adverse reactions 103 observed in clinical studies with AFLURIA administered by needle and syringe were 104 tenderness (≥60%), pain (≥40%), swelling (≥20%), redness and itching (≥10%). The most 105 common systemic adverse events observed were muscle aches (≥30%), headache and malaise 106 (≥20%). 107 108 In adults 18 through 64 years of age, using the PharmaJet Stratis Needle-Free Injection System, 109 the most common injection-site adverse reactions observed in a clinical study with AFLURIA 110 up to 7 days post-vaccination were tenderness (≥80%), swelling, pain, redness (≥60%), itching 111 (≥20%) and bruising (≥10%). The most common systemic adverse events within this period 112 were myalgia, malaise (≥30%) and headache (≥20%). 113 114 In adults 65 years of age and older, the most common injection-site adverse reactions observed 115 in clinical studies with AFLURIA administered by needle and syringe were tenderness (≥30%) 116 and pain (≥10%). No systemic adverse reactions occurred in ≥10% of subjects in this age 117 group. 118 119

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6.1 Clinical Trials Experience 120 Because clinical studies are conducted under widely varying conditions, adverse reaction rates 121 observed in the clinical studies of a vaccine cannot be directly compared to rates in the clinical 122 studies of another vaccine and may not reflect the rates observed in clinical practice. 123 124 Children 125 In clinical studies, AFLURIA has been administered to, and safety information collected for, 126 3,009 children ages 6 months through 17 years. The exposure in children includes 1,601 aged 127 6 months to less than 5 years, 756 children ages 5 years to less than 9 years and 652 children 128 ages 9 years through 17 years. Clinical safety data for AFLURIA in children are presented 129 from three clinical studies (Studies 1, 2 and 3). Data from a comparator-controlled trial (Study 130 1) are presented, followed by pooled data from two open label studies (Studies 2 and 3). 131 Subjects 6 months through 8 years of age received one or two vaccinations, administered by 132 needle and syringe, as determined by previous vaccination history (for further details on clinical 133 study design, dosing and demographics see Clinical Studies [14]). 134 135 Study 1 included 1,468 subjects for safety analysis, ages 6 months through 17 years, 136 randomized to receive AFLURIA (735 subjects) or another U.S.-licensed trivalent inactivated 137 influenza vaccine (manufactured by Sanofi Pasteur, Inc.) (733 subjects). 138 139 Study 2 included 1,976 subjects for safety analysis, ages 6 months through 17 years. All 140 subjects received AFLURIA. 141 142 Study 3 included 298 subjects for safety analysis, ages 6 months through 8 years. All subjects 143 received AFLURIA. 144 145 The safety assessment was similar for the three pediatric studies. Local (injection site) adverse 146 reactions and systemic adverse events were solicited for 7 days post-vaccination (Tables 2 and 147 3). Unsolicited adverse events were collected for 30 days post-vaccination. All adverse events 148 are presented regardless of any treatment causality assigned by study investigators. 149 150 Among the pediatric studies, there were no vaccine-related deaths or vaccine-related serious 151 adverse events reported in children 5 years of age and older. 152 153 In this section, safety data from the pediatric studies are limited to children 5 years of age and 154 older. AFLURIA is not approved for use in children less than 5 years of age. See Warnings 155 and Precautions [5.1] and Use in Specific Populations [8.4] for risks of AFLURIA in children 156 less than 5 years of age. 157 158 In the comparator-controlled trial (Study 1), the rate of fever after the first dose of AFLURIA 159 in subjects aged 5 through 8 years was 16% as compared to 8% in subjects who received the 160 comparator. The rate of fever in subjects aged 9 through 17 years following a single dose of 161

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AFLURIA was 6% as compared to 4% in subjects who received the comparator. In all three 162 pediatric studies, the rates of fever in subjects aged 5 through 8 years who received AFLURIA 163 were lower after dose 2 than dose 1. 164 165 Data in Tables 2 and 3 are presented for children 5 years and older. 166 167 Table 2: Proportion of Subjects 5 through 17 Years of Age with Solicited Local Adverse 168

Reactions or Systemic Adverse Events within 7 Days after Administration of 169 First or Second Dose of AFLURIA, Irrespective of Causality (Study 1) 170

171 Percentage a of Subjects in each Age Group Reporting Event

Subjects 5 through 8 years Subjects 9 through 17 years AFLURIA

N=161 b Comparator

N=165 b AFLURIA

N=254 b Comparator

N=250 b After the First Dose Local Adverse Reactions Pain 63 60 66 60 Redness 23 27 17 17 Induration 17 17 15 16 Systemic Adverse Events Myalgia 34 30 40 37 Malaise 24 13 22 20 Headache 21 19 27 26 Any Fever

Fever ≥102.2°F 16 5

8 1

6 3

4 1

Nausea/Vomiting 12 8 9 10 Diarrhea 7 7 8 10

AFLURIA N=39 b

Comparator N=53 b

After the Second Dose Local Adverse Reactions Pain 36 38 - - Redness 10 19 - - Induration 8 17 - - Systemic Adverse Events Diarrhea 13 6 - - Headache 13 13 - - Myalgia 13 17 - - Malaise 5 8 - - Nausea/Vomiting 3 8 - - Any Fever

Fever ≥102.2°F 0 0

2 0

- -

- -

a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on 172 the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). 173

b N = number of subjects in the Safety Population for each treatment group. 174 175

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Table 3: Proportion of Subjects 5 through 17 Years of Age with Solicited Local Adverse 176 Reactions or Systemic Adverse Events Within 7 Days after Administration of 177 AFLURIA, Irrespective of Causality (Studies 2 and 3) 178

179

Percentage a of Subjects in each Age Group Reporting Event

Studies 2 and 3 Subjects 5 through 8 years

Study 2 Subjects 9 through 17 years

Dose 1 N=82-595 b

Dose 2 N=82-426 b

Dose 1 N=397 b

Local Adverse Reactions Pain 61 56 68 Erythema 24 23 17 Swelling 17 17 13

Systemic Adverse Events Irritability d 18 16 - Headache 16 10 27 Malaise or feeling generally unwell c 16 8 17

Any Fever Fever ≥ 102.2°F

13 3

6 2

5 1

General Muscle Ache (Myalgia) 12 8 20

Nausea/Vomiting c 7 3 5 Vomiting/Diarrhea d 5 6 - Loss of appetite d 5 4 - Diarrhea c 4 2 5 a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on 180

the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). 181 b N = number of subjects in the Safety Population for each treatment group. Denominators for Dose 1 were: N=82 for 182

Vomiting/Diarrhea, Irritability, Loss of appetite, N=513 for Malaise, Diarrhea, Nausea/Vomiting and N=593-595 for all 183 other parameters. Denominators for Dose 2 were: N=82 for Vomiting/Diarrhea, Irritability, Loss of appetite, N=344 for 184 Malaise, Diarrhea and Nausea/Vomiting and N=421-426 for all other parameters. 185

c These preferred terms were used to describe Solicited Adverse Events in Study 2. 186 d These preferred terms were used to describe Solicited Adverse Events in Study 3. 187 188 In Study 1, unsolicited adverse events that occurred in ≥ 5% of subjects who received 189 AFLURIA in ages 5 years through 8 years following the first or second dose included cough 190 (15%) and pyrexia (9%). Unsolicited adverse events that occurred in ≥ 5% of subjects who 191 received AFLURIA in ages 9 years through 17 years following the first dose included cough 192 (7%), oropharyngeal pain (7%), headache (7%) and nasal congestion (6%). 193 194 In Studies 2 and 3, unsolicited adverse events that occurred in ≥ 5% of subjects ages 5 years 195 through 8 years after the first or second dose included the following: upper respiratory tract 196

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infection (13%), cough (10%), rhinorrhea (7%), headache (5%), nasopharyngitis (5%) and 197 pyrexia (5%). Unsolicited adverse events that occurred in ≥ 5% of subjects who received 198 AFLURIA in ages 9 years through 17 years following the first dose included upper respiratory 199 tract infection (9%) and headache (8%). 200 201 Adults 202 In clinical studies comparing AFLURIA to placebo or a comparator trivalent inactivated 203 influenza vaccine, a single dose of AFLURIA was administered to, and safety information 204 collected for, 11,104 subjects ages 18 through 64 years and 836 subjects ages 65 years and 205 older. Clinical safety data for AFLURIA in adults are presented from three clinical studies 206 (Studies 4 through 6) conducted in the US and one clinical study (Study 7) conducted in the 207 UK 208 209 Study 4 included 1,357 subjects for safety analysis, ages 18 through 64 years, randomized to 210 receive AFLURIA (1,089 subjects) or placebo (268 subjects) (see Clinical Studies [14]). 211 212 Study 5 included 15,020 subjects for safety analysis, ages 18 through 64 years, randomized to 213 receive AFLURIA (10,015 subjects) or placebo (5,005 subjects) (see Clinical Studies [14]). 214 215 Study 6 included 1,266 subjects for safety analysis, ages 65 years and older, randomized to 216 receive AFLURIA (630 subjects) or another U.S.-licensed trivalent inactivated influenza 217 vaccine (manufactured by Sanofi Pasteur Inc.) as an active comparator (636 subjects) (see 218 Clinical Studies [14]). Study 7 included 275 subjects for safety analysis, ages 65 years and 219 older, randomized to receive AFLURIA (206 subjects) or a UK-licensed trivalent inactivated 220 influenza vaccine (manufactured by GSK) as an active comparator (69 subjects). 221 222 The safety assessment was identical for the four adult studies. Local (injection-site) adverse 223 reactions and systemic adverse events were solicited for 5 days post-vaccination (Table 4, 224 studies 4 through 6). Unsolicited adverse events were collected for 21 days post-vaccination. 225 All adverse events are presented regardless of any treatment causality assigned by study 226 investigators. 227 228 Among adult studies, there were no vaccine-related deaths or vaccine-related serious adverse 229 events reported. 230 231

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Table 4: Proportion of Subjects 18 Years of Age and Older with Solicited Local Adverse 232 Reactions or Systemic Adverse Events within 5 Days after Administration of 233 AFLURIA or Placebo, Irrespective of Causality (Studies 4, 5 and 6) 234

235 Percentage a of Subjects in each Age Group Reporting Event

Study 4 Subjects 18 through 64

years

Study 5 Subjects 18 through 64

years

Study 6 Subjects ≥ 65 years

AFLURIA N=1087-1088 b

Placebo

N=266 b AFLURIA N=10,015 b

Placebo

N=5005 b AFLURIA

N=630 b Comparator

N=636 b Local Adverse Reactions Tenderness (Pain on touching) 60 18 69 17 36 31

Pain (without touching) 40 9 48 11 15 14 Redness 16 8 4 <1 3 1 Swelling 9 1 4 <1 7 8 Bruising 5 1 1 1 <1 1 Systemic Adverse Events Headache 26 26 25 23 9 11 Malaise 19 19 29 26 7 6 Muscle aches 13 9 21 12 9 8 Nausea 6 9 7 6 2 1 Chills/Shivering 3 2 5 4 2 2 Fever 1 1 3 2 <1 1

a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by treatment group based on 236 the number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). 237

b N = number of subjects in the Safety Population for each treatment group. 238 239 In Study 4, headache was the only unsolicited adverse event that occurred in ≥ 5% of subjects 240 who received AFLURIA or placebo (8% versus 6%, respectively). 241 242 In Study 5, unsolicited adverse events that occurred in ≥ 5% of subjects who received 243 AFLURIA or placebo included headache (AFLURIA 12%, placebo 11%) and oropharyngeal 244 pain (AFLURIA 5%, placebo 5%). 245 246 In Study 6, headache was the only unsolicited adverse event that occurred in ≥ 5% of subjects 247 who received AFLURIA (5%). 248 249 Studies 1 to 7 were all conducted when AFLURIA was administered by needle and syringe. 250 251 Additionally, safety information has been collected in a clinical study of AFLURIA 252 administered using the PharmaJet Stratis Needle-Free Injection System (Study 8). Study 8 253 included 1,247 subjects for safety analysis, ages 18 through 64 years, randomized to receive 254 AFLURIA by either the PharmaJet Stratis Needle-Free Injection System (624 subjects) or 255

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needle and syringe (623 subjects). No deaths or vaccine-related serious adverse events were 256 reported in Study 8. Local (injection-site) adverse reactions and systemic adverse events were 257 solicited for 7 days post-vaccination (Table 5). 258 259 Table 5: Proportion of Subjects 18 through 64 Years of Age with Solicited Local Adverse 260

Reactions or Systemic Adverse Events within 7 Days after Administration of 261 AFLURIA by PharmaJet Stratis Needle-Free Injection System or Needle and 262 Syringe Irrespective of Causality (Study 8). 263

264 Percentage a of Subjects Reporting Event

Study 8 Subjects 18 through 64 years

AFLURIA PharmaJet Stratis Needle-

Free Injection System N=540-616 b

Needle and Syringe N=599-606 b

Local Adverse Reactions Tenderness 89 78 Swelling 65 20 Pain 64 49 Redness 60 19 Itching c 28 10 Bruising 18 5 Systemic Adverse Events Myalgia 36 36 Malaise 31 28 Headache 25 22 Chills 7 7 Nausea 7 7 Vomiting 1 2 Fever 0 0

a Proportion of subjects reporting each local adverse reaction or systemic adverse event by treatment group based on the 265 number of subjects contributing at least one data value for an individual sign/symptom (individual event denominators). 266

b N = number of subjects in the Safety Population for each treatment group. Denominators for the PharmaJet Stratis Needle-267 Free Injection System group were: N=540 for itching and N=605-616 for all other parameters. Denominators for the needle 268 and syringe group were: N=527 for itching and N=599-606 for all other parameters. 269

c A total of 155 subjects (approximately randomly distributed between PharmaJet Stratis Needle-Free Injection System and 270 needle and syringe groups) received Diary Cards without itching listed as a solicited symptom. 271

272 In Study 8, no unsolicited adverse events occurred in ≥ 5% of subjects who received 273 AFLURIA administered via PharmaJet Stratis Needle-Free Injection System up to 28 days 274 post-vaccination. 275 276 277

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6.2 Postmarketing Experience 278 Because postmarketing reporting of adverse reactions is voluntary and from a population of 279 uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 280 relationship to vaccine exposure. The adverse reactions described have been included in this 281 section because they: 1) represent reactions that are known to occur following immunizations 282 generally or influenza immunizations specifically; 2) are potentially serious; or 3) have been 283 reported frequently. These adverse reactions reflect experience in both children and adults and 284 include those identified during post-approval use of AFLURIA outside the US since 1985. 285 286 Blood and lymphatic system disorders 287 Thrombocytopenia 288 289 Immune system disorders 290 Allergic or immediate hypersensitivity reactions including anaphylactic shock and serum 291 sickness 292 293 Nervous system disorders 294 Neuralgia, paresthesia, convulsions (including febrile seizures), encephalomyelitis, 295 encephalopathy, neuritis or neuropathy, transverse myelitis, and GBS 296 297 Vascular disorders 298 Vasculitis which may be associated with transient renal involvement 299 300 Skin and subcutaneous tissue disorders 301 Pruritus, urticaria, and rash 302 303 General disorders and administration site conditions 304 Cellulitis and large injection site swelling 305 Influenza-like illness 306 307 6.3 Adverse Reactions Associated With Influenza Vaccination 308 Anaphylaxis has been reported after administration of AFLURIA. Egg protein can induce 309 immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic 310 reactions include hives, angioedema, asthma, and systemic anaphylaxis (see Contraindications 311 [4]). 312 313 Neurological disorders temporally associated with influenza vaccination, such as 314 encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus 315 neuropathy, have been reported. 316 317 Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza 318 vaccination. 319

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320 321 7 DRUG INTERACTIONS 322 323 7.1 Concurrent Use With Other Vaccines 324 There are no data to assess the concomitant administration of AFLURIA with other vaccines. 325 If AFLURIA is given at the same time as another injectable vaccine(s), the vaccine(s) should 326 be administered in separate syringes and a separate arm should be used. 327 328 AFLURIA should not be mixed with any other vaccine in the same syringe or vial. 329 330 331 8 USE IN SPECIFIC POPULATIONS 332 333 8.1 Pregnancy 334 Pregnancy Category B: A reproductive and developmental toxicity study has been performed 335 in female rats at a dose approximately 265 times the human dose (on a mg/kg basis) and 336 revealed no evidence of impaired female fertility or harm to the fetus due to AFLURIA. There 337 are, however, no adequate and well-controlled studies in pregnant women. Because animal 338 reproduction studies are not always predictive of human response, AFLURIA should be given 339 to a pregnant woman only if clearly needed. 340 341 In the reproductive and developmental toxicity study, the effect of AFLURIA on embryo-fetal 342 and pre-weaning development was evaluated in pregnant rats. Animals were administered 343 AFLURIA by intramuscular injection twice prior to gestation, once during the period of 344 organogenesis (gestation day 6), and once later in pregnancy (gestation day 20), 0.5 345 mL/rat/occasion (approximately a 265-fold excess relative to the projected human dose on a 346 body weight basis). No adverse effects on mating, female fertility, pregnancy, parturition, 347 lactation parameters, and embryo-fetal or pre-weaning development were observed. There 348 were no vaccine-related fetal malformations or other evidence of teratogenesis. 349 350 Pregnancy exposure and safety surveillance 351 An exposure and surveillance study which monitors pregnancy outcomes in women exposed to 352 AFLURIA during pregnancy has been established. Women who are vaccinated with 353 AFLURIA during pregnancy should be encouraged to contact the pregnancy study center by 354 calling 1-877-311-8972 or visit the website http://www.pregnancystudies.org. 355 356 8.3 Nursing Mothers 357 AFLURIA has not been evaluated in nursing mothers. It is not known whether AFLURIA is 358 excreted in human milk. Because many drugs are excreted in human milk, caution should be 359 exercised when AFLURIA is administered to a nursing woman. 360 361

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8.4 Pediatric Use 362 AFLURIA is not approved for use in children less than 5 years of age. In a clinical study in 363 which children received AFLURIA or a US-licensed comparator vaccine (Study 1, see Clinical 364 Trials Experience, [6.1]), the incidence of fever in children 6 months through 35 months of age 365 following the first and second doses of AFLURIA were 37% and 15%, respectively, as 366 compared to 14% following each dose in the comparator group. Among children 3 years 367 through 4 years of age, the incidence of fever following the first and second doses of 368 AFLURIA were 32% and 14%, respectively, as compared to 11% and 16% in the comparator. 369 In an open-label study (Study 2), fever, irritability, loss of appetite, and vomiting/diarrhea 370 occurred more frequently in children 6 months through 35 months of age as compared to older 371 children. Across three pediatric studies of AFLURIA (Studies 1, 2, and 3), 1.2% of eligible 372 children (n=1,764) were discontinued from the second vaccination because of severe fever 373 (≥ 104ºF) within 48 hours of the first vaccination. Across the three pediatric studies, two 374 children, a 7-month old and a 3-year old, experienced vaccine-related febrile seizures (rate of 375 0.07% across studies), one of which was serious. 376 377 Administration of CSL’s 2010 Southern Hemisphere influenza vaccine was associated with 378 increased rates of fever and febrile seizures, predominantly in children below the age of 5 years 379 as compared to previous years, in postmarketing reports confirmed by postmarketing studies 380 (see Warnings and Precautions [5.1]). 381 382 The PharmaJet Stratis Needle-Free Injection System is not approved as a method of 383 administering AFLURIA to children and adolescents less than 18 years of age due to lack of 384 adequate data supporting safety and effectiveness in this population. 385 386 8.5 Geriatric Use 387 In clinical studies, AFLURIA has been administered to, and safety information collected for, 388 836 subjects ages 65 years and older (see Clinical Trials Experience [6.1]). After 389 administration of AFLURIA, hemagglutination-inhibiting antibody responses in persons 65 390 years of age and older were lower as compared to younger adult subjects (see Clinical Studies 391 [14]). 392 393 The PharmaJet Stratis Needle-Free Injection System is not approved as a method of 394 administering AFLURIA to adults 65 years of age and older due to lack of adequate data 395 supporting safety and effectiveness in this population. 396 397 398 11 DESCRIPTION 399 400 AFLURIA, Influenza Vaccine for intramuscular injection, is a sterile, clear, colorless to 401 slightly opalescent suspension with some sediment that resuspends upon shaking to form a 402 homogeneous suspension. AFLURIA is prepared from influenza virus propagated in the 403

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allantoic fluid of embryonated chicken eggs. Following harvest, the virus is purified in a 404 sucrose density gradient using continuous flow zonal centrifugation. The purified virus is 405 inactivated with beta-propiolactone, and the virus particles are disrupted using sodium 406 taurodeoxycholate to produce a “split virion”. The disrupted virus is further purified and 407 suspended in a phosphate buffered isotonic solution. 408 409 AFLURIA is standardized according to USPHS requirements for the 2016-2017 influenza 410 season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5 mL dose in the 411 recommended ratio of 15 mcg HA for each of the three influenza strains recommended for the 412 2016-2017 Northern Hemisphere influenza season: A/California/7/2009 (H1N1), NYMC X-413 181, A/Hong Kong/4801/2014 (H3N2), NYMC X-263B, and B/Brisbane/60/2008. 414 415 Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose 416 presentations; therefore these products contain no preservative. The multi-dose presentation 417 contains thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury. 418 419 A single 0.5 mL dose of AFLURIA contains sodium chloride (4.1 mg), monobasic sodium 420 phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate 421 (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). From the 422 manufacturing process, each 0.5 mL dose may also contain residual amounts of sodium 423 taurodeoxycholate (≤ 10 ppm), ovalbumin (< 1 mcg), sucrose (< 10 mcg), neomycin sulfate 424 (≤ 3 nanograms [ng]), polymyxin B (≤ 0.5 ng), and beta-propiolactone (≤ 2 ng). 425 426 The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the 427 rubber stoppers used for the multi-dose vial were not made with natural rubber latex. 428 429 430 12 CLINICAL PHARMACOLOGY 431 432 12.1 Mechanism of Action 433 Influenza illness and its complications follow infection with influenza viruses. Global 434 surveillance of influenza identifies yearly antigenic variants. For example, since 1977 435 antigenic variants of influenza A (H1N1 and H3N2) and influenza B viruses have been in 436 global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-437 vaccination with inactivated influenza vaccine have not been correlated with protection from 438 influenza virus. In some human studies, antibody titers of 1:40 or greater have been associated 439 with protection from influenza illness in up to 50% of subjects.2,3 440 441 Antibody against one influenza virus type or subtype confers limited or no protection against 442 another. Furthermore, antibody to one antigenic variant of influenza virus might not protect 443 against a new antigenic variant of the same type or subtype. Frequent development of 444 antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the 445

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reason for the usual change to one or more new strains in each year’s influenza vaccine. 446 Therefore, inactivated influenza vaccines are standardized to contain the HA of three strains 447 (i.e., typically two type A and one type B) representing the influenza viruses likely to be 448 circulating in the US during the upcoming winter. 449 450 Annual revaccination with the current vaccine is recommended because immunity declines 451 during the year after vaccination and circulating strains of influenza virus change from year to 452 year.1 453 454 455 13 NONCLINICAL TOXICOLOGY 456 457 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 458 AFLURIA has not been evaluated for carcinogenic or mutagenic potential, or male infertility 459 in animals. A reproductive study of female rats vaccinated with AFLURIA revealed no 460 impairment of fertility (see Pregnancy, 8.1). 461 462 463 14 CLINICAL STUDIES 464 465 14.1 Efficacy Against Laboratory-Confirmed Influenza 466 In Study 5, the efficacy of AFLURIA was demonstrated in a randomized, observer-blind, 467 placebo-controlled study conducted in 15,044 subjects. Healthy subjects 18 through 64 years of 468 age were randomized in a 2:1 ratio to receive a single dose of AFLURIA (enrolled subjects: 469 10,033; evaluable subjects: 9,889) or placebo (enrolled subjects: 5,011; evaluable subjects: 470 4,960). The mean age of all randomized subjects was 35.5 years. 54.4% were female and 471 90.2% were White. Laboratory-confirmed influenza was assessed by active and passive 472 surveillance of influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of 473 the influenza season, approximately 6 months post-vaccination. ILI was defined as at least one 474 respiratory symptom (e.g., cough, sore throat, nasal congestion) and at least one systemic 475 symptom (e.g., oral temperature of 100.0ºF or higher, feverishness, chills, body aches). Nasal 476 and throat swabs were collected from subjects who presented with an ILI for laboratory 477 confirmation by viral culture and real-time reverse transcription polymerase chain reaction. 478 Influenza virus strain was further characterized using gene sequencing and pyrosequencing. 479 480 Attack rates and vaccine efficacy, defined as the relative reduction in the influenza infection 481 rate for AFLURIA compared to placebo, were calculated using the per protocol population. 482 Vaccine efficacy against laboratory-confirmed influenza infection due to influenza A or B 483 virus strains contained in the vaccine was 60% with a lower limit of the 95% CI of 41% (Table 484 6). 485 486

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Table 6: Laboratory-Confirmed Influenza Infection Rate and Vaccine Efficacy in Adults 487 18 through 64 Years of Age (Study 5) 488

489 Subjects a Laboratory-

Confirmed Influenza

Cases

Influenza Infection

Rate

Vaccine Efficacy b

N N n/N % % Lower Limit of the 95% CI

Vaccine-matched Strains AFLURIA 9889 58 0.59 60 41 Placebo 4960 73 1.47 Any Influenza Virus Strain AFLURIA 9889 222 2.24 42 28 Placebo 4960 192 3.87 Abbreviations: CI, confidence interval 490 a The Per Protocol Population was identical to the Evaluable Population in this study. 491 b Vaccine efficacy = 1 minus the ratio of AFLURIA/placebo infection rates. The objective of the study was to demonstrate that 492

the lower limit of the CI for vaccine efficacy was greater than 40%. 493 494 14.2 Immunogenicity in Children – Administration via Needle and Syringe 495 Study 1 was a randomized, observer-blind, comparator-controlled study to evaluate the 496 immunological non-inferiority of AFLURIA to a U.S.-licensed trivalent inactivated influenza 497 vaccine (manufactured by Sanofi Pasteur, Inc.) in subjects 6 months through 17 years of age. 498 Study vaccines were administered by needle and syringe. Results are presented for children 5 499 through 17 years of age (Table 7). A total of 832 subjects (aged 5 through 17 years) were 500 enrolled. Subjects were randomized in a 1:1 ratio to receive AFLURIA (enrolled subjects: 501 417; evaluable subjects: 383) or the comparator vaccine (enrolled subjects: 415; evaluable 502 subjects: 383). 503 504 Children 6 months through 8 years of age with no history of influenza vaccination received 2 505 doses approximately 28 days apart. Children 6 months through 8 years of age with a history of 506 influenza vaccination and children 9 years of age and older received 1 dose. Children 6 507 months through 35 months of age received 0.25 mL of AFLURIA or comparator influenza 508 vaccine, and children 3 years of age and older received 0.5 mL of AFLURIA or comparator 509 influenza vaccine. Nearly equal proportions of subjects were male (49.9%) and female 510 (50.1%), and the majority were White (85.0%) or Black (10.3%). 511 512 Immunogenicity assessments were performed prior to vaccination and at 21 days after 513 vaccination. The co-primary endpoints were HI Geometric Mean Titer (GMT) ratios (adjusted 514 for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days 515 after the final vaccination. Pre-specified non-inferiority criteria required that the upper bound 516 of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the 517 upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus 518 AFLURIA) did not exceed 10.0% for each strain. As shown in Table 7, non-inferiority of 519

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AFLURIA to the comparator vaccine was demonstrated in the per protocol population for 520 influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For influenza type 521 B, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Note that 522 the study was powered to assess the pre-specified non-inferiority criteria based on 1400 523 evaluable subjects. Analysis of the 761 subjects aged 5 through 17 years reduced the power of 524 the study and widened the confidence intervals. In the pre-specified analysis, AFLURIA was 525 not inferior to the comparator vaccine for all three virus strains. Post-hoc analyses of 526 immunogenicity by gender did not demonstrate significant differences between males and 527 females. The study was not sufficiently diverse to assess differences between races or 528 ethnicities. 529 530 Table 7: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of 531

Non-Inferiority of AFLURIA to a U.S.-Licensed Comparator, Subjects 5 532 through 17 Years of Age (Study 1) 533

534

Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined

non-inferiority criteria? c Strain Comparator

N=381 AFLURIA

N=380

Comparator over AFLURIA

(95% CI)

Comparator N=381

AFLURIA N=380

Comparator minus

AFLURIA (95% CI)

A(H1N1) 526.2 507.4 1.03 (0.88, 1.21) 62.7 62.6 0.1 (-6.8, 7.0) Yes

A(H3N2) 1060.0 961.3 1.07 (0.94, 1.23) 72.2 69.7 2.4 (-4.0, 8.9) Yes

B 123.3 110.1 1.10 (0.94, 1.29) 75.1 70.0 5.1 (-1.3, 11.4) No

Abbreviations: CI, confidence interval; GMT, geometric mean titer. 535 a GMT ratios are adjusted for baseline HI titers 536 b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or 537

an increase in titer from < 1:10 to ≥ 1:40. 538 c Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects. 539 540 14.3 Immunogenicity in Adults and Older Adults – Administration via Needle 541 and Syringe 542 Two randomized, controlled clinical studies of AFLURIA evaluated the immune responses by 543 measuring HI antibody titers to each virus strain in the vaccine in adults as compared to 544 placebo (adults 18 through 64 years) or another U.S.-licensed trivalent influenza vaccine 545 (adults ≥ 65 years). In these studies, post-vaccination immunogenicity was evaluated on sera 546 obtained 21 days after administration of a single dose of AFLURIA. 547 548 Study 4 was a randomized, double-blinded, placebo-controlled, multi-center study in healthy 549 subjects ages 18 through 64 years. A total of 1,357 subjects were vaccinated (1,089 subjects 550 with AFLURIA and 268 with a placebo). Subjects who received AFLURIA were vaccinated 551 using either the preservative-free or thimerosal-containing presentation. The evaluable 552

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population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo 553 group). The mean age of the entire evaluable population receiving AFLURIA was 38 years. 554 62.5% of subjects were female, 81.3% were White, 12.1% were Black, and 6.2% were Asian. 555 556 Serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria 557 for all three virus strains (Table 8). Similar responses were observed between genders. The 558 study was not sufficiently diverse to assess immunogenicity by race or ethnicity. 559 560 Table 8: Serum Antibody Responses in Subjects 18 through 64 Years of Age Receiving 561

AFLURIA (Study 4) 562 563

Strain Variable

AFLURIA N=1077

value (95% CI)

Placebo N=264

value (95% CI) A(H1N1)

HI Titer ≥ 1:40 a 97.8% (96.7, 98.6) 74.6% (68.9, 79.8)

Seroconversion Rate (%) b 48.7% (45.6, 51.7) 2.3% (0.8, 4.9)

A(H3N2)

HI Titer ≥ 1:40 a 99.9% (99.5, 100.0) 72.0% (66.1, 77.3)

Seroconversion Rate (%) b 71.5% (68.7, 74.2) 0.0% (N/A)

B

HI Titer ≥ 1:40 a 94.2% (92.7, 95.6) 47.0% (40.8, 53.2)

Seroconversion Rate (%) b 69.7% (66.9, 72.5) 0.4% (< 0.1, 2.1) a HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. Lower 564

bound of 95% CI for HI antibody titer ≥ 1:40 should be > 70% for the study population. 565 b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or 566

an increase in titer from < 1:10 to ≥ 1:40. Lower bound of 95% CI for seroconversion should be > 40% for the study 567 population. 568

569 Study 6 was a randomized, observer-blind, comparator-controlled study that enrolled 1,268 570 subjects 65 years of age and older (Table 9). This study compared the immune response 571 following administration of AFLURIA to that following a US-licensed trivalent inactivated 572 influenza vaccine (manufactured by Sanofi Pasteur Inc.). Subjects were randomized in a 1:1 573 ratio to receive a single vaccination of AFLURIA (enrolled subjects: 631; evaluable subjects: 574 605) or the comparator vaccine (enrolled subjects: 637; evaluable subjects: 610). 575 Immunogenicity assessments were performed prior to vaccination and at 21 days after 576 vaccination. Most of the subjects in the per-protocol immunogenicity population were female 577 (56.7%) and White (97.4%). 2.0% were Black and less than 1.0% were of other races or 578 ethnicities. 579 580 The co-primary endpoints were HI GMT ratios (adjusted for baseline HI titers) and the 581

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difference in seroconversion rates for each vaccine strain 21 days after vaccination. Pre-582 specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the 583 GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 584 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 585 10.0% for each strain. As shown in Table 9, non-inferiority of AFLURIA to the comparator 586 vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) 587 and A(H3N2), but not for influenza type B. For the B strain, non-inferiority was demonstrated 588 for HI GMTs, but not for seroconversion rates. Post-hoc analyses of immunogenicity by 589 gender did not demonstrate significant differences between males and females. The study was 590 not sufficiently diverse to assess differences between races or ethnicities. 591 592 Table 9: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of 593

Non-Inferiority of AFLURIA to a U.S. Licensed Comparator, Adults 65 Years of 594 Age and Older (Study 6) 595

596

Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined

non-inferiority criteria? Strain Comparator

N=610 AFLURIA

N=605

Comparator over AFLURIA

(95% CI)

Comparator N=610

AFLURIA N=605

Comparator minus

AFLURIA (95% CI)

A(H1N1) 59.2 59.4 1.04 (0.92, 1.18) 43.0 38.8 4.1 (-1.4, 9.6) Yes

A(H3N2) 337.7 376.8 0.95 (0.83, 1.08) 68.7 69.4 -0.7 (-5.9, 4.5) Yes

B 33.4 30.4 1.12 (1.01, 1.25) 34.4 29.3 5.2 (-0.1, 10.4) No

Abbreviations: CI, confidence interval; GMT, geometric mean titer. 597 a Post-vaccination GMTs were adjusted for baseline HI titers. 598 b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or 599

an increase in titer from < 1:10 to ≥ 1:40. 600 601 14.4 Immunogenicity in Adults – Administration via PharmaJet Stratis Needle-602 Free Injection System 603 Study 8 was a randomized, comparator-controlled non-inferiority study that enrolled 1,250 604 subjects 18 through 64 years of age. This study compared the immune response following 605 administration of AFLURIA when delivered IM using either the PharmaJet Stratis Needle-Free 606 Injection System or needle and syringe. Immunogenicity assessments were performed prior to 607 vaccination and at 28 days after vaccination in the immunogenicity population (1,130 subjects, 608 562 PharmaJet Stratis Needle-Free Injection System group, 568 needle and syringe group). 609 The co-primary endpoints were HI GMT ratios for each vaccine strain and the absolute 610 difference in seroconversion rates for each vaccine strain 28 days after vaccination. As shown 611 in Table 10, non-inferiority of administration of AFLURIA by the PharmaJet Stratis Needle-612 Free Injection System compared to administration of AFLURIA by needle and syringe was 613 demonstrated in the immunogenicity population for all strains. Post-hoc analyses of 614

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immunogenicity by age showed that younger subjects (18 through 49 years) elicited higher 615 immunological responses than older subjects (50 through 64 years). Post-hoc analyses of 616 immunogenicity according to gender and body mass index did not reveal significant influences 617 of these variables on immune responses. The study population was not sufficiently diverse to 618 assess immunogenicity by race or ethnicity. 619 620 Table 10: Baseline and Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and 621

Analyses of Non-Inferiority of AFLURIA Administered by PharmaJet Stratis 622 Needle-Free Injection System or Needle and Syringe, Adults 18 through 64 623 Years of Age (Study 8) 624

625

Baseline GMT Post-vaccination GMT GMT Ratio a Seroconversion % b Difference

Met both pre-defined

non-inferiority criteria? c Strain

Needle and

Syringe N=568

PharmaJet Stratis Needle-

Free Injection System N=562

Needle and

Syringe N=568



Needle and Syringe over PharmaJet

Stratis Needle-Free

Injection System

(95% CI)

Needle and

Syringe N=568



Needle and Syringe minus


Free Injection System

(95% CI)

A(H1N1) 79.5 83.7 280.6 282.9 0.99 (0.88, 1.12) 38.4 37.5 0.8

(-4.8, 6.5) Yes

A(H3N2) 75.4 68.1 265.9 247.3 1.08 (0.96, 1.21) 45.1 43.8 1.3

(-4.5, 7.1) Yes

B 12.6 13.5 39.7 42.5 0.94 (0.83, 1.06) 35.2 34.9 0.3

(-5.2, 5.9) Yes

Abbreviations: CI, confidence interval; GMT, geometric mean titer 626 a GMT ratio is defined as post-vaccination GMT for Needle and Syringe/PharmaJet Stratis Needle-Free Injection System 627 b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or 628

an increase in titer from < 1:10 to ≥ 1:40. 629 c Non-inferiority (NI) criteria for the GMT ratio: upper bound of 2-sided 95% CI on the ratio of Needle and Syringe/PharmaJet 630

Stratis Needle-Free Injection System. GMT should not exceed 1.5. NI criteria for the seroconversion rate (SCR) difference: 631 upper bound of 2-sided 95% CI on the difference between SCR Needle and Syringe – SCR PharmaJet Stratis Needle-Free 632 Injection System should not exceed 10%. 633

634 635 15 REFERENCES 636 637

1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: 638 Recommendations of the Advisory Committee on Immunization Practices (ACIP). 639 MMWR Recomm Rep 2010;59 (RR-8):1-62. 640

2. Hannoun C, Megas F, Piercy J. Immunogenicity and Protective Efficacy of Influenza 641 Vaccination. Virus Res 2004;103:133-138. 642

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3. Hobson D, Curry RL, Beare AS, et al. The Role of Serum Hemagglutination-643 Inhibiting Antibody in Protection against Challenge Infection with Influenza A2 and B 644 Viruses. J Hyg Camb 1972;70:767-777. 645

646 647 16 HOW SUPPLIED/STORAGE AND HANDLING 648 649 16.1 How Supplied 650 Each product presentation includes a package insert and the following components: 651

Presentation Carton NDC Number Components

Pre-Filled Syringe 33332-016-01 • Ten 0.5 mL single-dose syringes fitted with a Luer-Lok™ attachment without needles [NDC 33332-016-02]

Multi-Dose Vial 33332-116-10 • One 5 mL vial, which contains ten 0.5 mL doses [NDC 33332-116-11]

652 16.2 Storage and Handling 653

• Store refrigerated at 2−8°C (36−46°F). 654 • Do not freeze. Discard if product has been frozen. 655 • Protect from light. 656 • Do not use AFLURIA beyond the expiration date printed on the label. 657 • Once the stopper of the multi-dose vial has been pierced the vial must be discarded 658

within 28 days. 659 660 661 17 PATIENT COUNSELING INFORMATION 662

• Inform the vaccine recipient or guardian of the potential benefits and risks of 663 immunization with AFLURIA. 664

• Ιnform the vaccine recipient or guardian that AFLURIA is an inactivated vaccine that 665 cannot cause influenza but stimulates the immune system to produce antibodies that 666 protect against influenza, and that the full effect of the vaccine is generally achieved 667 approximately 3 weeks after vaccination. 668

• Instruct the vaccine recipient or guardian to report any severe or unusual adverse 669 reactions to their healthcare provider. 670

• Encourage women who receive AFLURIA while pregnant to participate in the 671 exposure and surveillance study. Pregnant women can contact the pregnancy study 672 center by calling 1-877-311-8972 or visiting the website 673 http://www.pregnancystudies.org. 674

• Provide the vaccine recipient or guardian with Vaccine Information Statements which 675 are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to 676 immunization. These materials are available free of charge at the Centers for Disease 677 Control and Prevention (CDC) website (www.cdc.gov/vaccines). 678

http://www.cdc.gov/vaccines

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• Instruct the vaccine recipient or guardian that annual revaccination is recommended. 679 680 681 Manufactured by: 682 Seqirus Pty Ltd 683 Parkville, Victoria, 3052, Australia 684 US License No. 2044 685 686 Distributed by: 687 Seqirus USA Inc. 1020 First Avenue, King of Prussia, PA 19406, USA 688 689 AFLURIA is a trademark of Seqirus UK Limited or its affiliates. 690 PharmaJet® and STRATIS® are registered trademarks of PharmaJet. 691 Luer-Lok™ is a trademark of Becton, Dickinson and Company Corporation. 692 693

FLUAD™ - Seqirus, Inc. US Package Insert March 2016 Confidential Page 1 of 13

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUAD™ safely and effectively. See full prescribing information for FLUAD. FLUAD™ (Influenza Vaccine, Adjuvanted) Suspension for Intramuscular Injection 2016-2017 Formula Initial U.S. Approval: 2015 INDICATIONS AND USAGE FLUAD is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLUAD is approved for use in persons 65 years of age and older. (1)

Approval is based on the immune response elicited by FLUAD. Data demonstrating a decrease in influenza disease after vaccination with FLUAD are not available. (14)

DOSAGE AND ADMINISTRATION A single 0.5 mL dose for intramuscular injection. (2.1) DOSAGE FORMS AND STRENGTHS Suspension for injection supplied in 0.5 mL single-dose pre-filled syringes. (3) CONTRAINDICATIONS Severe allergic reaction to any component of the vaccine, including egg protein, or after a previous dose of any influenza vaccine. (4, 11)

WARNINGS AND PRECAUTIONS • 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. (5.1)

• The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions in latex sensitive individuals. (5.3)

ADVERSE REACTIONS • The most common (≥ 10%) local (injection site) adverse

reactions observed in clinical studies were injection site pain (25%) and tenderness (21%). (6)

• The most common (≥ 10%) systemic adverse reactions observed in clinical studies were myalgia (15%), headache (13%) and fatigue (13%). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1- 855-358-8966 or VAERS at 1-800-822-7967 and www.vaers.hhs.gov.

See 17 for PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION: CONTENTS

1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION

2.1.Dosage and Schedule 2.2.Administration

3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1.Guillain-Barré Syndrome 5.2.Preventing and Managing Allergic Reactions 5.3.Latex 5.4.Altered Immunocompetence 5.5.Syncope 5.6.Limitations of Vaccine Effectiveness 6. ADVERSE REACTIONS 6.1.Clinical Trials Experience 6.2.Postmarketing Experience

7. DRUG INTERACTIONS 7.1.Concomitant Use With Other Vaccines 7.2.Concurrent Use With Immunosuppressive

Therapies 8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.4.Pediatric Use

8.5.Geriatric Use 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 13. NONCLINICAL TOXICOLOGY

13.1.Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES 15. REFERENCES 16. HOW SUPPLIED/STORAGE AND

HANDLING 17. PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

http://www.vaers.hhs.gov/


FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE FLUAD is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLUAD is approved for use in persons 65 years of age and older. Approval is based on the immune response elicited by FLUAD. Data demonstrating a decrease in influenza disease after vaccination with FLUAD are not available. [see Clinical Studies (14)]

2. DOSAGE AND ADMINISTRATION For intramuscular injection only

2.1. Dosage and Schedule Administer FLUAD as a single 0.5 mL intramuscular injection in adults 65 years of age and older.

2.2. Administration • Gently shake each syringe. FLUAD has a milky white appearance. Parenteral drug

products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit [see Description (11)]. If either condition exists, FLUAD should not be administered.

• The vaccine should be administered by 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.

3. DOSAGE FORMS AND STRENGTHS FLUAD is a sterile suspension for intramuscular injection supplied in 0.5 mL single-dose pre-filled syringes.

4. CONTRAINDICATIONS Do not administer FLUAD to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein [see Description (11)], or to a previous influenza vaccine.


5. WARNINGS AND PRECAUTIONS

5.1. Guillain-Barré Syndrome If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD 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 relationship 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)]

5.2. Preventing and Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

5.3. Latex The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions in latex sensitive individuals. [see Description (11)]

5.4. Altered Immunocompetence The immune response to FLUAD in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. [see Concurrent Use With Immunosuppressive Therapies (7.2)]

5.5. Syncope Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD. Ensure procedures are in place to avoid injury from falling associated with syncope.

5.6 Limitations of Vaccine Effectiveness Vaccination with FLUAD may not protect all vaccine recipients against influenza disease.

6. ADVERSE REACTIONS

6.1. Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect rates observed in clinical practice.

Solicited adverse reactions were assessed in a multicenter, observer-blind, randomized controlled study (Study 1) conducted in the United States, Colombia, Panama and the Philippines. The safety analysis set included 3545 FLUAD recipients and 3537 AGRIFLU (Influenza Vaccine)


recipients. The enrolled subject population in Study 1 was 65 to 97 years of age (mean 72 years) and 64% were female. Within each treatment group, 53% were Asian, 28% were Caucasian, 18% were Hispanic, 1% were Black, and fewer than 1% each were Native American/Alaskan, Pacific Islander/Hawaiian, or Other.

Solicited local (injection site) and systemic adverse reactions were collected from subjects in Study 1 who completed a symptom diary card for seven days following vaccination. The reported frequencies of solicited local and systemic adverse events from Study 1 are presented in Table 1.

Table 1: Percentages of Subjects ≥ 65 Years of Age With Solicited Local and Systemic Adverse Reactions in Days 1-7 After Administration of FLUAD or AGRIFLU (a U.S. Licensed Comparator) NCT01162122

Study 1

FLUAD

(Na=3418-3496) Percentage

AGRIFLU (Na=3420-3488)

Percentage Local

Injection site Pain

Any 25.0 12.2 Moderateb 3.9 1.9 Severec 0.3 0.2

Tenderness Any 21.1 11.2 Moderate 3.0 1.0 Severe 0.1 0.2

Erythema

Any 1.2 0.5 25 to < 50 mm 1.1 0.5 51 to < 100 mm 0.2 <0.1 > 100 mm 0.0 0.0

Induration

Any 1.3 0.5 25 to < 50 mm 1.0 0.5 51 to < 100 mm 0.3 0.0 > 100 mm 0.0 0.0

Swelling

Any 1.2 0.4 25 to < 50 mm 1.0 0.4 51 to < 100 mm 0.2 <0.1 > 100 mm <0.1 0.0


Systemic

Myalgia Any 14.7 9.7 Moderate 2.6 1.8 Severe 0.3 0.7

Fatigue

Any 13.3 10.4 Moderate 3.1 2.4 Severe 0.4 0.6 PLTd 0.0 <0.1

Headache

Any 13.2 11.2 Moderate 3.0 2.6 Severe 0.4 0.6 PLT 0.0 <0.1

Arthralgia Any 8.5 7.8 Moderate 1.6 1.6 Severe 0.2 0.6

Chills

Any 6.7 4.7 Moderate 1.5 1.2 Severe 0.3 0.3 PLT <0.1 0.0

Diarrhea

Any 4.8 4.5 Moderate 1.3 0.9 Severe 0.3 0.2 PLT <0.1 <0.1

Fever

Any 3.6 3.4 ≥ 38.0°C to ≤ 38.4°C 1.8 1.7 ≥ 38.5°C to ≤ 38.9°C 1.3 1.3 39.0°C to ≤ 40.0°C 0.4 0.4 ≥ 40.0°C 0.1 0.0

Nausea

Any 2.9 2.8 Moderate 0.4 0.6 Severe 0.1 0.1 PLT <0.1 0.0

Vomiting

Any 1.4 1.7 Moderate 0.4 0.5 Severe <0.1 0.1 PLT <0.1 0.0

a N = number of subjects with safety data. b Moderate: pain, tenderness, myalgia, fatigue, headache, arthralgia, chills, nausea, vomiting defined as “some limitation in normal daily activity”, diarrhea defined as “4 to 5 stools a day”. c Severe: pain, tenderness, myalgia, fatigue, headache, arthralgia, chills, nausea, vomiting defined as “unable to perform normal daily activity”, diarrhea defined as “6 or more watery stools a day”. d Potentially life threatening (PLT) reaction defined as requiring emergency room visit or hospitalization.


Unsolicited Adverse Events (AEs): The clinical safety of FLUAD was assessed in fifteen (15) randomized, controlled studies. The total safety population in these trials included 10,952 adults 65 years of age and older, comprising 5,754 who received FLUAD and 5,198 who received other US licensed influenza vaccines. The percentage of subjects with an unsolicited AE within 30 days following vaccination was similar between vaccine groups (16.9% FLUAD vs. 18.0% active comparator).

Serious Adverse Events (SAEs) and Deaths: In Study 1, in which subjects were followed for SAEs and deaths for one year following vaccination (N=3,545 FLUAD, N=3,537 AGRIFLU), the percentages of subjects with an SAE were similar between vaccine groups (7% FLUAD vs. 7% AGRIFLU). Four SAEs (1 FLUAD and 3 AGRIFLU) were assessed as related to study vaccination over one year of observation and 2 of these occurred (1 FLUAD and 1 AGRIFLU) within 21 days following study vaccination. There were 98 deaths (n=52 FLUAD, n=46 AGRIFLU) over one year of which none occurred within the first 21 days following vaccination.

In 14 additional randomized, controlled studies, SAEs were collected over a 3 to 4-week period in 4 studies, over a 8-week period in 1 study, and over a 6-month period in 9 studies (N= 2,209 FLUAD, N=1,661 US licensed influenza vaccines). The percentages of subjects with an SAE within 30 days (1.1% FLUAD vs. 1.8% AGRIFLU) or within 6 months (4.3% FLUAD vs. 5.9% AGRIFLU) were similar between vaccine groups. The percentages of deaths within 30 days (0.3% FLUAD vs. 0.6% active comparator) or within 6 months (1.0% FLUAD vs. 1.5% active comparator) were also similar.

Adverse Events of Special Interest (AESIs): Rates of new onset neuroinflammatory and immune mediated diseases were assessed in a post hoc analysis of the 15 randomized controlled studies over the time periods specified above for SAEs. The percentage of subjects with an AESI at any time after vaccination was similar between vaccine groups (0.9% FLUAD vs. 0.9% active comparator). There were no notable imbalances for specific AESIs.

Safety of Annual Revaccination: In 5 of the randomized, controlled trials, subjects were followed for SAEs and deaths for 6 months following revaccination (N=492 FLUAD, N=330 US licensed and non-US licensed influenza vaccines). After the second annual vaccination, the percentages of subjects with an SAE were similar between vaccine groups (6.1% FLUAD vs. 5.5% comparator influenza vaccines); 23 deaths (n=17 FLUAD, n=6 comparator influenza vaccines) were reported. Causes of death included cardiovascular events, malignancy, trauma, gastrointestinal disorders, and respiratory failure. Clinical characteristics of the deaths, including the variable causes, timing since vaccination, and underlying medical conditions, do not provide evidence for a causal relationship with FLUAD.

6.2. Postmarketing Experience The following adverse events have been spontaneously reported during post-approval use of FLUAD in Europe and other regions since 1997. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.


Blood and lymphatic system disorders: Thrombocytopenia (some cases were severe with platelet counts less than 5,000 per mm3), lymphadenopathy

General disorders and administration site conditions: Extensive swelling of injected limb lasting more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week)

Immune system disorders: Allergic reactions including anaphylactic shock, anaphylaxis and angioedema

Musculoskeletal and connective tissue disorders: Muscular weakness

Nervous system disorders: Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, paraesthesia, syncope, presyncope

Skin and subcutaneous tissue disorders: Generalized skin reactions including erythema multiforme, urticaria, pruritis or non-specific rash

Vascular disorders: Vasculitis with transient renal involvement

7. DRUG INTERACTIONS

7.1. Concomitant Use With Other Vaccines There are no data to assess the concomitant administration of FLUAD with other vaccines. If FLUAD is given at the same time as other injectable vaccine(s), the vaccine(s) should be administered at different injection sites.

Do not mix FLUAD with any other vaccine in the same syringe.

7.2. Concurrent Use With Immunosuppressive Therapies Immunosuppressive or corticosteroid therapies may reduce the immune response to FLUAD.


8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy Pregnancy Category B: A reproductive and developmental toxicity study has been performed in rabbits with a dose level that was approximately 15 times the human dose based on body weight. The study revealed no evidence of impaired female fertility or harm to the fetus due to FLUAD. 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 FLUAD on embryo-fetal and post-natal development was evaluated in pregnant rabbits. Animals were administered FLUAD by intramuscular injection twice prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL (45 mcg)/rabbit/occasion (approximately 15-fold excess relative to the adult human dose based on body weight). 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.

8.4. Pediatric Use The safety and effectiveness of FLUAD in the pediatric population have not been established.

8.5. Geriatric Use Safety and immunogenicity of FLUAD have been evaluated in adults 65 years of age and older. [See Adverse Reactions (6.1) and Clinical Studies (14)]

11. DESCRIPTION FLUAD (Influenza Vaccine, Adjuvanted), a sterile suspension for intramuscular injection, is a trivalent, inactivated influenza vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension.

Each 0.5 mL dose contains at least 15 mcg of hemagglutinin (HA) from each of the following three influenza strains recommended for the 2016/2017influenza season: A/California/7/2009, NYMC X-181 (H1N1) (an A/California/7/2009 pdm09-like virus); A/Hong Kong/4801/2014, NYMC X-263B (H3N2) (an A/Hong Kong/4801/2014-like virus); and B/Brisbane/60/2008, wild type (a B/Brisbane/60/2008-like virus). FLUAD also contains MF59C.1 adjuvant (MF59®), a squalene based oil-in-water emulsion. Each of the 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). The antigen preparation is further purified.


FLUAD is prepared by combining the three virus antigens with the MF59C.1 adjuvant. After combining, FLUAD is a sterile, milky-white suspension supplied in 0.5 mL single-dose pre-filled syringe. Each 0.5 mL dose contains 15 mcg of hemagglutinin (HA) from each of the three recommended influenza strains and MF59C.1 adjuvant (9.75 mg squalene, 1.175 mg of polysorbate 80, 1.175 mg of sorbitan trioleate, 0.66 mg of sodium citrate dihydrate and 0.04 mg of citric acid monohydrate) at pH 6.9-7.7.

FLUAD may contain trace amounts of neomycin (≤ 0.02 mcg by calculation), kanamycin (≤ 0.03 mcg by calculation) and barium (˂ 0.5 mcg by calculation), which are used during the initial stages of manufacture, as well as residual egg proteins (˂ 0.4 mcg), formaldehyde (≤ 10 mcg), or CTAB (≤ 12 mcg).

FLUAD does not contain a preservative.

The tip caps of the prefilled syringes contain natural rubber latex. The syringe and syringe plunger stopper are not made with natural rubber latex.

12. CLINICAL PHARMACOLOGY

12.1. 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. In some human studies, HI antibody titers of 1:40 or greater have been associated with protection from influenza illness in up to 50% of subjects. [see References (2, 3)]

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated trivalent influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains (two subtypes A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter.

Annual influenza vaccination is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.


13. NONCLINICAL TOXICOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility FLUAD has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. FLUAD did not affect female fertility in a rabbit reproductive and developmental toxicity study.

14. CLINICAL STUDIES Study 1 (NCT01162122) evaluated the safety and immunogenicity of FLUAD in comparison to AGRIFLU. A total of 7,082 subjects were randomized and vaccinated with FLUAD (N=3,541) or AGRIFLU (N=3,541). The primary immunogenicity analyses were conducted on all vaccinated subjects with a blood sample collected at Day 22 (N=3,225-3,227 [91%] and 3,256-3,259 [92%] in the FLUAD and AGRIFLU groups, respectively). Non-inferiority of FLUAD compared with AGRIFLU was demonstrated for all three vaccine strains based on pre-defined thresholds for seroconversion rate differences and GMT ratios (Table 2).

Table 2: Immune Responses to Each Antigen 22 Days after Vaccination with FLUAD or AGRIFLU in Adults 65 Years and Oldera

FLUAD AGRIFLU

GMTs Against GMT N b= 3225-3227 (95% CI)

GMT N b =3256-3259 (95% CI)

GMT Ratioc (95% CI)

A/California/7/2009- like (H1N1)

99 (93-106)

70 (66-75)

1.4 (1.32-1.49)

A/Perth/16/2009-like (H3N2)

272 (257-288)

169 (159-179)

1.61 (1.52-1.7)

B/Brisbane/60/2008- like

28 (26-29)

24 (23-26)

1.15 (1.08-1.21)

Seroconversiond to: % of Subjects (95% CI)

% of Subjects (95% CI)

Difference in Seroconversion Ratee (95% CI)

A/California/7/2009- like (H1N1)

69% (67%–70%)

58% (57%–60%)

9.8% (7.5%–12.1%)


A/Perth/16/2009-like (H3N2)

73% (71%–74%)

58% (56%–60%)

13.9% (11.7%–16.1%)

B/Brisbane/60/2008- like

33% (31%–35%)

29% (28%–31%)

3.2% (1.1%–5.3%)

GMT = Geometric mean antibody titer; CI = Confidence Interval. a Results obtained following vaccination with influenza vaccine formulated for the 2010-2011 season. b N is the number of vaccinated participants with available data for the immunologic endpoint listed. c FLUAD met non-inferiority criteria based on GMT ratios if the lower limit of the 95% CI [FLUAD:AGRIFLU] for each strain was > 0.67. d Seroconversion was defined as prevaccination HI titer <10 and postvaccination HI titer ≥ 40 or at least a 4-fold increase in HI from prevaccination HI titer ≥ 10. e FLUAD met non-inferiority criteria based on seroconversion rate differences if the lower limit of the 95% CI [FLUAD -AGRIFLU] for each strain was >-10% .


15. REFERENCES

1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998; 339(25): 1797-1802.

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 hemagglutinin-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.

16. HOW SUPPLIED/STORAGE AND HANDLING FLUAD is supplied as a 0.5 mL pre-filled needleless syringe:

• package of 10 pre-filled syringes per carton (NDC number: 70461-001-01)

• pre-filled single syringe (NDC number: 70461-001-11)

Store FLUAD refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Do not freeze. Discard if the vaccine has been frozen. Do not use after expiration date.

The tip caps of prefilled syringes contain natural rubber latex. The syringe and syringe plunger stopper are not made with natural rubber latex.

17. PATIENT COUNSELING INFORMATION • Inform vaccine recipients of the potential benefits and risks of immunization with

FLUAD.

• Educate vaccine recipients regarding the potential side effects. Clinicians should emphasize that (1) FLUAD contains non-infectious particles and cannot cause influenza and (2) FLUAD is intended to help 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 and/or to Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 and www.vaers.hhs.gov. 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.



FLUAD is a registered trademark of Seqirus, Inc.

Manufactured by: Seqirus Vaccines Limited,

An affiliate of: Seqirus, Inc., 475 Green Oaks Parkway, Holly Springs, NC 27540 USA

1-855-358-8966

1

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUARIX QUADRIVALENT safely and effectively. See full prescribing information for FLUARIX QUADRIVALENT. FLUARIX QUADRIVALENT (Influenza Vaccine) Suspension for Intramuscular Injection 2016-2017 Formula Initial U.S. Approval: 2012

----------------------------INDICATIONS AND USAGE -------------------------- FLUARIX QUADRIVALENT is a vaccine indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FLUARIX QUADRIVALENT is approved for use in persons 3 years of age and older. (1)

----------------------- DOSAGE AND ADMINISTRATION --------------------- For intramuscular injection only. (2)

Age Vaccination Status Dose and Schedule Aged 3 through 8 years

Not previously vaccinated with influenza vaccine

Two doses (0.5-mL each) at least 4 weeks apart (2.1)

Vaccinated with influenza vaccine in a previous season

One or two dosesa (0.5-mL each) (2.1)

Aged 9 years and older

Not applicable One 0.5-mL dose (2.1)

a One dose or two doses (0.5-mL each) depending on vaccination history as per the annual Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and control of influenza with vaccines. If two doses, administer each 0.5-mL dose at least 4 weeks apart. (2.1)

--------------------- DOSAGE FORMS AND STRENGTHS ------------------- Suspension for injection supplied in 0.5-mL single-dose prefilled syringes. (3)

------------------------------- CONTRAINDICATIONS ----------------------------- History of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or following a previous dose of any influenza vaccine. (4, 11)

----------------------- WARNINGS AND PRECAUTIONS --------------------- • If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a

prior influenza vaccine, the decision to give FLUARIX QUADRIVALENT should be based on careful consideration of potential benefits and risks. (5.1)

• Syncope (fainting) can occur in association with administration of injectable vaccines, including FLUARIX QUADRIVALENT. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. (5.2)

------------------------------ ADVERSE REACTIONS ---------------------------- • In adults, the most common (≥10%) injection site adverse reaction was

pain (36%); the most common systemic adverse events were muscle aches (16%), headache (16%), and fatigue (16%). (6.1)

• In children aged 3 through 17 years, the injection site adverse reactions were pain (44%), redness (23%), and swelling (19%). (6.1)

• In children aged 3 through 5 years, the most common (≥10%) systemic adverse events were drowsiness (17%), irritability (17%), and loss of appetite (16%); in children aged 6 through 17 years, the most common systemic adverse events were fatigue (20%), muscle aches (18%), headache (16%), arthralgia (10%), and gastrointestinal symptoms (10%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

----------------------- USE IN SPECIFIC POPULATIONS --------------------- • Safety and effectiveness of FLUARIX QUADRIVALENT have not been

established in pregnant women or nursing mothers. (8.1, 8.3) • Register women who receive FLUARIX QUADRIVALENT while

pregnant in the pregnancy registry by calling 1-888-452-9622. (8.1) • Geriatric Use: Antibody responses were lower in geriatric subjects who

received FLUARIX QUADRIVALENT than in younger subjects. (8.5) See 17 for PATIENT COUNSELING INFORMATION.

Revised: x/2016

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Dosage and Schedule 2.2 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Guillain-Barré Syndrome 5.2 Syncope 5.3 Preventing and Managing Allergic Vaccine Reactions 5.4 Altered Immunocompetence 5.5 Limitations of Vaccine Effectiveness 5.6 Persons at Risk of Bleeding

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience

7 DRUG INTERACTIONS 7.1 Concomitant Vaccine Administration 7.2 Immunosuppressive Therapies




13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES 14.1 Efficacy against Culture-confirmed Influenza 14.2 Immunological Evaluation of FLUARIX QUADRIVALENT in Adults 14.3 Immunological Evaluation of FLUARIX QUADRIVALENT in Children

15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not

listed.


2

______________________________________________________________________

FULL PRESCRIBING INFORMATION 1

1 INDICATIONS AND USAGE 2

FLUARIX® QUADRIVALENT is indicated for active immunization for the prevention of 3 disease caused by influenza A subtype viruses and type B viruses contained in the vaccine [see 4 Description (11)]. FLUARIX QUADRIVALENT is approved for use in persons 3 years of age 5 and older. 6

2 DOSAGE AND ADMINISTRATION 7

For intramuscular injection only. 8

2.1 Dosage and Schedule 9

The dose and schedule for FLUARIX QUADRIVALENT are presented in Table 1. 10

Table 1. FLUARIX QUADRIVALENT: Dosing 11 Age Vaccination Status Dose and Schedule

Aged 3 through 8 years Not previously vaccinated with influenza vaccine

Two doses (0.5-mL each) at least 4 weeks apart


One or two dosesa (0.5-mL each)

Aged 9 years and older Not applicable One 0.5-mL dose a One dose or two doses (0.5-mL each) depending on vaccination history as per the annual 12

Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and 13 control of influenza with vaccines. If two doses, administer each 0.5-mL dose at least 4 weeks 14 apart. 15

2.2 Administration Instructions 16

Shake well before administration. Parenteral drug products should be inspected visually for 17 particulate matter and discoloration prior to administration, whenever solution and container 18 permit. If either of these conditions exists, the vaccine should not be administered. 19

Attach a sterile needle to the prefilled syringe and administer intramuscularly. 20

The preferred site for intramuscular injection is the deltoid muscle of the upper arm. Do not 21 inject in the gluteal area or areas where there may be a major nerve trunk. 22

Do not administer this product intravenously, intradermally, or subcutaneously. 23

3

3 DOSAGE FORMS AND STRENGTHS 24

FLUARIX QUADRIVALENT is a suspension for injection. Each 0.5-mL dose is supplied in 25 single-dose prefilled TIP-LOK® syringes. 26

4 CONTRAINDICATIONS 27

Do not administer FLUARIX QUADRIVALENT to anyone with a history of severe allergic 28 reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or 29 following a previous administration of any influenza vaccine [see Description (11)]. 30

5 WARNINGS AND PRECAUTIONS 31

5.1 Guillain-Barré Syndrome 32

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza 33 vaccine, the decision to give FLUARIX QUADRIVALENT should be based on careful 34 consideration of the potential benefits and risks. 35

The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence 36 for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is 37 inconclusive. If influenza vaccine does pose a risk, it is probably slightly more than 38 one additional case/one million persons vaccinated. 39

5.2 Syncope 40

Syncope (fainting) can occur in association with administration of injectable vaccines, including 41 FLUARIX QUADRIVALENT. Syncope can be accompanied by transient neurological signs 42 such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be 43 in place to avoid falling injury and to restore cerebral perfusion following syncope. 44

5.3 Preventing and Managing Allergic Vaccine Reactions 45

Prior to administration, the healthcare provider should review the immunization history for 46 possible vaccine sensitivity and previous vaccination-related adverse reactions. Appropriate 47 medical treatment and supervision must be available to manage possible anaphylactic reactions 48 following administration of FLUARIX QUADRIVALENT. 49

5.4 Altered Immunocompetence 50

If FLUARIX QUADRIVALENT is administered to immunosuppressed persons, including 51 individuals receiving immunosuppressive therapy, the immune response may be lower than in 52 immunocompetent persons. 53

5.5 Limitations of Vaccine Effectiveness 54

Vaccination with FLUARIX QUADRIVALENT may not protect all susceptible individuals. 55

4

5.6 Persons at Risk of Bleeding 56

As with other intramuscular injections, FLUARIX QUADRIVALENT should be given with 57 caution in individuals with bleeding disorders such as hemophilia or on anticoagulant therapy, to 58 avoid the risk of hematoma following the injection. 59

6 ADVERSE REACTIONS 60

The safety experience with FLUARIX (trivalent influenza vaccine) is relevant to FLUARIX 61 QUADRIVALENT because both vaccines are manufactured using the same process and have 62 overlapping compositions [see Description (11)]. 63

6.1 Clinical Trials Experience 64

Because clinical trials are conducted under widely varying conditions, adverse reaction rates 65 observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical 66 trials of another vaccine, and may not reflect the rates observed in practice. There is the 67 possibility that broad use of FLUARIX QUADRIVALENT could reveal adverse reactions not 68 observed in clinical trials. 69

In adults who received FLUARIX QUADRIVALENT, the most common (≥10%) injection site 70 adverse reaction was pain (36%). The most common (≥10%) systemic adverse events were 71 muscle aches (16%), headache (16%), and fatigue (16%). 72

In children aged 3 through 17 years who received FLUARIX QUADRIVALENT, injection site 73 adverse reactions were pain (44%), redness (23%), and swelling (19%). In children aged 3 74 through 5 years, the most common (≥10%) systemic adverse events were drowsiness (17%), 75 irritability (17%), and loss of appetite (16%); in children aged 6 through 17 years, the most 76 common systemic adverse events were fatigue (20%), muscle aches (18%), headache (16%), 77 arthralgia (10%), and gastrointestinal symptoms (10%). 78

FLUARIX QUADRIVALENT in Adults 79

Trial 1 was a randomized, double-blind (2 arms) and open-label (one arm), active-controlled, 80 safety, and immunogenicity trial. In this trial, subjects received FLUARIX QUADRIVALENT 81 (N = 3,036) or one of two formulations of comparator trivalent influenza vaccine (FLUARIX, 82 TIV-1, N = 1,010 or TIV-2, N = 610), each containing an influenza type B virus that 83 corresponded to one of the two type B viruses in FLUARIX QUADRIVALENT (a type B virus 84 of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 85 18 years and older (mean age: 58 years) and 57% were female; 69% were white, 27% were 86 Asian, and 4% were of other racial/ethnic groups. Solicited events were collected for 7 days (day 87 of vaccination and the next 6 days). The frequencies of solicited adverse events are shown in 88 Table 2. 89

5

Table 2. FLUARIX QUADRIVALENT: Incidence of Solicited Local Adverse Reactions 90 and Systemic Adverse Events within 7 Daysa of Vaccination in Adultsb (Total Vaccinated 91 Cohort) 92

FLUARIX QUADRIVALENTc

N = 3,011-3,015 %

Trivalent Influenza Vaccine (TIV) TIV-1

(B Victoria)d N = 1,003

%

TIV-2 (B Yamagata)e

N = 607 %

Local Pain 36 37 31 Redness 2 2 2 Swelling 2 2 1 Systemic Muscle aches 16 19 16 Headache 16 16 13 Fatigue 16 18 15 Arthralgia 8 10 9 Gastrointestinal symptomsf 7 7 6 Shivering 4 5 4 Fever ≥99.5°F (37.5°C) 2 1 2

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 93 available. 94 a 7 days included day of vaccination and the subsequent 6 days. 95 b Trial 1: NCT01204671. 96 c Contained the same composition as FLUARIX (trivalent formulation) manufactured for the 97

2010-2011 season and an additional influenza type B virus of Yamagata lineage. 98 d Contained the same composition as FLUARIX manufactured for the 2010-2011 season (2 99

influenza A subtype viruses and an influenza type B virus of Victoria lineage). 100 e Contained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-101

2011 season and an influenza type B virus of Yamagata lineage. 102 f Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 103

Unsolicited events occurring within 21 days of vaccination (Day 0 to 20) were reported in 13%, 104 14%, and 15% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, 105 respectively. The unsolicited adverse reactions that occurred most frequently (≥0.1% for 106 FLUARIX QUADRIVALENT) included dizziness, injection site hematoma, injection site 107 pruritus, and rash. Serious adverse events occurring within 21 days of vaccination were reported 108 in 0.5%, 0.6%, and 0.2% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or 109

6

TIV-2, respectively. 110

FLUARIX QUADRIVALENT in Children 111

Trial 2 was a randomized, double-blind, active-controlled, safety, and immunogenicity trial. In 112 this trial, subjects received FLUARIX QUADRIVALENT (N = 915) or one of two formulations 113 of comparator trivalent influenza vaccine (FLUARIX, TIV-1, N = 912 or TIV-2, N = 911), each 114 containing an influenza type B virus that corresponded to one of the two type B viruses in 115 FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the 116 Yamagata lineage). Subjects were aged 3 through 17 years and 52% were male; 56% were white, 117 29% were Asian, 12% were black, and 3% were of other racial/ethnic groups. Children aged 3 118 through 8 years with no history of influenza vaccination received 2 doses approximately 28 days 119 apart. Children aged 3 through 8 years with a history of influenza vaccination and children aged 120 9 years and older received one dose. Solicited local adverse reactions and systemic adverse 121 events were collected using diary cards for 7 days (day of vaccination and the next 6 days). The 122 frequencies of solicited adverse events are shown in Table 3. 123

7

Table 3. FLUARIX QUADRIVALENT: Incidence of Solicited Local Adverse Reactions 124 and Systemic Adverse Events within 7 Daysa after First Vaccination in Children Aged 3 125 through 17 Yearsb (Total Vaccinated Cohort) 126

FLUARIX QUADRIVALENTc

%


(B Victoria)d %

TIV-2 (B Yamagata)e

% Aged 3 through 17 Years Local N = 903 N = 901 N = 905 Painf 44 42 40 Redness 23 21 21 Swelling 19 17 15 Aged 3 through 5 Years Systemic N = 291 N = 314 N = 279 Drowsiness 17 12 14 Irritability 17 13 14 Loss of appetite 16 8 10 Fever ≥99.5°F (37.5°C) 9 9 8 Aged 6 through 17 Years Systemic N = 613 N = 588 N = 626 Fatigue 20 19 16 Muscle aches 18 16 16 Headache 16 19 15 Arthralgia 10 9 7 Gastrointestinal symptomsg 10 10 7 Shivering 6 4 5 Fever ≥99.5°F (37.5°C) 6 9 6

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 127 available. 128 a 7 days included day of vaccination and the subsequent 6 days. 129 b Trial 2: NCT01196988. 130 c Contained the same composition as FLUARIX (trivalent formulation) manufactured for the 131

2010-2011 season and an additional influenza type B virus of Yamagata lineage. 132 d Contained the same composition as FLUARIX manufactured for the 2010-2011 season (2 133

influenza A subtype viruses and an influenza type B virus of Victoria lineage). 134 e Contained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-135

2011 season and an influenza type B virus of Yamagata lineage. 136 f Percentage of subjects with pain by age subgroup: 39%, 38%, and 37% for FLUARIX 137

8

QUADRIVALENT, TIV-1, and TIV-2, respectively, in children aged 3 through 8 years and 138 52%, 50%, and 46% for FLUARIX QUADRIVALENT, TIV-1, and TIV-2, respectively, in 139 children aged 9 through 17 years. 140

g Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 141

In children who received a second dose of FLUARIX QUADRIVALENT, TIV-1, or TIV-2, the 142 incidences of adverse events following the second dose were generally lower than those 143 observed after the first dose. 144

Unsolicited adverse events occurring within 28 days of any vaccination were reported in 31%, 145 33%, and 34% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, 146 respectively. The unsolicited adverse reactions that occurred most frequently (≥0.1% for 147 FLUARIX QUADRIVALENT) included injection site pruritus and rash. Serious adverse events 148 occurring within 28 days of any vaccination were reported in 0.1%, 0.1%, and 0.1% of subjects 149 who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. 150

FLUARIX (Trivalent Formulation) 151

FLUARIX has been administered to 10,317 adults aged 18 through 64 years, 606 subjects aged 152 65 years and older, and 2,115 children aged 6 months through 17 years in clinical trials. The 153 incidence of solicited adverse events in each age group is shown in Tables 4 and 5. 154

9

Table 4. FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse 155 Reactions and Systemic Adverse Events within 4 Daysa of Vaccination in Adults (Total 156 Vaccinated Cohort) 157

Trial 3b Trial 4c Aged 18 through 64 Years Aged 65 Years and Older

FLUARIX N = 760

%

Placebo N = 192

%

FLUARIX N = 601-602

%

Comparator N = 596

% Local Pain 55 12 19 18 Redness 18 10 11 13 Swelling 9 6 6 9 Systemic Muscle aches 23 12 7 7 Fatigue 20 18 9 10 Headache 19 21 8 8 Arthralgia 6 6 6 5 Shivering 3 3 2 2 Fever ≥100.4°F (38.0°C)

2 2 – –

Fever ≥99.5°F (37.5°C)

– – 2 1

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 158 available. 159 a 4 days included day of vaccination and the subsequent 3 days. 160 b Trial 3 was a randomized, double-blind, placebo-controlled, safety, and immunogenicity trial 161

(NCT00100399). 162 c Trial 4 was a randomized, single-blind, active-controlled, safety, and immunogenicity trial 163

(NCT00197288). The active control was FLUZONE®, a US-licensed trivalent, inactivated 164 influenza vaccine (Sanofi Pasteur SA). 165

10

Table 5. FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse 166 Reactions and Systemic Adverse Events within 4 Daysa of First Vaccination in Children 167 Aged 3 through 17 Yearsb (Total Vaccinated Cohort) 168

Aged 3 through 4 Years Aged 5 through 17 Years FLUARIX

N = 350 %

Comparator N = 341

%

FLUARIX N = 1,348

%

Comparator N = 451

% Local Pain 35 38 56 56 Redness 23 20 18 16 Swelling 14 13 14 13 Systemic Irritability 21 22 – – Loss of appetite 13 15 – – Drowsiness 13 20 – – Fever ≥99.5°F (37.5°C) 7 8 4 3 Muscle aches – – 29 29 Fatigue – – 20 19 Headache – – 15 16 Arthralgia – – 6 6 Shivering – – 3 4

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 169 available. 170 a 4 days included day of vaccination and the subsequent 3 days. 171 b Trial 6 was a single-blind, active-controlled, safety, and immunogenicity US trial 172

(NCT00383123). The active control was FLUZONE, a US-licensed trivalent, inactivated 173 influenza vaccine (Sanofi Pasteur SA). 174

In children who received a second dose of FLUARIX or the comparator vaccine, the incidences 175 of adverse events following the second dose were similar to those observed after the first dose. 176

Serious Adverse Events: In the 4 clinical trials in adults (N = 10,923), there was a single case 177 of anaphylaxis within one day following administration of FLUARIX (<0.01%). 178

6.2 Postmarketing Experience 179

Beyond those events reported above in the clinical trials for FLUARIX QUADRIVALENT or 180 FLUARIX, the following adverse events have been spontaneously reported during postapproval 181 use of FLUARIX (trivalent influenza vaccine). This list includes serious events or events which 182 have causal connection to FLUARIX. Because these events are reported voluntarily from a 183 population of uncertain size, it is not always possible to reliably estimate their frequency or 184 establish a causal relationship to the vaccine. 185

11

Blood and Lymphatic System Disorders 186

Lymphadenopathy. 187

Cardiac Disorders 188

Tachycardia. 189

Ear and Labyrinth Disorders 190

Vertigo. 191

Eye Disorders 192

Conjunctivitis, eye irritation, eye pain, eye redness, eye swelling, eyelid swelling. 193

Gastrointestinal Disorders 194

Abdominal pain or discomfort, swelling of the mouth, throat, and/or tongue. 195

General Disorders and Administration Site Conditions 196

Asthenia, chest pain, feeling hot, injection site mass, injection site reaction, injection site 197 warmth, body aches. 198

Immune System Disorders 199

Anaphylactic reaction including shock, anaphylactoid reaction, hypersensitivity, serum sickness. 200

Infections and Infestations 201

Injection site abscess, injection site cellulitis, pharyngitis, rhinitis, tonsillitis. 202

Nervous System Disorders 203

Convulsion, encephalomyelitis, facial palsy, facial paresis, Guillain-Barré syndrome, 204 hypoesthesia, myelitis, neuritis, neuropathy, paresthesia, syncope. 205

Respiratory, Thoracic, and Mediastinal Disorders 206

Asthma, bronchospasm, dyspnea, respiratory distress, stridor. 207

Skin and Subcutaneous Tissue Disorders 208

Angioedema, erythema, erythema multiforme, facial swelling, pruritus, Stevens-Johnson 209 syndrome, sweating, urticaria. 210

Vascular Disorders 211

Henoch-Schönlein purpura, vasculitis. 212

7 DRUG INTERACTIONS 213

7.1 Concomitant Vaccine Administration 214

FLUARIX QUADRIVALENT should not be mixed with any other vaccine in the same syringe 215

12

or vial. 216

There are insufficient data to assess the concurrent administration of FLUARIX 217 QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is 218 required, the vaccines should be administered at different injection sites. 219

7.2 Immunosuppressive Therapies 220

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic 221 drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune 222 response to FLUARIX QUADRIVALENT. 223

8 USE IN SPECIFIC POPULATIONS 224

8.1 Pregnancy 225

Pregnancy Category B. A reproductive and developmental toxicity study has been performed in 226 female rats at doses approximately 80 times the human dose (on a mg/kg basis) and revealed no 227 evidence of impaired female fertility or harm to the fetus due to FLUARIX QUADRIVALENT. 228 There are, however, no adequate and well-controlled studies in pregnant women. Because animal 229 reproduction studies are not always predictive of human response, FLUARIX 230 QUADRIVALENT should be given to a pregnant woman only if clearly needed. 231

In a reproductive and developmental toxicity study, the effect of FLUARIX QUADRIVALENT 232 on embryo-fetal and pre-weaning development was evaluated in rats. Animals were administered 233 FLUARIX QUADRIVALENT by intramuscular injection twice prior to gestation, during the 234 period of organogenesis (gestation Days 3, 8, 11, and 15), and during lactation (Day 7), 235 0.2 mL/rat/occasion (approximately 80-fold excess relative to the projected human dose on a 236 body weight basis). No adverse effects on mating, female fertility, pregnancy, parturition, 237 lactation parameters, and embryo-fetal or pre-weaning development were observed. There were 238 no vaccine-related fetal malformations or other evidence of teratogenesis. 239

Pregnancy Registry 240

GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy outcomes and 241 newborn health status outcomes following vaccination with FLUARIX QUADRIVALENT 242 during pregnancy. Women who receive FLUARIX QUADRIVALENT during pregnancy should 243 be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact 244 GlaxoSmithKline by calling 1-888-452-9622. 245

8.3 Nursing Mothers 246

It is not known whether FLUARIX QUADRIVALENT is excreted in human milk. Because 247 many drugs are excreted in human milk, caution should be exercised when FLUARIX 248 QUADRIVALENT is administered to a nursing woman. 249

13

8.4 Pediatric Use 250

Safety and effectiveness of FLUARIX QUADRIVALENT in children younger than 3 years have 251 not been established. 252

Safety and immunogenicity of FLUARIX QUADRIVALENT in children aged 3 through 253 17 years have been evaluated [see Adverse Reactions (6.1), Clinical Studies (14.3)]. 254

8.5 Geriatric Use 255

In a randomized, double-blind (2 arms) and open-label (one arm), active-controlled trial, 256 immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who 257 received FLUARIX QUADRIVALENT (N = 1,517); 469 of these subjects were aged 75 years 258 and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-259 vaccination and seroconversion rates were lower than in younger subjects (aged 18 through 260 64 years) and the frequencies of solicited and unsolicited adverse events were generally lower 261 than in younger subjects. 262

11 DESCRIPTION 263

FLUARIX QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a sterile 264 colorless and slightly opalescent suspension. FLUARIX QUADRIVALENT is prepared from 265 influenza viruses propagated in embryonated chicken eggs. Each of the influenza viruses is 266 produced and purified separately. After harvesting the virus-containing fluids, each influenza 267 virus is concentrated and purified by zonal centrifugation using a linear sucrose density gradient 268 solution containing detergent to disrupt the viruses. Following dilution, the vaccine is further 269 purified by diafiltration. Each influenza virus solution is inactivated by the consecutive effects of 270 sodium deoxycholate and formaldehyde leading to the production of a “split virus.” Each split 271 inactivated virus is then suspended in sodium phosphate-buffered isotonic sodium chloride 272 solution. Each vaccine is formulated from the split inactivated virus solutions. 273

FLUARIX QUADRIVALENT has been standardized according to USPHS requirements for the 274 2016-2017 influenza season and is formulated to contain 60 micrograms (mcg) hemagglutinin 275 (HA) per 0.5-mL dose, in the recommended ratio of 15 mcg HA of each of the following 276 4 influenza virus strains: A/Christchurch/16/2010 (H1N1) NIB-74XP (an A/California/7/2009 277 (H1N1) pdm09-like virus), A/Hong Kong/4801/2014 (H3N2) NYMC X-263B, 278 B/Phuket/3073/2013, and B/Brisbane/60/2008. 279

FLUARIX QUADRIVALENT is formulated without preservatives. FLUARIX 280 QUADRIVALENT does not contain thimerosal. Each 0.5-mL dose also contains octoxynol-10 281 (TRITON® X-100) ≤0.115 mg, α-tocopheryl hydrogen succinate ≤0.135 mg, and polysorbate 80 282 (Tween 80) ≤0.550 mg. Each dose may also contain residual amounts of hydrocortisone 283 ≤0.0016 mcg, gentamicin sulfate ≤0.15 mcg, ovalbumin ≤0.050 mcg, formaldehyde ≤5 mcg, and 284 sodium deoxycholate ≤65 mcg from the manufacturing process. 285

14

The tip caps and plungers of the prefilled syringes of FLUARIX QUADRIVALENT are not 286 made with natural rubber latex. 287

12 CLINICAL PHARMACOLOGY 288

12.1 Mechanism of Action 289

Influenza illness and its complications follow infection with influenza viruses. Global 290 surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of 291 influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. 292

Public health authorities give annual influenza vaccine composition recommendations. 293 Inactivated influenza vaccines are standardized to contain the hemagglutinins of influenza 294 viruses representing the virus types or subtypes likely to circulate in the United States during the 295 influenza season. Two influenza type B virus lineages (Victoria and Yamagata) are of public 296 health importance because they have co-circulated since 2001. FLUARIX (trivalent influenza 297 vaccine) contains 2 influenza A subtype viruses and one influenza type B virus. 298

Specific levels of hemagglutination-inhibition (HI) antibody titer post-vaccination with 299 inactivated influenza virus vaccines have not been correlated with protection from influenza 300 illness but the HI antibody titers have been used as a measure of vaccine activity. In some human 301 challenge studies, HI antibody titers of ≥1:40 have been associated with protection from 302 influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype 303 confers little or no protection against another virus. Furthermore, antibody to one antigenic 304 variant of influenza virus might not protect against a new antigenic variant of the same type or 305 subtype. Frequent development of antigenic variants through antigenic drift is the virological 306 basis for seasonal epidemics and the reason for the usual replacement of one or more influenza 307 viruses in each year’s influenza vaccine. 308

Annual revaccination is recommended because immunity declines during the year after 309 vaccination, and because circulating strains of influenza virus change from year to year.3 310

13 NONCLINICAL TOXICOLOGY 311

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 312

FLUARIX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential. 313 Vaccination of female rats with FLUARIX QUADRIVALENT, at doses shown to be 314 immunogenic in the rat, had no effect on fertility. 315

14 CLINICAL STUDIES 316

14.1 Efficacy against Culture-confirmed Influenza 317

The efficacy experience with FLUARIX is relevant to FLUARIX QUADRIVALENT because 318 both vaccines are manufactured using the same process and have overlapping compositions [see 319

15

Description (11)]. 320

The efficacy of FLUARIX was evaluated in a randomized, double-blind, placebo-controlled trial 321 conducted in 2 European countries during the 2006-2007 influenza season. Efficacy of 322 FLUARIX, containing A/New Caledonia/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and 323 B/Malaysia/2506/2004 influenza virus strains, was defined as the prevention of culture-324 confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with 325 placebo. Healthy subjects aged 18 through 64 years (mean age: 40 years) were randomized (2:1) 326 to receive FLUARIX (N = 5,103) or placebo (N = 2,549) and monitored for influenza-like 327 illnesses (ILI) starting 2 weeks post-vaccination and lasting for approximately 7 months. In the 328 overall population, 60% of subjects were female and 99.9% were white. Culture-confirmed 329 influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was 330 defined as at least one general symptom (fever ≥100°F and/or myalgia) and at least one 331 respiratory symptom (cough and/or sore throat). After an episode of ILI, nose and throat swab 332 samples were collected for analysis; attack rates and vaccine efficacy were calculated (Table 6). 333

Table 6. FLUARIX (Trivalent Formulation): Attack Rates and Vaccine Efficacy against 334 Culture-confirmed Influenza A and/or B in Adults (Total Vaccinated Cohort) 335

Attack Rates (n/N) Vaccine Efficacy N N % % LL UL

Antigenically Matched Strainsa FLUARIX 5,103 49 1.0 66.9b 51.9 77.4 Placebo 2,549 74 2.9 – – – All Culture-confirmed Influenza (Matched, Unmatched, and Untyped)c FLUARIX 5,103 63 1.2 61.6b 46.0 72.8 Placebo 2,549 82 3.2 – – –

a There were no vaccine matched culture-confirmed cases of A/New Caledonia/20/1999 336 (H1N1) or B/Malaysia/2506/2004 influenza virus strains with FLUARIX or placebo. 337

b Vaccine efficacy for FLUARIX exceeded a pre-defined threshold of 35% for the lower limit 338 of the 2-sided 95% CI. 339

c Of the 22 additional cases, 18 were unmatched and 4 were untyped; 15 of the 22 cases were A 340 (H3N2) (11 cases with FLUARIX and 4 cases with placebo). 341

In a post-hoc, exploratory analysis by age, vaccine efficacy (against culture-confirmed influenza 342 A and/or B cases, for vaccine antigenically matched strains) in subjects aged 18 through 49 years 343 was 73.4% (95% CI: 59.3, 82.8) [number of influenza cases: FLUARIX (n = 35/3,602) and 344 placebo (n = 66/1,810)]. In subjects aged 50 through 64 years, vaccine efficacy was 13.8% 345 (95% CI: -137.0, 66.3) [number of influenza cases: FLUARIX (n = 14/1,501) and placebo 346 (n = 8/739)]. As the trial lacked statistical power to evaluate efficacy within age subgroups, the 347 clinical significance of these results is unknown. 348

16

14.2 Immunological Evaluation of FLUARIX QUADRIVALENT in Adults 349

Trial 1 was a randomized, double-blind (2 arms) and open-label (one arm), active-controlled, 350 safety, immunogenicity, and non-inferiority trial. In this trial, subjects received FLUARIX 351 QUADRIVALENT (N = 1,809) or one of two formulations of comparator trivalent influenza 352 vaccine (FLUARIX, TIV-1, N = 608 or TIV-2, N = 534), each containing an influenza type B 353 virus that corresponded to one of the two type B viruses in FLUARIX QUADRIVALENT (a 354 type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). Subjects aged 355 18 years and older (mean age: 58 years) were evaluated for immune responses to each of the 356 vaccine antigens 21 days following vaccination. In the overall population, 57% of subjects were 357 female; 69% were white, 27% were Asian, and 4% were of other racial/ethnic groups. 358

The immunogenicity endpoints were GMTs of serum hemagglutination-inhibition (HI) 359 antibodies adjusted for baseline, and the percentage of subjects who achieved seroconversion, 360 defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 361 4-fold increase in serum HI antibody titer over baseline to ≥1:40 following vaccination, 362 performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results 363 were available after vaccination. FLUARIX QUADRIVALENT was non-inferior to both TIVs 364 based on adjusted GMTs (upper limit of the 2-sided 95% CI for the GMT ratio [TIV/FLUARIX 365 QUADRIVALENT] ≤1.5) and seroconversion rates (upper limit of the 2-sided 95% CI on 366 difference of the TIV minus FLUARIX QUADRIVALENT ≤10%). The antibody response to 367 influenza B strains contained in FLUARIX QUADRIVALENT was higher than the antibody 368 response after vaccination with a TIV containing an influenza B strain from a different lineage. 369 There was no evidence that the addition of the second B strain resulted in immune interference to 370 other strains included in the vaccine (Table 7). 371

17

Table 7. FLUARIX QUADRIVALENT: Immune Responses to Each Antigen 21 Days after 372 Vaccination in Adults (ATP Cohort for Immunogenicity) 373

FLUARIX QUADRIVALENTa


(B Victoria)b TIV-2

(B Yamagata)c GMTs N = 1,809

(95% CI) N = 608

(95% CI) N = 534

(95% CI) A/California/7/2009 (H1N1)

201.1 (188.1, 215.1)

218.4 (194.2, 245.6)

213.0 (187.6, 241.9)

A/Victoria/210/2009 (H3N2)

314.7 (296.8, 333.6)

298.2 (268.4, 331.3)

340.4 (304.3, 380.9)

B/Brisbane/60/2008 (Victoria lineage)

404.6 (386.6, 423.4)

393.8 (362.7, 427.6)

258.5 (234.6, 284.8)

B/Brisbane/3/2007 (Yamagata lineage)

601.8 (573.3, 631.6)

386.6 (351.5, 425.3)

582.5 (534.6, 634.7)

Seroconversiond N = 1,801 %

(95% CI)

N = 605 %

(95% CI)

N = 530 %


77.5 (75.5, 79.4)

77.2 (73.6, 80.5)

80.2 (76.5, 83.5)


71.5 (69.3, 73.5)

65.8 (61.9, 69.6)

70.0 (65.9, 73.9)


58.1 (55.8, 60.4)

55.4 (51.3, 59.4)

47.5 (43.2, 51.9)


61.7 (59.5, 64.0)

45.6 (41.6, 49.7)

59.1 (54.7, 63.3)

ATP = According-to-protocol; GMT = Geometric mean antibody titer; CI = Confidence Interval. 374

ATP cohort for immunogenicity included subjects for whom assay results were available after 375 vaccination for at least one trial vaccine antigen. 376 a Contained the same composition as FLUARIX (trivalent formulation) manufactured for the 377

2010-2011 season and an additional influenza type B virus of Yamagata lineage. 378 b Contained the same composition as FLUARIX manufactured for the 2010-2011 season (2 379

influenza A subtype viruses and an influenza type B virus of Victoria lineage). 380 c Contained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-381

2011 season and an influenza type B virus of Yamagata lineage. 382 d Seroconversion defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer 383

≥1:40 or at least a 4-fold increase in serum titers of HI antibodies to ≥1:40. 384

18

14.3 Immunological Evaluation of FLUARIX QUADRIVALENT in Children 385

Trial 2 was a randomized, double-blind, active-controlled, safety, immunogenicity, and non-386 inferiority trial. In this trial, subjects received FLUARIX QUADRIVALENT (N = 791) or one of 387 two formulations of comparator trivalent influenza vaccine (FLUARIX, TIV-1, N = 819 or TIV-388 2, N = 801), each containing an influenza type B virus that corresponded to one of the two type 389 B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B 390 virus of the Yamagata lineage). In children aged 3 through 17 years, immune responses to each 391 of the vaccine antigens were evaluated in sera 28 days following 1 or 2 doses. In the overall 392 population, 52% of subjects were male; 56% were white, 29% were Asian, 12% were black, and 393 3% were of other racial/ethnic groups. 394

The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects 395 who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-396 vaccination titer ≥1:40 or at least a 4-fold increase in serum HI titer over baseline to ≥1:40, 397 following vaccination, performed on the According-to-Protocol (ATP) cohort for whom 398 immunogenicity assay results were available after vaccination. FLUARIX QUADRIVALENT 399 was non-inferior to both TIVs based on adjusted GMTs (upper limit of the 2-sided 95% CI for 400 the GMT ratio [TIV/FLUARIX QUADRIVALENT] ≤1.5) and seroconversion rates (upper limit 401 of the 2-sided 95% CI on difference of the TIV minus FLUARIX QUADRIVALENT ≤10%). 402 The antibody response to influenza B strains contained in FLUARIX QUADRIVALENT was 403 higher than the antibody response after vaccination with a TIV containing an influenza B strain 404 from a different lineage. There was no evidence that the addition of the second B strain resulted 405 in immune interference to other strains included in the vaccine (Table 8). 406

19

Table 8. FLUARIX QUADRIVALENT: Immune Responses to Each Antigen 28 Days after 407 Last Vaccination in Children Aged 3 through 17 Years (ATP Cohort for Immunogenicity) 408

FLUARIX

QUADRIVALENTa


(B Victoria)b TIV-2

(B Yamagata)c GMTs N = 791

(95% CI) N = 818

(95% CI) N = 801


386.2 (357.3, 417.4)

433.2 (401.0, 468.0)

422.3 (390.5, 456.5)


228.8 (215.0, 243.4)

227.3 (213.3, 242.3)

234.0 (219.1, 249.9)


244.2 (227.5, 262.1)

245.6 (229.2, 263.2)

88.4 (81.5, 95.8)


569.6 (533.6, 608.1)

224.7 (207.9, 242.9)

643.3 (603.2, 686.1)

Seroconversiond N = 790 %

(95% CI)

N = 818 %

(95% CI)

N = 800 %


91.4 (89.2, 93.3)

89.9 (87.6, 91.8)

91.6 (89.5, 93.5)


72.3 (69.0, 75.4)

70.7 (67.4, 73.8)

71.9 (68.6, 75.0)


70.0 (66.7, 73.2)

68.5 (65.2, 71.6)

29.6 (26.5, 32.9)


72.5 (69.3, 75.6)

37.0 (33.7, 40.5)

70.8 (67.5, 73.9)

ATP = According-to-protocol; GMT = Geometric mean antibody titer; CI = Confidence Interval. 409

ATP cohort for immunogenicity included subjects for whom assay results were available after 410 vaccination for at least one trial vaccine antigen. 411 a Contained the same composition as FLUARIX (trivalent formulation) manufactured for the 412

2010-2011 season and an additional influenza type B virus of Yamagata lineage. 413 b Contained the same composition as FLUARIX manufactured for the 2010-2011 season (2 414

influenza A subtype viruses and an influenza type B virus of Victoria lineage). 415 c Contained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-416

2011 season and an influenza B virus of Yamagata lineage. 417 d Seroconversion defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer 418

≥1:40 or at least a 4-fold increase in serum titers of HI antibodies to ≥1:40. 419

20

15 REFERENCES 420

1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 421 vaccination. Virus Res. 2004;103:133-138. 422

2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting 423 antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg 424 Camb. 1972;70:767-777. 425

3. Centers for Disease Control and Prevention. Prevention and Control of Influenza with 426 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). 427 MMWR 2010;59(RR-8):1-62. 428

16 HOW SUPPLIED/STORAGE AND HANDLING 429

NDC 58160-905-41 Syringe in Package of 10: NDC 58160-905-52 430

Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has 431 been frozen. Store in the original package to protect from light. 432

17 PATIENT COUNSELING INFORMATION 433

Provide the following information to the vaccine recipient or guardian: 434

• Inform of the potential benefits and risks of immunization with FLUARIX 435 QUADRIVALENT. 436

• Educate regarding potential side effects, emphasizing that: (1) FLUARIX 437 QUADRIVALENT contains non-infectious killed viruses and cannot cause influenza and (2) 438 FLUARIX QUADRIVALENT is intended to provide protection against illness due to 439 influenza viruses only, and cannot provide protection against all respiratory illness. 440

• Inform that safety and efficacy have not been established in pregnant women. Register 441 women who receive FLUARIX QUADRIVALENT while pregnant in the pregnancy registry 442 by calling 1-888-452-9622. 443

• Give the Vaccine Information Statements, which are required by the National Childhood 444 Vaccine Injury Act of 1986 prior to each immunization. These materials are available free of 445 charge at the Centers for Disease Control and Prevention (CDC) website 446 (www.cdc.gov/vaccines). 447

• Instruct that annual revaccination is recommended. 448

FLUARIX and TIP-LOK are registered trademarks of the GSK group of companies. The other 449 brands listed are trademarks of their respective owners and are not trademarks of the GSK group 450 of companies. The makers of these brands are not affiliated with and do not endorse the GSK 451 group of companies or its products. 452

http://www.cdc.gov/nip

21

453 Manufactured by GlaxoSmithKline Biologicals, Dresden, Germany, 454 a branch of SmithKline Beecham Pharma GmbH & Co. KG, Munich, Germany 455 Licensed by GlaxoSmithKline Biologicals, Rixensart, Belgium, US License 1617 456 Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709 457

©201X the GSK group of companies. All rights reserved. 458

FLQ:XPI 459

Protein Sciences Corporation Influenza Vaccine Package Insert BLA STN 125285

Flublok PI (V4.0), 2016 Page 1 of 16

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Flublok® safely and effectively. See full prescribing information for Flublok. Flublok (Influenza Vaccine) Sterile Solution for Intramuscular Injection 2016-2017 Formula Initial U.S. Approval: 2013 --------------RECENT MAJOR CHANGES------------ Indications and Usage (1) 10/2014 --------------INDICATIONS AND USAGE------------- • Flublok is a vaccine indicated for active

immunization against disease caused by influenza virus subtypes A and type B contained in the vaccine. Flublok is approved for use in persons 18 years of age and older. (1)

• In persons 18 through 49 years of age, this indication is based on a controlled clinical study demonstrating a decrease in influenza disease after vaccination with Flublok. In persons 50 years of age and older, this indication is based on the immune response elicited by Flublok; data demonstrating a decrease in influenza disease in persons 50 years and older after vaccination with Flublok are not available. (14)

---------DOSAGE AND ADMINISTRATION-------- For intramuscular (IM) injection only (0.5 mL). (2) -------DOSAGE FORMS AND STRENGTHS-------- A sterile solution for injection supplied in 0.5mL single dose vials. (3) --------------CONTRAINDICATIONS------------------ • Severe allergic reaction (e.g., anaphylaxis) to any

component of the vaccine. (4, 6.2, 11) ----------WARNINGS AND PRECAUTIONS--------- • Appropriate medical treatment and supervision

must be available to manage possible

anaphylactic reactions following administration of Flublok. (5.1)

• If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give Flublok should be based on careful consideration of potential benefits and risks. (5.2)

---------------ADVERSE REACTIONS----------------- • In adults 18 through 49 years of age, the most

common (≥10%) injection-site reaction was pain (37%); the most common (≥10%) solicited systemic adverse reactions were headache (15%), fatigue (15%) and myalgia (11%). (6.1)

• In adults 50 through 64 years of age, the most common (≥10%) injection site reaction was pain (32%); the most common (≥10%) solicited systemic adverse reactions were headache (17%), fatigue (13%), and muscle pain (11%). (6.1)

• In adults 65 years of age and older, the most common (≥10%) injection site reaction was pain (19%); the most common (≥10%) solicited systemic adverse reactions were fatigue (13%) and headache (10%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Protein Sciences Corporation at 1-888-855-7871 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. -----------USE IN SPECIFIC POPULATIONS------- • Pregnancy: A registry is available for Flublok. Contact: Protein Sciences Corporation by calling 1-888-855-7871. (8.1) See 17 for PATIENT COUNSELING INFORMATION.

Revised: April 2016




2.1 Dosage 2.2 Administration

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Managing Allergic Reactions

5.2 Guillain Barré Syndrome 5.3 Altered Immunocompetence 5.4 Limitations of Vaccine Effectiveness


7 DRUG INTERACTIONS



12.1 Mechanism of Action 13 NONCLINICAL TOXICOLOGY 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING


17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. ___________________________________________




1 INDICATIONS AND USAGE

Flublok is a vaccine indicated for active immunization against disease caused by influenza virus subtypes A and type B contained in the vaccine. Flublok is approved for use in persons 18 years of age and older.

In persons 18 through 49 years of age, this indication is based on a controlled clinical study demonstrating a decrease in influenza disease after vaccination with Flublok. In persons 50 years of age and older, this indication is based on the immune response elicited by Flublok; data demonstrating a decrease in influenza disease in persons 50 years and older after vaccination with Flublok are not available. (see Clinical Studies [14])

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Dosage

Administer Flublok as a single 0.5-mL dose.

2.2 Administration

Shake the single-dose vial gently before withdrawing the vaccine dose.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits. If either of these conditions exists, the vaccine should not be administered.

The preferred site for injection is the deltoid muscle. Administration is by sterile needle and syringe.

Flublok should not be mixed with any other vaccine in the same syringe or vial.

3 DOSAGE FORMS AND STRENGTHS

Flublok is a sterile solution supplied in single-dose vials, 0.5 mL.

4 CONTRAINDICATIONS

Flublok is contraindicated in individuals with known severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine (see Description [11] and Postmarketing Experience [6.2]).

5 WARNINGS AND PRECAUTIONS

5.1 Managing Allergic Reactions



Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

5.2 Guillain Barré Syndrome

The 1976 swine influenza vaccine was associated with an increased frequency 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 one additional case per 1 million persons vaccinated. If GBS has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give Flublok should be based on careful consideration of the potential benefits and risks.

5.3 Altered Immunocompetence

If Flublok is administered to immunocompromised individuals, including persons receiving immunosuppressive therapy, the immune response may be diminished.

5.4 Limitations of Vaccine Effectiveness

Vaccination with Flublok may not protect all vaccine recipients.

6 ADVERSE REACTIONS

In adults 18 through 49 years of age, the most common (≥10%) injection-site reaction was pain (37%); the most common (≥10%) solicited systemic adverse reactions were headache (15%), fatigue (15%) and muscle pain (11%). (6.1)

In adults 50 through 64 years of age, the most common (≥10%) injection site reaction was pain (32%); the most common (≥10%) solicited systemic adverse reactions were headache (17%), fatigue (13%), and muscle pain (11%). (6.1) In adults 65 years of age and older, the most common (≥10%) injection site reaction was pain (19%); the most common (≥10%) solicited systemic adverse reactions were fatigue (13%) and headache (10%). (6.1)

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to rates in the clinical studies of another vaccine and may not reflect the rates observed in clinical practice.

Flublok has been administered to and safety data collected from 2497 adults 18 through 49 years of age, 972 adults 50 through 64 years of age, and 1078 adults aged 65 years and older enrolled in five randomized, placebo- or active-controlled clinical trials. Clinical safety data for Flublok are presented from four clinical trials (Studies 1, 2, 3, and 4). Data from a placebo-controlled trial in adults 18 through 49 years of age (Study 1) are presented, followed by data pooled according to age group from Studies 2 and 4 (adults 50 through 64 years of age) and Studies 3 and 4 (adults aged 65 years and older). Reactogenicity data from a small Phase 2 trial (Study 5) in adults 18 through 49 years of age, 153 of whom



received Flublok 135mcg, are not presented. However, subjects from Study 5 are included in the description of deaths and serious adverse events (SAEs). In all studies local (injection site) and systemic adverse reactions were solicited with the use of a memory aid for 7 days following vaccination, and unsolicited adverse reactions were collected for 28-30 days post-vaccination. In Studies 1- 3 and 5, SAEs were collected for 6 months post-vaccination via clinic visit or telephone follow up on Day 28, telephone follow up on Day 180, or by spontaneous reporting. Study 4 collected SAEs through 30 days following receipt of vaccine. Study 4 also actively solicited pre-specified common hypersensitivity-type reactions through 30 days following receipt of vaccine as a primary endpoint.

Study 1 included 4648 subjects 18 through 49 years of age for safety analysis, randomized to receive Flublok (n=2344) or placebo (n=2304) (2) (see Clinical Studies [14]).

Study 2 included 602 subjects 50 through 64 years of age for safety analysis, randomized to receive Flublok (n=300) or another U.S.-licensed trivalent influenza vaccine (Fluzone, manufactured by Sanofi Pasteur, Inc.) as an active control (n=302) (3) (see Clinical Studies [14]).

Study 3 included 869 subjects aged 65 years and older for safety analysis, randomized to receive Flublok (n=436) or another U.S.-licensed trivalent influenza vaccine (Fluzone) as an active control (n=433) (4) (see Clinical Studies [14]).

Study 4 included 2627 subjects aged 50 years and older for safety analysis, randomized to receive Flublok (n=1314) or another U.S.-licensed trivalent influenza vaccine (Afluria, manufactured by bioCSL Pty Ltd.) as an active control (n=1313). Among subjects 50 through 64 years of age, 672 received Flublok and 665 received Afluria. Among subjects aged 65 years and older, 642 received Flublok and 648 received Afluria (see Clinical Studies [14]).

In a clinical trial of adults 18-49 years of age (Study 1, Table 1) the mean age of participants was 32.5 years, 59% were female, and 67% were Caucasian (see Clinical Studies [14]).



Table 1: Frequency of Solicited Local Injection Site Reactions and Systemic Adverse Reactions within 7 Days of Administration of Flublok or Placebo in Adults 18-49 Years of Age, Study 1, Total Vaccinated Cohort1,2,3

Flublok N=2272

Placebo N=2231

Local % % Any Mod4 Sev4 Any Mod4 Sev4

Pain 37 2 <1 8 <1 <1 Redness 4 <1 <1 2 <1 <1 Swelling 3 <1 <1 2 <1 <1 Bruising 3 <1 <1 3 <1 <1

Systemic % % Headache 15 3 <1 16 3 <1 Fatigue 15 3 <1 14 3 <1 Muscle Pain 11 2 <1 7 <1 <1 Nausea 6 1 <1 5 1 <1 Joint pain 4 <1 <1 4 <1 <1 Chills 3 <1 <1 3 <1 <1 Fever‡ <1 <1 <1 <1 <1 <1

NOTE: Data based on the most severe response reported by subjects. Results ≥1% reported to nearest whole percent; results >0 but <1% reported as <1%. ‡ Fever defined as ≥100.4°F (38°C). Mild (≥100.4º to <101.1ºF); Moderate (≥101.2ºF to <102.2ºF); Severe (≥102.2ºF) 1 Total Vaccinated Cohort is defined as all randomized subjects who received study vaccine according to the treatment actually received and who provided data. 2 Study 1 is registered as NCT00539981 under the National Clinical Trials registry. 3 Denominators for Study 1: The total number of enrolled, randomized, and vaccinated subjects was 2344 in the Flublok group and 2304 in the placebo group. For all categories except fever, the number of subjects with missing values was 72 in the Flublok group and 73 in the Placebo group so that these denominators are 2272 and 2231 respectively. For fever, 89 Flublok recipients and 104 Placebo recipients were missing data, making these denominators 2255 and 2200 respectively. 4 Moderate = had it, and it was bad enough to prevent a significant part of usual activities; Severe = had it, and it prevented most or all of normal activities, or had to see a doctor for prescription medicine.

Across three clinical trials (Studies 2 – 4, Tables 2 and 3) a total of 2050 adults age 50 years and older received Flublok and 2048 received a U.S.-licensed IIV3 comparator. The mean age of these study participants was 65 years; 56% were female and 80% were Caucasian (see Clinical Studies [14]).



The incidence of solicited reactogenicity differed between adults 50 through 64 years of age and adults aged 65 years and older. Therefore, data from Studies 2, 3, and 4 were pooled according to age group and are presented separately (Tables 2 and 3).

Most events in both age groups were mild in severity. Table 2: Frequency of Solicited Local Injection Site Reactions and Systemic Adverse Reactions within 7 Days of Administration of Flublok or Comparator in Adults 50-64 Years of Age, Studies 2 and 4, Total Vaccinated Cohort1,2

Flublok N=972

IIV32 N=967

Any Mod3 Sev3 Any Mod3 Sev3 Local % Pain 32 2 <1 37 <1 0 Firmness/Swelling 7 2 <1 6 1 <1 Redness 6 2 <1 5 1 <1 Systemic % Headache 17 4 <1 16 3 <1 Fatigue 13 3 <1 17 3 <1 Muscle Pain 11 2 <1 11 2 <1 Joint Pain 8 2 <1 8 2 <1 Nausea 6 1 0 5 <1 <1 Shivers/Chills 5 1 0 4 <1 <1 Fever‡ <1 <1 <1 <1 0 0 NOTE: Data based on the most severe response reported by subjects. Results ≥1% reported to nearest whole percent; results >0 but <1% reported as <1%. ‡ Fever defined as ≥100.4°F (38°C). Mild (≥100.4º to <101.1ºF); Moderate (≥101.2ºF to <102.2ºF); Severe (≥102.2ºF) For fever, 12 Flublok recipients and 5 IIV3 recipients were missing data, making these denominators 964 and 962, respectively. 1 Total Vaccinated Cohort is defined as all randomized subjects who received study vaccine according to the treatment actually received and who provided data. 2 Pooled Data from Studies 2 and 4. For Studies 2 and 4, the U.S.-licensed IIV3 comparators were Fluzone and Afluria, respectively. Studies 2 and 4 are registered as NCT00539864 and NCT01825200, respectively, under the National Clinical Trials registry. 3 Moderate = had it, and it was bad enough to prevent a significant part of usual activities; Severe = had it, and it prevented most or all of normal activities, or had to see a doctor for prescription medicine.



Table 3: Frequency of Solicited Local Injection Site Reactions and Systemic Adverse Reactions within 7 Days of Administration of Flublok or Comparator in Adults ≥65 Years of Age, Studies 3 and 4, Total Vaccinated Cohort 1,2

Flublok N=1078

IIV32 N=1081

Any Mod3 Sev3 Any Mod3 Sev3 Local % Pain 19 <1 <1 20 <1 <1 Redness 7 1 <1 7 1 1 Firmness/Swelling 7 2 <1 7 <1 <1 Systemic % Fatigue 13 3 <1 15 2 <1 Headache 10 <1 <1 9 1 <1 Muscle Pain 8 2 <1 8 1 <1 Joint Pain 6 1 <1 6 1 <1 Shivers/Chills 5 <1 <1 5 <1 <1 Nausea 4 <1 <1 3 <1 <1 Fever‡ 3 <1 <1 2 0 0 NOTE: Data based on the most severe response reported by subjects. Results ≥1% reported to nearest whole percent; results >0 but <1% reported as <1%. ‡ Fever defined as ≥100.4°F (38°C). Mild (≥100.4º to <101.1ºF); Moderate (≥101.2ºF to <102.2ºF); Severe (≥102.2ºF) 1 Total Vaccinated Cohort is defined as all randomized subjects who received study vaccine according to the treatment actually received and who provided data. 2 Pooled Data from Studies 3 and 4. For Studies 3 and 4, the U.S.-licensed IIV3 comparators were Fluzone and Afluria, respectively. Studies 3 and 4 are registered as NCT00395174 and NCT01825200, respectively, under the National Clinical Trials registry. 3 Moderate = had it, and it was bad enough to prevent a significant part of usual activities; Severe = had it, and it prevented most or all of normal activities, or had to see a doctor for prescription medicine.

Among adults 18-49 years of age (Studies 1 and 5 pooled), through 6 months post-vaccination, two deaths were reported, one in a Flublok recipient and one in a placebo recipient. Both deaths occurred more than 28 days following vaccination and neither was considered vaccine-related. SAEs were reported by 32 Flublok recipients and 35 placebo recipients. One SAE in a Flublok recipient was assessed as possibly related to the vaccine: pleuropericarditis with effusions requiring hospitalization and drainage. No specific cause was identified. The patient recovered.

Among adults 50-64 years of age (Studies 2 and 4 pooled), through up to 6 months post-vaccination, there were no deaths; SAEs were reported by 10 subjects, 6 Flublok recipients and 4 IIV3 recipients. One of the SAEs, vasovagal syncope following injection of Flublok, was considered related to study vaccine. Among adults 65 years of age and older (Studies 3 and 4 pooled), through up to 6 months post-vaccination, there were 4 deaths, 2 in Flublok recipients and 2 in IIV3 recipients. None were considered related to the study vaccines. SAEs were reported from 80 subjects, 37 Flublok recipients, 43 in IIV3 recipients. None were considered related to the study vaccines.



In Study 1(adults 18-49 years of age), the most frequent unsolicited adverse events, occurring in 1%-2% of subjects, were nasopharyngitis, upper respiratory infection, headache, cough, nasal congestion, pharyngolaryngeal pain, and rhinorrhea.

Among adults 50-64 years of age (Studies 2 and 4 pooled), the most frequent unsolicited adverse events, occurring in 1% of subjects, were diarrhea and cough. Among adults ≥65 years of age (Studies 3 and 4 pooled), the most frequent unsolicited adverse events, occurring in 1% of subjects, were nasopharyngitis and cough.

Among adults 50 years of age and older (Study 4) for whom the incidence of rash, urticaria, swelling, non-pitting edema, or other potential hypersensitivity reactions were actively solicited for 30 days following vaccination, a total of 2.4% of Flublok recipients and 1.6% of IIV3 recipients reported such events over the 30 day follow-up period. A total of 1.9% and 0.9% of Flublok and IIV3 recipients, respectively, reported these events in the 7 days following vaccination. Of these solicited events, rash was most frequently reported (Flublok 1.3%, IIV3 0.8%) over the 30 day follow-up period.

6.2 Postmarketing Experience

The following events have been spontaneously reported during post approval use of Flublok. They are described because of the strength of the causal relationship to Flublok and their potential seriousness. 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.

Immune system disorders: anaphylaxis, anaphylactoid reactions, allergic reactions, and other forms of hypersensitivity.

7 DRUG INTERACTIONS

Data evaluating the concomitant administration of Flublok with other vaccines are not available.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats at a dose approximately 300 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Flublok. 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. The effect of Flublok on embryo-fetal and pre-weaning development was evaluated in pregnant rats. Animals were administered Flublok by intramuscular injection twice prior to gestation and once during the period of organogenesis (gestation days 6), 0.5 ml/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis). No adverse effects on mating, female fertility, pregnancy, parturition, lactation, embryo-fetal and pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.



8.3 Nursing Mothers

Flublok has not been evaluated in nursing mothers. It is not known whether Flublok is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Flublok is administered to a nursing woman.

8.4 Pediatric Use

Data from a randomized, controlled trial demonstrated that children 6 months to less than 3 years of age had diminished hemagglutinin inhibition (HAI) responses to Flublok as compared to a U.S.-licensed influenza vaccine approved for use in this population, strongly suggesting that Flublok would not be effective in children younger than 3 years of age. Safety and effectiveness of Flublok in children 3 years to less than 18 years of age have not been established.

8.5 Geriatric Use

In clinical studies, Flublok has been administered to, and safety information collected for, 1078 subjects ages 65 years and older (see Clinical Trials Experience [6.1]). Clinical effectiveness in adults aged 65 and older is based on the immune response elicited by Flublok and not on demonstration of decreased influenza disease. After administration of Flublok, hemagglutination-inhibiting antibody responses in persons 65 years of age and older were lower as compared to younger adult subjects (see Clinical Studies [14]).

11 DESCRIPTION

Flublok [Influenza Vaccine] is a sterile, clear, colorless solution of recombinant hemagglutinin (HA) proteins from three influenza viruses for intramuscular injection. It contains purified HA proteins produced in a continuous insect cell line (expresSF+®) that is derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda (which is related to moths, caterpillars and butterflies), and grown in serum-free medium composed of chemically-defined lipids, vitamins, amino acids, and mineral salts. Each of the three HAs is expressed in this cell line using a baculovirus vector (Autographa californica nuclear polyhedrosis virus), extracted from the cells with Triton X-100 and further purified by column chromatography. The purified HAs are then blended and filled into single-dose vials.

Flublok is standardized according to United States Public Health Service (USPHS) requirements. For the –2016-2017 influenza season it is formulated to contain 135 mcg HA per 0.5 mL dose, with 45 mcg HA of each of the following 3 influenza virus strains: A/California/7/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008.

A single 0.5 mL dose of Flublok contains sodium chloride (4.4 mg), monobasic sodium phosphate (0.195 mcg), dibasic sodium phosphate (1.3 mg), and polysorbate 20 (Tween®20) (27.5 mcg). Each 0.5 mL dose of Flublok may also contain residual amounts of baculovirus and Spodoptera frugiperda cell proteins (≤ 28.5 mcg), baculovirus and cellular DNA (≤ 10 ng), and Triton X-100 (≤ 100 mcg).

Flublok contains no egg proteins, antibiotics, or preservatives. The stoppers used for the single-dose vials are not made with natural rubber latex.



12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Flublok contains recombinant HA proteins of the three strains of influenza virus specified by health authorities for inclusion in the annual seasonal vaccine. These proteins function as antigens which induce a humoral immune response, measured by hemagglutination inhibition (HI) antibody).

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 replacement of one or more influenza virus strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the U.S. in the upcoming winter.

13 NONCLINICAL TOXICOLOGY

Flublok has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals.

Reproduction studies performed in female rats revealed no evidence of impaired fertility due to Flublok (see Pregnancy [8.1]).

14 CLINICAL STUDIES

Efficacy Against Culture-Confirmed Influenza The efficacy of Flublok was evaluated in a randomized, observer-blind, placebo-controlled multicenter trial conducted in the U.S. during the 2007-2008 influenza season (Study 1) (2). The trial enrolled and vaccinated 4648 healthy adults (mean age 32.5 years) randomized in a 1:1 ratio to receive a single dose of Flublok (n=2344) or saline placebo (n=2304). Among enrolled subjects, 59% were female, 67% were white, 19% African-American, 11% Latino/Hispanic, 2% Asian and < 1% other. The two groups were similar in demographics. Culture-confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 7 months post- vaccination. ILI was defined as having at least 2 of 3 symptoms (no specified duration) in the following categories: 1) fever ≥ 100ºF; 2) respiratory symptoms (cough, sore throat, runny nose/stuffy nose); or 3) systemic symptoms (myalgias, arthralgias, headache, chills/sweats, tiredness/malaise). For subjects with an episode of ILI, nasal and throat swab samples were collected for viral culture. The primary efficacy endpoint was Centers for Disease Control-defined influenza-like illness (CDC-ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok. CDC-ILI is defined as fever of ≥100°F oral accompanied by cough, sore throat, or both on the same day or



on consecutive days. Attack rates and vaccine efficacy (VE), defined as the relative reduction in the influenza rate for Flublok relative to placebo, were calculated for the total vaccinated cohort (n=4,648). The pre-defined success criterion for the primary efficacy analysis was that the lower bound of the 95% confidence interval (CI) of VE should be at least 40%. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained from subjects in Study 1 were not antigenically matched to the strains represented in the vaccine. An exploratory analysis of VE of Flublok against all strains regardless of antigenic match isolated from any subject with an ILI, not necessarily CDC-defined ILI, demonstrated an efficacy estimate of 44.8% (95% CI 24.4, 60.0). See Table 4 for a presentation of VE by case definition and antigenic similarity.

Table 4: Vaccine Efficacy Against Culture-Confirmed Influenza in Healthy Adults 18-49 Years of Age, Study 1* Case definition Flublok

(N=2344) Saline Placebo

(N=2304) Flublok Vaccine

Efficacy1, %

95% Confidence

Interval Cases, n Rate, % Cases, n Rate, % Positive culture with a strain represented in the vaccine CDC-ILI, all matched strains2,3 1 0.04 4 0.2 75.4 (-148.0, 99.5) Any ILI, all matched strains4,5 2 0.1 6 0.3 67.2 (-83.2, 96.8) Positive culture with any strain, regardless of match to the vaccine CDC-ILI, all strains2,6 44 1.9 78 3.4 44.6 (18.8, 62.6) Sub-Type A 26 1.1 56 2.4 54.4 (26.1, 72.5) Type B 18 0.8 23 1.0 23.1 (-49.0, 60.9) Any ILI, all strains4 64 2.7 114 4.9 44.8 (24.4, 60.0) Sub-Type A 41 1.7 79 3.4 49.0 (24.7, 65.9) Type B 23 1.0 36 1.6 37.2 (-8.9, 64.5) *In Study 1 (NCT00539981) vaccine efficacy analyses were conducted on the Total Vaccinated Cohort (all randomized subjects who received study vaccine according to the treatment actually received and who provided data). Vaccine efficacy (VE) = 1 minus the ratio of Flublok/placebo infection rates. 1 Determined under the assumption of Poisson event rates, according to Breslow and Day, 1987. 2 Meets CDC influenza-like illness (CDC-ILI) defined as fever of ≥100ºF oral accompanied by cough and/or sore throat, on the same day or on consecutive days. 3 Primary endpoint of trial. 4 All culture-confirmed cases are considered, regardless of whether they qualified as CDC-ILI. 5 Secondary endpoint of trial. 6 Exploratory (prespecified) endpoint of trial.

Immunogenicity in Adults 50 years of Age and Older

Two randomized controlled clinical trials of Flublok in adults aged 50 years and older evaluated immune responses by measuring hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine in adults as compared to another U.S.-licensed trivalent influenza vaccine (IIV3). In these studies, post-vaccination immunogenicity was evaluated on sera obtained 28 days after administration of a single dose of Flublok or comparator vaccine. Hemagglutination inhibition geometric mean titers (GMTs) were determined for each vaccine antigen. Immunogenicity was evaluated by calculating GMT ratios of IIV3 to Flublok.



Study 2 was a randomized, observer-blind, comparator-controlled, multi-center trial in healthy adults 50 through 64 years of age to evaluate the immunogenicity of Flublok as compared to a U.S.-licensed IIV3 (Fluzone). (3) Results are presented in Table 5. A total of 602 subjects were enrolled, randomized 1:1, and vaccinated with Flublok (300 subjects) or IIV3 (302 subjects). Of the total vaccinated population, 601 subjects (299 Flublok and 302 IIV3 recipients, respectively) were evaluable for immune response (per protocol population for immunogenicity). Subjects were predominantly white (71%) and female (63%) with a mean age of 55.8 years. Immune response endpoints were HI GMTs for each vaccine antigen at baseline and at 28 days post-vaccination. GMTs were compared based on the upper bound of the two-sided 95% confidence interval (CI) of the GMT ratio of IIV3 to Flublok. Success in meeting this endpoint was pre-defined as an upper bound (UB) of the two-sided 95% CI of GMTIIV3 / GMTFlublok ≤ 1.5 (5). Flublok met the success criterion for HI GMTs for all three antigens. Sub-population analyses of immunogenicity did not reveal significant differences between genders. Sub-analyses according to race and ethnicity were not informative because the study population was not sufficiently diverse.

Study 3 was a randomized, observer-blind, comparator-controlled, multi-center trial in 869 medically stable elderly adults ≥65 years of age to evaluate the immunogenicity of Flublok as compared to a U.S.-licensed IIV3 (Fluzone) (4). Subjects were randomized 1:1 to receive Flublok (436 vaccinated; 431 evaluable) or IIV3 (433 vaccinated; 430 evaluable). Subjects were predominantly white (98%) and female (53%) with a mean age of 73 years. Immune responses (HI GMTs and GMT ratios) were evaluated in the same manner as for Study 2. The UB of the two-sided 95% CI for the GMT ratio of IIV3 to Flublok was ≤ 1.5 for all three vaccine antigens. Sub-population analyses of immunogenicity did not reveal significant differences between genders, but were not informative with respect to race or ethnicity because the study population was not sufficiently diverse.

Table 5: Comparison of Pre- and Post-Vaccination Geometric Mean Titers (GMT) for Flublok and Fluzone, Study 2 (adults 50 through 64 years) and Study 3 (adults ≥65 years)1,2

Study Number Antigen

Post-vaccination GMT

Flublok N=299


Fluzone N=302

GMT Ratio Fluzone/Flublok

[95% CI]

Study 2 Age 50-64 years

A/H1N1 181.3 139.7 0.77 (0.75, 0.79)

A/H3N2 105.4 60.9 0.58 (0.53, 0.62)

B 110.9 116.0 1.05 (1.01, 1.09)

Study 3 Age ≥65 years

Antigen


Flublok N=431


Fluzone N=430

GMT Ratio Fluzone/Flublok

[95% CI]

A/H1N1 176.8 148.1 0.84 (0.81, 0.86)

A/H3N2 338.5 199.2 0.59 (0.57, 0.60)



B 149.6 194.8 1.3 (1.26, 1.34)

Abbreviations: CI, confidence interval; GMT, geometric mean titer 1The pre-defined success criterion for the GMT ratio of Fluzone to Flublok was that the upper bound of the 2-sided 95% CI of the GMT ratio, GMT Fluzone / GMT Flublok at 28 days post-vaccination, must not exceed 1.5. 2 HI titers were assayed using BEVS-derived (non-egg-derived) antigens.



15 REFERENCES

1. Treanor JJ, Schiff GM, Hayden FG, et.al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: a randomized controlled trial. JAMA. 2007, Vol. 297, pp. 1577-1582.

2. Treanor JJ, El Sahly HM, King J, et. al. Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok) against influenza in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011, Vol. 29, pp. 7733-7739.

3. Baxter R, Patriarca PA, Ensor K, et al. Evaluation of the safety, reactogenicity and immunogenicity of FluBlok trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age. Vaccine. 2011, Vol. 29, pp. 2272-2278.

4. Keitel WA, Treanor JJ, El Sahly HM, et.al. Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccines (TIVs) among persons ≥65 years old. Vaccine. 2009, Vol. 28, pp. 379-385.

5. CBER/FDA. Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. s.l. : DHHS/CBER/FDA, 2007.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Flublok is supplied as a single-dose, 0.5 mL vial in a 10 vial carton:

Presentation Carton NDC Number Components and NDC Number

Single-Dose Vial 42874-016-10 Ten 0.5 mL single-dose vials [NDC 42874-016-01]

16.2 Storage and Handling

• Store refrigerated between 2° and 8°C (36° and 46°F). • Do not freeze. Discard if product has been frozen. • Protect vials from light • Do not use after expiration date shown on the label. 17 PATIENT COUNSELING INFORMATION

Inform the vaccine recipient of the potential benefits and risks of vaccination with Flublok.

Inform the vaccine recipient that:



• Flublok contains non-infectious proteins that cannot cause influenza.

• Flublok stimulates the immune system to produce antibodies that help protect against influenza viruses contained in the vaccine, but does not prevent other respiratory infections.

Instruct the vaccine recipient to report any adverse events to their healthcare provider and/or to the Vaccine Adverse Event Reporting System (VAERS). Provide the vaccine recipient with the Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to vaccination. These materials are available free of charge at the Centers for Disease Control (CDC) website (www.cdc.gov/vaccines). Inform the vaccine recipient that safety and efficacy have not been established in pregnant women. Register women who receive Flublok while pregnant in the pregnancy registry by calling 1-888-855-7871. Instruct the vaccine recipient that annual vaccination to prevent influenza is recommended.

Manufactured by Protein Sciences Corporation (Meriden, CT)

US license 1795

Distributed by Protein Sciences Corporation

Flublok is a registered trademark of Protein Sciences Corporation.

FLUCELVAX QUADRIVALENT - Seqirus, Inc. 1.14.1.3 US Package Insert

23 May 2016 Page 1 of 16

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

FLUCELVAX® QUADRIVALENT safely and effectively. See full

prescribing information for FLUCELVAX QUADRIVALENT.

FLUCELVAX QUADRIVALENT (Influenza Vaccine)

Suspension for Intramuscular Injection

2016-2017 Formula

Initial U.S. Approval: 23 May 2016

--------------------INDICATIONS AND USAGE----------------------

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. (1)

(1) FLUCELVAX is approved for use in persons 4 years of age

and older. (1)

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 children and adolescents 4 through 17

years of age with FLUCELVAX QUADRIVALENT are not

available. (14)

-----------------DOSAGE AND ADMINISTRATION----------------

For intramuscular use only

Age Dose Schedule

4 through 8 years of age

One or two dosesa, 0.5 mL each

If 2 doses,

administer at least4 weeks apart

9 years of age and older

One dose, 0.5mL Not Applicable

a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on

prevention and control of influenza with vaccines.

---------------DOSAGE FORMS AND STRENGTHS---------------

Suspension for injection supplied in 0.5-mL single-dose pre-filled

syringes. (3)

------------------------CONTRAINDICATIONS-----------------------

History of severe allergic reactions (e.g., anaphylaxis) to any

component of the vaccine. (4, 11)

----------------WARNINGS AND PRECAUTIONS-----------------

If Guillain-Barré syndrome has occurred within 6

weeks of receipt of a prior influenza vaccine, the decision to give FLUCELVAX QUADRIVALENT

should be based on careful consideration of the

potential benefits and risks. (5.1)

------------------------ADVERSE REACTIONS-----------------

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%). (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%). (6)

The most common (≥10%) local and systemic reactions in children 4 to <6 years of age 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%).

(6)

The most common (≥10%) local and systemic reactions

in children 6 through 8 years of age were pain at the injection site (54%), injection site erythema (22%),

injection site induration (16%), headache (14%), fatigue

(13%) and myalgia (12%). (6)

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%). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Seqirus

Inc. at 1-855-358-8966 or VAERS at 1-800-822-7967 and www.vaers.hhs.gov.

---------------USE IN SPECIFIC POPULATIONS------------------

Safety and effectiveness of FLUCELVAX

QUADRIVALENT have not been established in

pregnant women or nursing mothers. (8.1, 8.3)

Geriatric Use: Antibody responses were lower in adults

65 years and older than in younger adults. (8.5)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 05/2016

FULL PRESCRIBING INFORMATION: CONTENTS*



2.1 Dosage and Schedule

2.2 Administration


4 CONTRAINDICATIONS


5.1 Guillain-Barré Syndrome 5.2 Preventing and Managing Allergic Reactions

5.3 Syncope

5.4 Altered Immunocompetence 5.5 Limitations of Vaccine Effectiveness

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience 6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Concomitant use with Other Vaccines


8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use 8.5 Geriatric Use

11 DESCRIPTION





14 CLINICAL STUDIES

14.1 Efficacy against Culture-Confirmed Influenza

14.2 Immunogenicity in Adults 18 Years of Age and Older

14.3 Immunogenicity in Children and Adolescents 4 through

17 years of age

15 REFERENCES


17 PATIENT COUNSELING INFORMATION



23 May 2016 Page 2 of 16

*Sections or subsections omitted from the full prescribing

information are not listed


23 May 2016 Page 3 of 16



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 (14)]


For intramuscular injection only.

2.1 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 doses1, 0.5 mL each

If 2 doses, administer at

least 4 weeks apart

9 years of age and older One dose, 0.5mL 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.

2.2 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 (11)] 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.


FLUCELVAX QUADRIVALENT is a suspension for injection supplied in a 0.5 mL single-

dose pre-filled Luer Lock syringe.

4 CONTRAINDICATIONS

Do not administer FLUCELVAX QUADRIVALENTto anyone with a history of severe

allergic reaction (e.g. anaphylaxis) to any component of the vaccine [see Description (11)].


5.1 Guillain-Barré Syndrome


23 May 2016 Page 4 of 16

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 QUADRIVALENTshould be based on careful

consideration of the potential benefits and risks.

5.2 Preventing and Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible

anaphylactic reactions following administration of the vaccine.

5.3 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.

5.4 Altered Immunocompetence

After vaccination with FLUCELVAX QUADRIVALENT, immunocompromised individuals,

including those receiving immunosuppressive therapy, may have a reduced immune response.


Vaccination with FLUCELVAX QUADRIVALENT may not protect all vaccine recipients

against influenza disease.

6 ADVERSE REACTIONS

6.1 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:


23 May 2016 Page 5 of 16

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

FLUCEL

VAX

QUADRI

VALENT

N=663

Trivalent Influenza

Vaccine

FLUCELV

AX

QUADRIV

ALENT

N=656

Trivalent Influenza

Vaccine

TIV1c

N=330

TIV2c

N=327

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)


23 May 2016 Page 6 of 16

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.


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 3and 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


Injection site

induration 13 (1) 20 (2) 13 (0)

Injection site 18 (1) 23 (1) 17 (0)


23 May 2016 Page 7 of 16


Percentages (%)2

FLUCELVAX

QUADRIVALENT

N=182

Trivalent Influenza Vaccine

TIV1c

N=91

TIV2c

N=93

erythema

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)


safety data. 2Percentage of subjects with severe adverse reactions are presented in parenthesis.



23 May 2016 Page 8 of 16

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)


Percentages (%)2

FLUCELVAX

QUADRIVALE

NT

N=371-372

Trivalent

Influenza vaccine

FLUCELVAX

QUADRIVAL

ENT

N=579

Trivalent Influenza

Vaccine

TIV1c

N=185

TIV2

c

N=18

6

TIV1c

N=294

TIV2c

N=281-

282


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)


safety data. 2Percentage of subjects with severe adverse reactions are presented in parenthesis.

Study 2: NCT 01992107


23 May 2016 Page 9 of 16

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.

6.2 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 post-approval 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.

7 DRUG INTERACTIONS

7.1 Concomitant use with Other Vaccines

No data are available to assess the concomitant administration of FLUCELVAX

QUADRIVALENT with other vaccines.


8.1 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 Fluclevax, 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.


23 May 2016 Page 10 of 16

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.

8.3 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.

8.4 Pediatric Use

Safety and effectiveness have not been established in children less than 4 years of age.

8.5 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 (14.3)]

11 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.


23 May 2016 Page 11 of 16



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



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.

14 CLINICAL STUDIES

14.1 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


23 May 2016 Page 12 of 16

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 One-

Sided 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.


23 May 2016 Page 13 of 16

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.

14.2 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).


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/H

1N

1 GMT

(95% CI)

302.8

(281.8-325.5)

298.9

(270.3-330.5)

1.0

(0.9-1.1) -

Seroconversi

on Rate2

(95% CI)

49.2%

(46.4-52.0)

48.7%

(44.7-52.6) -

-0.5%

(-5.3-4.2)

A/H

3N

2 GMT

(95% CI)

372.3

(349.2-396.9)

378.4

(345.1-414.8)

1.0

(0.9-1.1) -

Seroconversi

on Rate2

38.3% 35.6% - -2.7%


23 May 2016 Page 14 of 16

(95% CI) (35.6-41.1) (31.9-39.5) (-7.2-1.9) B

1

GMT

(95% CI)

133.2

(125.3-141.7)

115.6

(106.4-125.6)

0.9

(0.8-1.0) -

Seroconversi

on 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) -

Seroconversi

on 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. 3 Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10

and post-vaccination 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


14.3 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 section 6.1) 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)


23 May 2016 Page 15 of 16

Table 8: The Percentage of Children and Adolescents 4 through 17 years of Age with

Seroconversion2 andHI 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


(95% CI) 47% (44-50)

HI titer≥1:40 100% (99-100)

B1

N = 1013


(95% CI) 66% (63-69)

HI titer≥1:40 92% (91-94)

B2

N = 1009


(95% CI) 73% (70-76)

HI titer≥1:40 91% (89-93)

Abbreviations: HI = hemagglutinin inhibition. CI = confidence interval. 1 Analyses are performed on data for day 22 for previously vaccinated subjects and day 50 for

not previously vaccinated subjects. 2 Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10

and post-vaccination 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

15 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.

2. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza

vaccination. Virus Res 2004;103:133-138.


23 May 2016 Page 16 of 16

3. Hobson D, Curry RL, Beare A, et.al. The role of serum hemagglutinin-inhibiting antibody

in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb

1972; 767-777.

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.


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 (36ºF to 46ºF). Do not freeze. Protect from light.

Do not use after the expiration date.

17 PATIENT COUNSELING 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.

FLUCELVAX® QUADRIVALENT is a registered trademark of Seqirus, Inc.

Manufactured by: Seqirus, Inc.

475 Green Oaks Parkway

Holly Springs, North Carolina (NC) 27540, United States (USA)

1-919-577-5000

1

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLULAVAL QUADRIVALENT safely and effectively. See full prescribing information for FLULAVAL QUADRIVALENT. FLULAVAL QUADRIVALENT (Influenza Vaccine) Suspension for Intramuscular Injection 2016-2017 Formula Initial U.S. Approval: 2013

----------------------------INDICATIONS AND USAGE ---------------------------- FLULAVAL QUADRIVALENT is a vaccine indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FLULAVAL QUADRIVALENT is approved for use in persons 3 years of age and older. (1)

----------------------- DOSAGE AND ADMINISTRATION ----------------------- For intramuscular injection only. (2)

Age Vaccination Status Dose and Schedule Aged 3 through 8 years

Not previously vaccinated with influenza vaccine

Two doses (0.5-mL each) at least 4 weeks apart (2.1)


One or two dosesa (0.5-mL each) (2.1)

Aged 9 years and older

Not applicable One 0.5-mL dose (2.1)

a One dose or two doses (0.5-mL each) depending on vaccination history as per the annual Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and control of influenza with vaccines. If two doses, administer each 0.5-mL dose at least 4 weeks apart. (2.1)

--------------------- DOSAGE FORMS AND STRENGTHS --------------------- Suspension for injection: • 0.5-mL single-dose prefilled syringes (3) • 5-mL multi-dose vials containing 10 doses (each dose is 0.5 mL). (3)

------------------------------- CONTRAINDICATIONS ------------------------------- History of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or following a previous dose of any influenza vaccine. (4, 11)

----------------------- WARNINGS AND PRECAUTIONS --------------------- • If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a

prior influenza vaccine, the decision to give FLULAVAL QUADRIVALENT should be based on careful consideration of the potential benefits and risks. (5.1)

• Syncope (fainting) can occur in association with administration of injectable vaccines, including FLULAVAL QUADRIVALENT. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. (5.2)

------------------------------ ADVERSE REACTIONS ---------------------------- • In adults, the most common (≥10%) solicited local adverse reaction was

pain (60%); most common solicited systemic adverse events were muscle aches (26%), headache (22%), fatigue (22%), and arthralgia (15%). (6.1)

• In children aged 3 through 17 years, the most common (≥10%) solicited local adverse reaction was pain (65%). (6.1)

• In children aged 3 through 4 years, the most common (≥10%) solicited systemic adverse events were irritability (26%), drowsiness (21%), and loss of appetite (17%). (6.1)

• In children aged 5 through 17 years, the most common (≥10%) solicited systemic adverse events were muscle aches (29%), fatigue (22%), headache (22%), arthralgia (13%), and gastrointestinal symptoms (10%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

----------------------- USE IN SPECIFIC POPULATIONS --------------------- • Safety and effectiveness of FLULAVAL QUADRIVALENT have not

been established in pregnant women or nursing mothers. (8.1, 8.3) • Register women who receive FLULAVAL QUADRIVALENT while

pregnant in the pregnancy registry by calling 1-888-452-9622. (8.1) • Geriatric Use: Antibody responses were lower in geriatric subjects who

received FLULAVAL QUADRIVALENT than in younger subjects. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: x/2016


2.1 Dosage and Schedule 2.2 Administration Instructions


5.1 Guillain-Barré Syndrome 5.2 Syncope 5.3 Preventing and Managing Allergic Vaccine Reactions 5.4 Altered Immunocompetence 5.5 Limitations of Vaccine Effectiveness 5.6 Persons at Risk of Bleeding


7 DRUG INTERACTIONS 7.1 Concomitant Administration with Other Vaccines

7.2 Immunosuppressive Therapies 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use




14 CLINICAL STUDIES 14.1 Efficacy against Influenza 14.2 Immunological Evaluation

15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not

listed.

2

______________________________________________________________________

FULL PRESCRIBING INFORMATION 1


FLULAVAL® QUADRIVALENT is indicated for active immunization for the prevention of 3 disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. 4 FLULAVAL QUADRIVALENT is approved for use in persons 3 years of age and older. 5


For intramuscular injection only. 7

2.1 Dosage and Schedule 8

The dose and schedule for FLULAVAL QUADRIVALENT are presented in Table 1. 9

Table 1. FLULAVAL QUADRIVALENT: Dosing 10 Age Vaccination Status Dose and Schedule

Aged 3 through 8 years Not previously vaccinated with influenza vaccine

Two doses (0.5-mL each) at least 4 weeks apart


One or two dosesa (0.5-mL each)

Aged 9 years and older Not applicable One 0.5-mL dose a One dose or two doses (0.5-mL each) depending on vaccination history as per the annual 11

Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and 12 control of influenza with vaccines. If two doses, administer each 0.5-mL dose at least 4 weeks 13 apart. 14

2.2 Administration Instructions 15

Shake well before administration. Parenteral drug products should be inspected visually for 16 particulate matter and discoloration prior to administration, whenever solution and container 17 permit. If either of these conditions exists, the vaccine should not be administered. 18

Attach a sterile needle to the prefilled syringe and administer intramuscularly. 19

For the multi-dose vial, use a sterile needle and sterile syringe to withdraw the 0.5-mL dose from 20 the multi-dose vial and administer intramuscularly. A sterile syringe with a needle bore no larger 21 than 23 gauge is recommended for administration. It is recommended that small syringes 22 (0.5 mL or 1 mL) be used to minimize any product loss. Use a separate sterile needle and syringe 23 for each dose withdrawn from the multi-dose vial. 24

Between uses, return the multi-dose vial to the recommended storage conditions, between 2º and 25 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen. Once entered, a multi-26

3

dose vial, and any residual contents, should be discarded after 28 days. 27

The preferred site for intramuscular injection is the deltoid muscle of the upper arm. Do not 28 inject in the gluteal area or areas where there may be a major nerve trunk. 29



FLULAVAL QUADRIVALENT is a suspension for injection available in 0.5-mL prefilled 32 TIP-LOK® syringes and 5-mL multi-dose vials containing 10 doses (each dose is 0.5 mL). 33


Do not administer FLULAVAL QUADRIVALENT to anyone with a history of severe allergic 35 reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or 36 following a previous dose of any influenza vaccine [see Description (11)]. 37



If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza 40 vaccine, the decision to give FLULAVAL QUADRIVALENT should be based on careful 41 consideration of the potential benefits and risks. 42

The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a 43 causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is 44 probably slightly more than one additional case/one million persons vaccinated. 45

5.2 Syncope 46

Syncope (fainting) can occur in association with administration of injectable vaccines, including 47 FLULAVAL QUADRIVALENT. Syncope can be accompanied by transient neurological signs 48 such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be 49 in place to avoid falling injury and to restore cerebral perfusion following syncope. 50

5.3 Preventing and Managing Allergic Vaccine Reactions 51

Prior to administration, the healthcare provider should review the immunization history for 52 possible vaccine sensitivity and previous vaccination-related adverse reactions. Appropriate 53 medical treatment and supervision must be available to manage possible anaphylactic reactions 54 following administration of FLULAVAL QUADRIVALENT. 55


If FLULAVAL QUADRIVALENT is administered to immunosuppressed persons, including 57 individuals receiving immunosuppressive therapy, the immune response may be lower than in 58 immunocompetent persons. 59

4


Vaccination with FLULAVAL QUADRIVALENT may not protect all susceptible individuals. 61

5.6 Persons at Risk of Bleeding 62

As with other intramuscular injections, FLULAVAL QUADRIVALENT should be given with 63 caution in individuals with bleeding disorders such as hemophilia or on anticoagulant therapy to 64 avoid the risk of hematoma following the injection. 65



Because clinical trials are conducted under widely varying conditions, adverse reaction rates 68 observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical 69 trials of another vaccine, and may not reflect the rates observed in practice. There is the 70 possibility that broad use of FLULAVAL QUADRIVALENT could reveal adverse reactions not 71 observed in clinical trials. 72

In adults who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited 73 local adverse reaction was pain (60%); the most common (≥10%) solicited systemic adverse 74 events were muscle aches (26%), headache (22%), fatigue (22%), and arthralgia (15%). 75

In children aged 3 through 17 years who received FLULAVAL QUADRIVALENT, the most 76 common (≥10%) solicited local adverse reaction was pain (65%). In children aged 3 through 77 4 years, the most common (≥10%) solicited systemic adverse events were irritability (26%), 78 drowsiness (21%), and loss of appetite (17%). In children aged 5 through 17 years, the most 79 common (≥10%) systemic adverse events were muscle aches (29%), fatigue (22%), headache 80 (22%), arthralgia (13%), and gastrointestinal symptoms (10%). 81

FLULAVAL QUADRIVALENT has been administered to 1,384 adults aged 18 years and older 82 and 3,516 pediatric subjects aged 3 through 17 years in 4 clinical trials. 83

FLULAVAL QUADRIVALENT in Adults 84

Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial. In 85 this trial, subjects received FLULAVAL QUADRIVALENT (N = 1,272), or one of two 86 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, N = 213 or TIV-87 2, N = 218), each containing an influenza type B virus that corresponded to one of the two B 88 viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B 89 virus of the Yamagata lineage). The population was aged 18 years and older (mean age: 90 50 years) and 61% were female; 61% of subjects were white, 3% were black, 1% were Asian, 91 and 35% were of other racial/ethnic groups. Solicited adverse events were collected for 7 days 92 (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic 93 adverse events occurring within 7 days of vaccination in adults are shown in Table 2. 94

5

Table 2. FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions 95 and Systemic Adverse Events within 7 Daysa of Vaccination in Adults Aged 18 Years and 96 Olderb (Total Vaccinated Cohort) 97

FLULAVAL QUADRIVALENTc

N = 1,260 %


(B Victoria)d N = 208

%

TIV-2 (B Yamagata)e

N = 216 %

Local Adverse Reactions Pain 60 45 41 Swelling 3 1 4 Redness 2 3 1 Systemic Adverse Events Muscle aches 26 25 19 Headache 22 20 23 Fatigue 22 22 17 Arthralgia 15 17 15 Gastrointestinal symptomsf 9 10 7 Shivering 9 8 6 Fever ≥100.4°F (38.0°C) 2 1 1

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 98 available. 99 a 7 days included day of vaccination and the subsequent 6 days. 100 b Trial 1: NCT01196975. 101 c Contained two A strains and two B strains, one of Victoria lineage and one of Yamagata 102

lineage. 103 d Contained two A strains and a B strain of Victoria lineage. 104 e Contained the same two A strains as FLULAVAL and a B strain of Yamagata lineage. 105 f Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 106

Unsolicited adverse events occurring within 21 days of vaccination were reported in 19%, 23%, 107 and 23% of subjects who received FLULAVAL QUADRIVALENT (N = 1,272), TIV-1 108 (B Victoria) (N = 213), or TIV-2 (B Yamagata) (N = 218), respectively. The unsolicited adverse 109 events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included 110 nasopharyngitis, upper respiratory tract infection, headache, cough and oropharyngeal pain. 111 Serious adverse events occurring within 21 days of vaccination were reported in 0.4%, 0%, and 112 0% of subjects who received FLULAVAL QUADRIVALENT, TIV-1 (B Victoria), or TIV-2 113 (B Yamagata), respectively. 114

6

FLULAVAL QUADRIVALENT in Children 115

Trial 2 was a randomized, double-blind, active-controlled trial. In this trial, subjects received 116 FLULAVAL QUADRIVALENT (N = 932), or one of two formulations of a comparator trivalent 117 influenza vaccine [FLUARIX® (Influenza Vaccine), TIV-1, N = 929 or TIV-2, N = 932], each 118 containing an influenza type B virus that corresponded to one of the two B viruses in 119 FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the 120 Yamagata lineage). The population was aged 3 through 17 years (mean age: 9 years) and 53% 121 were male; 65% were white, 13% were Asian, 9% were black, and 13% were of other 122 racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccination 123 received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of 124 influenza vaccination and children aged 9 years and older received one dose. Solicited local 125 adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and 126 the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring 127 within 7 days of vaccination in children are shown in Table 3. 128

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Table 3. FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions 129 and Systemic Adverse Events within 7 Daysa of First Vaccination in Children Aged 3 130 through 17 Yearsb (Total Vaccinated Cohort) 131

FLULAVAL QUADRIVALENTc

%


(B Victoria)d %

TIV-2 (B Yamagata)e

% Aged 3 through 17 Years Local Adverse Reactions N = 913 N = 911 N = 915 Pain 65 55 56 Swelling 6 3 4 Redness 5 3 4 Aged 3 through 4 Years Systemic Adverse Events N = 185 N = 187 N = 189 Irritability 26 17 22 Drowsiness 21 20 23 Loss of appetite 17 16 13 Fever ≥100.4°F (38.0°C) 5 6 4 Aged 5 through 17 Years Systemic Adverse Events N = 727 N = 724 N = 725 Muscle aches 29 25 25 Fatigue 22 24 23 Headache 22 22 20 Arthralgia 13 12 11 Gastrointestinal symptomsf 10 10 9 Shivering 7 7 7 Fever ≥100.4°F (38.0°C) 2 4 3

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 132 available. 133 a 7 days included day of vaccination and the subsequent 6 days. 134 b Trial 2: NCT01198756. 135 c Contained two A strains and two B strains, one of Victoria lineage and one of Yamagata 136

lineage. 137 d Contained two A strains and a B strain of Victoria lineage. 138 e Contained the same two A strains as FLUARIX and a B strain of Yamagata lineage. 139 f Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 140

In children who received a second dose of FLULAVAL QUADRIVALENT, FLUARIX TIV-1 141 (B Victoria), or TIV-2 (B Yamagata), the incidences of adverse events following the second dose 142

8

were generally lower than those observed after the first dose. 143

Unsolicited adverse events occurring within 28 days of vaccination were reported in 30%, 31% 144 and 30% of subjects who received FLULAVAL QUADRIVALENT (N = 932), FLUARIX TIV-145 1 (B Victoria) (N = 929), or TIV-2 (B Yamagata) (N = 932), respectively. The unsolicited 146 adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) 147 included vomiting, pyrexia, bronchitis, nasopharyngitis, pharyngitis, upper respiratory tract 148 infection, headache, cough, oropharyngeal pain, and rhinorrhea. Serious adverse events 149 occurring within 28 days of any vaccination were reported in 0.1%, 0.2%, and 0.2% of subjects 150 who received FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 151 (B Yamagata), respectively. 152

Trial 3 was a randomized, observer-blind, non-influenza vaccine-controlled trial evaluating the 153 efficacy of FLULAVAL QUADRIVALENT. The trial included subjects aged 3 through 8 years 154 who received FLULAVAL QUADRIVALENT (N = 2,584) or HAVRIX® (Hepatitis A Vaccine) 155 (N = 2,584), as a control vaccine. Children with no history of influenza vaccination received 156 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children 157 with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or 158 HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% 159 were of other racial/ethnic groups. The mean age of subjects was 5 years. Solicited local adverse 160 reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 161 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 162 days of vaccination in children are shown in Table 4. 163

9

Table 4. FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions 164 and Systemic Adverse Events within 7 Daysa of First Vaccination in Children Aged 3 165 through 8 Yearsb (Total Vaccinated Cohort) 166

FLULAVAL QUADRIVALENT

% HAVRIXc

% Aged 3 through 8 Years Local Adverse Reactions N = 2,546 N = 2,551 Pain 39 28 Swelling 1 0.3 Redness 0.4 0.2 Aged 3 through 4 Years Systemic Adverse Events N = 898 N = 895 Loss of appetite 9 8 Irritability 8 8 Drowsiness 8 7 Fever ≥100.4°F (38.0°C) 4 4 Aged 5 through 8 Years Systemic Adverse Events N = 1,648 N = 1,654 Muscle aches 12 10 Headache 11 11 Fatigue 8 7 Arthralgia 6 5 Gastrointestinal symptomsd 6 6 Shivering 3 3 Fever ≥100.4°F (38.0°C) 3 3

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were 167 available. 168 a 7 days included day of vaccination and the subsequent 6 days. 169 b Trial 3: NCT01218308. 170 c Hepatitis A Vaccine used as a control vaccine. 171 d Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 172

In children who received a second dose of FLULAVAL QUADRIVALENT or HAVRIX, the 173 incidences of adverse events following the second dose were generally lower than those 174 observed after the first dose. 175

The frequency of unsolicited adverse events occurring within 28 days of vaccination was similar 176 in both groups (33% for both FLULAVAL QUADRIVALENT and HAVRIX). The unsolicited 177 adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) 178

10

included diarrhea, pyrexia, gastroenteritis, nasopharyngitis, upper respiratory tract infection, 179 varicella, cough, and rhinorrhea. Serious adverse events occurring within 28 days of any 180 vaccination were reported in 0.7% of subjects who received FLULAVAL QUADRIVALENT 181 and in 0.2% of subjects who received HAVRIX. 182

6.2 Postmarketing Experience 183

There are no postmarketing data available for FLULAVAL QUADRIVALENT. The following 184 adverse events have been spontaneously reported during postapproval use of FLULAVAL 185 (trivalent influenza vaccine). Because these events are reported voluntarily from a population of 186 uncertain size, it is not always possible to reliably estimate their incidence rate or establish a 187 causal relationship to the vaccine. Adverse events described here are included because: a) they 188 represent reactions which are known to occur following immunizations generally or influenza 189 immunizations specifically; b) they are potentially serious; or c) the frequency of reporting. 190

Blood and Lymphatic System Disorders 191

Lymphadenopathy. 192

Eye Disorders 193

Eye pain, photophobia. 194

Gastrointestinal Disorders 195

Dysphagia, vomiting. 196

General Disorders and Administration Site Conditions 197

Chest pain, injection site inflammation, asthenia, injection site rash, influenza-like symptoms, 198 abnormal gait, injection site bruising, injection site sterile abscess. 199

Immune System Disorders 200

Allergic reactions including anaphylaxis, angioedema. 201

Infections and Infestations 202

Rhinitis, laryngitis, cellulitis. 203

Musculoskeletal and Connective Tissue Disorders 204

Muscle weakness, arthritis. 205

Nervous System Disorders 206

Dizziness, paresthesia, hypoesthesia, hypokinesia, tremor, somnolence, syncope, Guillain-Barré 207 syndrome, convulsions/seizures, facial or cranial nerve paralysis, encephalopathy, limb paralysis. 208

Psychiatric Disorders 209

Insomnia. 210

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Respiratory, Thoracic, and Mediastinal Disorders 211

Dyspnea, dysphonia, bronchospasm, throat tightness. 212

Skin and Subcutaneous Tissue Disorders 213

Urticaria, localized or generalized rash, pruritus, sweating. 214

Vascular Disorders 215

Flushing, pallor. 216


7.1 Concomitant Administration with Other Vaccines 218

FLULAVAL QUADRIVALENT should not be mixed with any other vaccine in the same 219 syringe or vial. 220

There are insufficient data to assess the concomitant administration of FLULAVAL 221 QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is 222 required, the vaccines should be administered at different injection sites. 223

7.2 Immunosuppressive Therapies 224

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic 225 drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune 226 response to FLULAVAL QUADRIVALENT. 227


8.1 Pregnancy 229

Pregnancy Category B. A reproductive and developmental toxicity study has been performed in 230 female rats at a dose 80-fold the human dose (on a mg/kg basis) and showed no evidence of 231 impaired female fertility or harm to the fetus due to FLULAVAL QUADRIVALENT. There are, 232 however, no adequate and well-controlled studies in pregnant women. Because animal 233 reproduction studies are not always predictive of human response, FLULAVAL 234 QUADRIVALENT should be given to a pregnant woman only if clearly needed. 235

In a reproductive and developmental toxicity study, the effect of FLULAVAL 236 QUADRIVALENT on embryo-fetal and pre-weaning development was evaluated in rats. 237 Animals were administered FLULAVAL QUADRIVALENT by intramuscular injection twice 238 prior to gestation, during the period of organogenesis (gestation Days 3, 8, 11, and 15), and 239 during lactation (Day 7), 0.2 mL/dose/rat (80-fold higher than the projected human dose on a 240 body weight basis). No adverse effects on mating, female fertility, pregnancy, parturition, 241 lactation parameters, and embryo-fetal or pre-weaning development were observed. There were 242 no vaccine-related fetal malformations or other evidence of teratogenesis. 243

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Pregnancy Registry 244

GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy outcomes and 245 newborn health status outcomes following vaccination with FLULAVAL QUADRIVALENT 246 during pregnancy. Women who receive FLULAVAL QUADRIVALENT during pregnancy 247 should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should 248 contact GlaxoSmithKline by calling 1-888-452-9622. 249

8.3 Nursing Mothers 250

It is not known whether FLULAVAL QUADRIVALENT is excreted in human milk. Because 251 many drugs are excreted in human milk, caution should be exercised when FLULAVAL 252 QUADRIVALENT is administered to a nursing woman. 253


Safety and effectiveness of FLULAVAL QUADRIVALENT in children younger than 3 years 255 have not been established. 256

Safety and immunogenicity of FLULAVAL QUADRIVALENT in children aged 3 through 257 17 years have been evaluated [see Adverse Reactions (6.1), Clinical Studies (14.2)]. 258


In a randomized, double-blind, active-controlled trial, immunogenicity and safety were evaluated 260 in a cohort of subjects aged 65 years and older who received FLULAVAL QUADRIVALENT 261 (N = 397); approximately one-third of these subjects were aged 75 years and older. In subjects 262 aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and 263 seroconversion rates were lower than in younger subjects (aged 18 to 64 years) and the 264 frequencies of solicited and unsolicited adverse events were generally lower than in younger 265 subjects [see Adverse Reactions (6.1), Clinical Studies (14.2)]. 266

11 DESCRIPTION 267

FLULAVAL QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a 268 quadrivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in 269 the allantoic cavity of embryonated hens’ eggs. Each of the influenza viruses is produced and 270 purified separately. The virus is inactivated with ultraviolet light treatment followed by 271 formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate. 272

FLULAVAL QUADRIVALENT is a sterile, opalescent, translucent to off-white suspension in a 273 phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon 274 shaking to form a homogeneous suspension. 275

FLULAVAL QUADRIVALENT has been standardized according to USPHS requirements for 276 the 2016-2017 influenza season and is formulated to contain 60 micrograms (mcg) 277 hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the 278

13

following 4 viruses (two A strains and two B strains): A/California/7/2009 NYMC X-179A 279 (H1N1), A/Hong Kong/4801/2014 (H3N2) NYMC X-263B, B/Phuket/3073/2013, and 280 B/Brisbane/60/2008. 281

The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 282 0.5-mL dose from the multi-dose vial contains 50 mcg thimerosal (<25 mcg mercury); 283 thimerosal, a mercury derivative, is added as a preservative. 284

Each 0.5-mL dose of either presentation may also contain residual amounts of ovalbumin 285 (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), α-tocopheryl hydrogen 286 succinate (≤320 mcg) and polysorbate 80 (≤887 mcg) from the manufacturing process. 287 Antibiotics are not used in the manufacture of this vaccine. 288

The tip caps and plungers of the prefilled syringes are not made with natural rubber latex. The 289 vial stoppers are not made with natural rubber latex. 290



Influenza illness and its complications follow infection with influenza viruses. Global 293 surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of 294 influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. 295

Public health authorities recommend influenza vaccine strains annually. Inactivated influenza 296 vaccines are standardized to contain the hemagglutinins of strains representing the influenza 297 viruses likely to circulate in the United States during the influenza season. Two B strain lineages 298 (Victoria and Yamagata) are of public health importance because they have co-circulated since 299 2001. FLULAVAL (trivalent influenza vaccine) contains only two influenza A subtype viruses 300 and one influenza type B virus. In 6 of the last 11 seasons, the most predominant circulating 301 influenza B lineage was not included in the annual trivalent vaccine. Quadrivalent vaccines, such 302 as FLULAVAL QUADRIVALENT, contain two influenza A subtype viruses and two influenza 303 type B viruses (one of the Victoria lineage and one of the Yamagata lineage). 304

Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with 305 inactivated influenza virus vaccines have not been correlated with protection from influenza 306 illness but the antibody titers have been used as a measure of vaccine activity. In some human 307 challenge studies, antibody titers of ≥1:40 have been associated with protection from influenza 308 illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers 309 little or no protection against another virus. Furthermore, antibody to one antigenic variant of 310 influenza virus might not protect against a new antigenic variant of the same type or subtype. 311 Frequent development of antigenic variants through antigenic drift is the virological basis for 312 seasonal epidemics and the reason for the usual change of one or more new strains in each year’s 313 influenza vaccine. 314

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Annual revaccination is recommended because immunity declines during the year after 315 vaccination, and because circulating strains of influenza virus change from year to year.3 316

13 NONCLINICAL TOXICOLOGY 317


FLULAVAL QUADRIVALENT has not been evaluated for carcinogenic or mutagenic 319 potential. Vaccination of female rats with FLULAVAL QUADRIVALENT, at doses shown to 320 be immunogenic in the rat, had no effect on fertility. 321


14.1 Efficacy against Influenza 323

The efficacy of FLULAVAL QUADRIVALENT was evaluated in Trial 3, a randomized, 324 observer-blind, non-influenza vaccine-controlled trial conducted in 3 countries in Asia, 3 in Latin 325 America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy 326 subjects aged 3 through 8 years were randomized (1:1) to receive FLULAVAL 327 QUADRIVALENT (N = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 328 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) 329 influenza strains, or HAVRIX (N = 2,584), as a control vaccine. Children with no history of 330 influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX 331 approximately 28 days apart. Children with a history of influenza vaccination received one dose 332 of FLULAVAL QUADRIVALENT or HAVRIX [see Adverse Reactions (6.1)]. 333

Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse 334 transcriptase polymerase chain reaction (RT-PCR)-positive influenza A and/or B disease 335 presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥100°F in the 336 presence of at least one of the following symptoms on the same day: cough, sore throat, runny 337 nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for 338 approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or 339 B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine 340 efficacy was calculated based on the ATP cohort for efficacy (Table 5). 341

15

Table 5. FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy 342 against Influenza A and/or B in Children Aged 3 through 8 Yearsa (According-to-Protocol 343 Cohort for Efficacy) 344

Nb nc

Influenza Attack Rate

% (n/N) Vaccine Efficacy

% (CI) All RT-PCR-positive Influenza FLULAVAL QUADRIVALENT 2,379 58 2.4 55.4d

(95% CI: 39.1, 67.3) HAVRIXe 2,398 128 5.3 – All Culture-confirmed Influenzaf FLULAVAL QUADRIVALENT 2,379 50 2.1 55.9

(97.5% CI: 35.4, 69.9) HAVRIXe 2,398 112 4.7 – Antigenically Matched Culture-confirmed Influenza FLULAVAL QUADRIVALENT 2,379 31 1.3 45.1g

(97.5% CI: 9.3, 66.8) HAVRIXe 2,398 56 2.3 –

CI = Confidence Interval; RT-PCR = Reverse transcriptase polymerase chain reaction. 345 a Trial 3: NCT01218308. 346 b According-to-protocol cohort for efficacy included subjects who met all eligibility criteria, 347

were successfully contacted at least once post-vaccination, and complied with the protocol-348 specified efficacy criteria. 349

c Number of influenza cases. 350 d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% 351

for the lower limit of the 2-sided 95% CI. 352 e Hepatitis A Vaccine used as a control vaccine. 353 f Of 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 354

21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and 355 nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 356 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with 357 HAVRIX)]. 358

g Since only 67% of cases could be typed, the clinical significance of this result is unknown. 359

In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or 360 B disease presenting as ILI was evaluated in subjects aged 3 through 4 years and 5 through 361 8 years; vaccine efficacy was 35.3% (95% CI: -1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), 362

16

respectively. As the trial lacked statistical power to evaluate efficacy within age subgroups, the 363 clinical significance of these results is unknown. 364

As a secondary objective in the trial, subjects with RT-PCR-positive influenza A and/or B were 365 prospectively classified based on the presence of adverse outcomes that have been associated 366 with influenza infection (defined as fever >102.2°F/39.0°C, physician-verified shortness of 367 breath, pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary congestion, croup and/or 368 acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including 369 myositis, encephalitis, seizure and/or myocarditis). 370

The risk reduction of fever >102.2°F/39.0°C associated with RT-PCR-positive influenza was 371 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL 372 QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse 373 outcomes had too few cases to calculate a risk reduction. The incidence of these adverse 374 outcomes is presented in Table 6. 375

Table 6. FLULAVAL QUADRIVALENT: Incidence of Adverse Outcomes Associated with 376 RT-PCR-positive Influenza in Children Aged 3 through 8 Yearsa (Total Vaccinated 377 Cohort)b 378

FLULAVAL QUADRIVALENT

N = 2,584 HAVRIXc N = 2,584

Adverse Outcomed Number of

Events Number of Subjectse %

Number of Events

Number of Subjectse %

Fever >102.2°F/39.0°C 16f 15 0.6 51f 50 1.9 Shortness of breath 0 0 0 5 5 0.2 Pneumonia 0 0 0 3 3 0.1 Wheezing 1 1 0 1 1 0 Bronchitis 1 1 0 1 1 0 Pulmonary congestion 0 0 0 1 1 0 Acute otitis media 0 0 0 1 1 0 Bronchiolitis 0 0 0 0 0 0 Croup 0 0 0 0 0 0 Encephalitis 0 0 0 0 0 0 Myocarditis 0 0 0 0 0 0 Myositis 0 0 0 0 0 0 Seizure 0 0 0 0 0 0 a Trial 3: NCT01218308. 379 b Total vaccinated cohort included all vaccinated subjects for whom data were available. 380 c Hepatitis A Vaccine used as a control vaccine. 381

17

d In subjects who presented with more than one adverse outcome, each outcome was counted in 382 the respective category. 383

e Number of subjects presenting with at least one event in each group. 384 f One subject in each group had sequential influenza due to influenza type A and type B 385

viruses. 386

14.2 Immunological Evaluation 387

Adults 388

Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial 389 conducted in subjects aged 18 years and older. In this trial, subjects received FLULAVAL 390 QUADRIVALENT (N = 1,246), or one of two formulations of a comparator trivalent influenza 391 vaccine (FLULAVAL, TIV-1, N = 204 or TIV-2, N = 211), each containing an influenza type B 392 virus that corresponded to one of the two B viruses in FLULAVAL QUADRIVALENT (a type 393 B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see Adverse Reactions 394 (6.1)]. 395

Immune responses, specifically hemagglutination inhibition (HI) antibody titers to each virus 396 strain in the vaccine, were evaluated in sera obtained 21 days after administration of 397 FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoint was GMTs 398 adjusted for baseline, performed on the According-to-Protocol (ATP) cohort for whom 399 immunogenicity assay results were available after vaccination. FLULAVAL QUADRIVALENT 400 was non-inferior to both TIVs based on adjusted GMTs (Table 7). The antibody response to 401 influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody 402 response after vaccination with a TIV containing an influenza B strain from a different lineage. 403 There was no evidence that the addition of the second B strain resulted in immune interference to 404 other strains included in the vaccine (Table 7). 405

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Table 7. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza 406 Vaccine (TIV) 21 Days Post-vaccination in Adults Aged 18 Years and Oldera (According-407 to-Protocol Cohort for Immunogenicity)b 408

FLULAVAL

QUADRIVALENTc TIV-1

(B Victoria)d TIV-2

(B Yamagata)e Geometric Mean Titers Against

N = 1,245-1,246 (95% CI)

N = 204 (95% CI)

N = 210-211 (95% CI)

A/California/7/2009 (H1N1) 204.6f (190.4, 219.9)

176.0 (149.1, 207.7)

149.0 (122.9, 180.7)

A/Victoria/210/2009 (H3N2) 125.4f (117.4, 133.9)

147.5 (124.1, 175.2)

141.0 (118.1, 168.3)


177.7f (167.8, 188.1)

135.9 (118.1, 156.5)

71.9 (61.3, 84.2)

B/Florida/4/2006 (Yamagata lineage)

399.7f (378.1, 422.6)

176.9 (153.8, 203.5)

306.6 (266.2, 353.3)

CI = Confidence Interval. 409 a Trial 1: NCT01196975. 410 b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom 411

assay results were available after vaccination for at least one trial vaccine antigen. 412 c Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 413

(Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage) 414 d Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 415

B/Brisbane/60/2008 (Victoria lineage) 416 e Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 417

B/Florida/04/2006 (Yamagata lineage). 418 f Non-inferior to both TIVs based on adjusted GMTs [upper limit of the 2-sided 95% CI for the 419

GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5]; superior to TIV-1 (B Victoria) with 420 respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B 421 strain of Victoria lineage based on adjusted GMTs [lower limit of the 2-sided 95% CI for the 422 GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5]. 423

Children 424

Trial 2 was a randomized, double-blind, active-controlled trial conducted in children aged 425 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT (N = 878), or 426 one of two formulations of a comparator trivalent influenza vaccine (FLUARIX, TIV-1, N = 871 427 or TIV-2 N = 878), each containing an influenza type B virus that corresponded to one of the two 428 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B 429

19

virus of the Yamagata lineage) [see Adverse Reactions (6.1)]. 430

Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were 431 evaluated in sera obtained 28 days following one or 2 doses of FLULAVAL QUADRIVALENT 432 or the comparators. The immunogenicity endpoints were GMTs adjusted for baseline, and the 433 percentage of subjects who achieved seroconversion, defined as at least a 4-fold increase in 434 serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. 435 FLULAVAL QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs and 436 seroconversion rates (Table 8). The antibody response to influenza B strains contained in 437 FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a 438 TIV containing an influenza B strain from a different lineage. There was no evidence that the 439 addition of the second B strain resulted in immune interference to other strains included in the 440 vaccine (Table 8). 441

Table 8. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza 442 Vaccine (TIV) at 28 Days Post-vaccination in Children Aged 3 through 17 Yearsa 443 (According-to-Protocol Cohort for Immunogenicity)b 444

FLULAVAL

QUADRIVALENTc TIV-1

(B Victoria)d TIV-2

(B Yamagata)e Geometric Mean Titers Against

N = 878 (95% CI)

N = 871 (95% CI)

N = 877-878 (95% CI)

A/California/7/2009 (H1N1)

362.7f (335.3, 392.3)

429.1 (396.5, 464.3)

420.2 (388.8, 454.0)


143.7f (134.2, 153.9)

139.6 (130.5, 149.3)

151.0 (141.0, 161.6)


250.5f (230.8, 272.0)

245.4 (226.9, 265.4)

68.1 (61.9, 74.9)


512.5f (477.6, 549.9)

197.0 (180.7, 214.8)

579.0 (541.2, 619.3)

Seroconversiong to: N = 876

% (95% CI) N = 870

% (95% CI) N = 876-877 % (95% CI)

A/California/7/2009 (H1N1)

84.4f (81.8, 86.7)

86.8 (84.3, 89.0)

85.5 (83.0, 87.8)


70.1f (66.9, 73.1)

67.8 (64.6, 70.9)

69.6 (66.5, 72.7)


74.5f (71.5, 77.4)

71.5 (68.4, 74.5)

29.9 (26.9, 33.1)


75.2f (72.2, 78.1)

41.3 (38.0, 44.6)

73.4 (70.4, 76.3)

CI = Confidence Interval. 445

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a Trial 2: NCT01198756. 446 b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom 447

assay results were available after vaccination for at least one trial vaccine antigen. 448 c Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 449

(Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). 450 d Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 451

B/Brisbane/60/2008 (Victoria lineage). 452 e Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 453

B/Florida/04/2006 (Yamagata lineage). 454 f Non-inferior to both TIVs based on adjusted GMTs [upper limit of the 2-sided 95% CI for the 455

GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper 456 limit of the 2-sided 95% CI on difference of the TIV minus FLULAVAL QUADRIVALENT 457 ≤10%); superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to 458 TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs 459 [lower limit of the 2-sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) 460 >1.5] and seroconversion rates (lower limit of the 2-sided 95% CI on difference of 461 FLULAVAL QUADRIVALENT minus the TIV >10%). 462

g Seroconversion defined as a 4-fold increase in post-vaccination antibody titer from pre-463 vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40. 464

15 REFERENCES 465

1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 466 vaccination. Virus Res 2004;103:133-138. 467

2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting 468 antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg 469 Camb 1972;70:767-777. 470

3. Centers for Disease Control and Prevention. Prevention and control of influenza with 471 vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). 472 MMWR 2010;59(RR-8):1-62. 473


FLULAVAL QUADRIVALENT is available in 0.5-mL single-dose disposable prefilled TIP-475 LOK syringes (packaged without needles) and in 5-mL multi-dose vials containing 10 doses 476 (0.5 mL each). 477

NDC 19515-908-41 Syringe in Package of 10: NDC 19515-908-52 478

NDC 19515-903-01 Multi-Dose Vial (containing 10 doses) in Package of 1: NDC 19515-903-11 479

21

Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has 480 been frozen. Store in the original package to protect from light. Once entered, a multi-dose vial 481 should be discarded after 28 days. 482


Provide the following information to the vaccine recipient or guardian: 484

• Inform of the potential benefits and risks of immunization with FLULAVAL 485 QUADRIVALENT. 486

• Educate regarding potential side effects, emphasizing that (1) FLULAVAL 487 QUADRIVALENT contains non-infectious killed viruses and cannot cause influenza, and 488 (2) FLULAVAL QUADRIVALENT is intended to provide protection against illness due to 489 influenza viruses only, and cannot provide protection against all respiratory illness. 490

• Inform that safety and efficacy have not been established in pregnant women. Register 491 women who receive FLULAVAL QUADRIVALENT while pregnant in the pregnancy 492 registry by calling 1-888-452-9622. 493

• Give the Vaccine Information Statements, which are required by the National Childhood 494 Vaccine Injury Act of 1986 prior to each immunization. These materials are available free of 495 charge at the Centers for Disease Control and Prevention (CDC) website 496 (www.cdc.gov/vaccines). 497

• Instruct that annual revaccination is recommended. 498

FLUARIX, FLULAVAL, HAVRIX, and TIP-LOK are registered trademarks of the GSK group 499 of companies. 500

501 Manufactured by ID Biomedical Corporation of Quebec 502 Quebec City, QC, Canada, US License 1739 503 Distributed by GlaxoSmithKline 504 Research Triangle Park, NC 27709 505

©201X the GSK group of companies. All rights reserved. 506

FVQ: XPI 507

http://www.cdc.gov/vaccines

Seqirus Vaccines Limited BL 2055

US Package Insert Page 1 of 20

Influenza Virus Vaccine Fluvirin®

2016-2017 FORMULA HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUVIRIN® (Influenza Virus Vaccine) safely and effectively. See full prescribing information for FLUVIRIN®. FLUVIRIN® (Influenza Virus Vaccine) Suspension for Intramuscular Injection 2016-2017 Formula Initial US Approval: 1988 INDICATIONS AND USAGE • FLUVIRIN® is an inactivated influenza virus vaccine indicated for active

immunization of persons 4 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine (1).

• FLUVIRIN® is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group (8.4).

DOSAGE AND ADMINISTRATION • For intramuscular use only. Age Dose Schedule

4 years through 8 years One or two doses a, 0.5 mL each If 2 doses, administer at least 1 month apart

9 years and older One dose, 0.5 mL - a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines. "-" indicates information is not applicable DOSAGE FORMS AND STRENGTHS

FLUVIRIN®, a sterile suspension for intramuscular injection, is supplied in two presentations: • 0.5 mL single-dose prefilled syringe (3, 11) • 5.0 mL multi-dose vial containing 10 doses (each dose is 0.5 mL) (3,11) CONTRAINDICATIONS • History of severe allergic reactions (e.g., anaphylaxis) to egg proteins, or any

component of FLUVIRIN®, or life-threatening reactions to previous influenza vaccinations. (4.1, 11)

WARNINGS AND PRECAUTIONS • If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza

vaccine, the decision to give FLUVIRIN® should be based on careful consideration of the potential benefits and risks. (5.1)

• Immunocompromised persons may have a reduced immune response to FLUVIRIN®. (5.2)



• The tip caps of the FLUVIRIN® prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals.

ADVERSE REACTIONS The most frequently reported adverse reactions are mild hypersensitivity reactions (such as rash), local reactions at the injection site, and influenza-like symptoms. (6) To report SUSPECTED ADVERSE REACTIONS contact Seqirus at 1-855-358-8966 or VAERS at 1-800-822-7967 and www.vaers.hhs.gov. DRUG INTERACTIONS • Do not mix with any other vaccine in the same syringe or vial. (7.1) • Immunosuppressive therapies may reduce immune response to FLUVIRIN®. (7.2) USE IN SPECIFIC POPULATIONS • Safety and effectiveness of FLUVIRIN® have not been established in pregnant

women, nursing mothers or children less than 4 years of age. (8.1, 8.3, 8.4) • Antibody responses were lower in the geriatric population than in younger subjects.

(8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: March 2016





2.1 Preparation for Administration 2.2 Recommended Dose and Schedule

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome 5.2 Altered Immunocompetence

5.3 Preventing and Managing Allergic Reactions 5.4 Limitations of Vaccine Effectiveness 5.5 Syncope

6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile 6.2 Clinical Trial Experience

6.3 Postmarketing Experience 6.4 Other Adverse Reactions Associated with Influenza Vaccination

7 DRUG INTERACTIONS 7.1 Concomitant Administration with Other Vaccines

7.2 Concurrent Use with Immunosuppressive Therapies 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 13 NONCLINICAL TOXICOLOGY


14.1 Immunogenicity in Adults (18 to 64 years of age) 14.2 Immunogenicity in Geriatric Subjects (65 years of age and over) 14.3 Immunogenicity in Pediatric Subjects

15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING


17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.



FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE FLUVIRIN® is an inactivated influenza virus vaccine indicated for immunization of persons 4 years of age and older against influenza virus disease caused by influenza virus subtypes A and type B contained in the vaccine [see DOSAGE FORMS AND STRENGTHS (3)].

FLUVIRIN® is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group. 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration

Shake the syringe vigorously before administering the vaccine and shake the multidose vial preparation each time before withdrawing a dose of vaccine.

Inspect FLUVIRIN® syringes and multidose vials visually for particulate matter and/or discoloration prior to administration [see DESCRIPTION (11)]. If either of these conditions exists, the vaccine should not be administered.

Between uses, return the multidose vial to the recommended storage conditions between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen.

A separate sterile syringe and needle must be used for each injection to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and not recapped.

It is recommended that small syringes (0.5 mL or 1 mL) should be used to minimize any product loss.

For intramuscular use only. 2.2 Recommended Dose and Schedule The dose and schedule for Fluvirin is presented in Table 1.

TABLE 1 Fluvirin Dose and Schedule

Age Dose Schedule

4 years through 8 years One or two doses a, 0.5 mL each If 2 doses, administer at least 1 month apart

9 years and older One dose, 0.5 mL - a 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines. "-" indicates information is not applicable In children, the needle size may range from 7/8 to 1¼ inches, depending on the size of the child’s deltoid muscle, and should be of sufficient length to penetrate the muscle tissue. The anterolateral thigh can be used, but the needle should be longer, usually 1 inch.

In adults, a needle of ≥1 inch is preferred because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults. The preferred site for intramuscular injection is the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal region or areas where there may be a major nerve trunk.




FLUVIRIN®, a sterile suspension for intramuscular injection, is supplied in two presentations:

• 0.5 mL single-dose prefilled syringe • 5.0 mL multi-dose vial containing 10 doses (each dose is 0.5 mL)

4 CONTRAINDICATIONS 4.1 Hypersensitivity

Do not administer FLUVIRIN® to anyone with known history of severe allergic reactions (e.g., anaphylaxis) to egg proteins (eggs or egg products), or to any component of FLUVIRIN®, or who has had a life-threatening reaction to previous influenza vaccinations. 5 WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome

If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUVIRIN® should be based on careful consideration of the potential benefits and risks. 5.2 Altered Immunocompetence

If FLUVIRIN® is administered to immunocompromised persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained.

5.3 Preventing and Managing Allergic Reactions

Prior to administration of any dose of FLUVIRIN®, the healthcare provider should review the patient’s prior immunization history for possible adverse events, to determine the existence of any contraindication to immunization with FLUVIRIN® and to allow an assessment of benefits and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

The tip caps of the FLUVIRIN® prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals.


Vaccination with FLUVIRIN® may not protect all individuals.

5.5 Syncope Syncope (fainting) can occur in association with administration of injectable

vaccines, including Fluvirin. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope by maintaining a supine or Trendelenburg position. 6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile Serious allergic reactions, including anaphylactic shock, have been observed in individuals receiving FLUVIRIN® during postmarketing surveillance.



6.2 Clinical Trial Experience

Adverse event information from clinical trials provides a basis for identifying adverse events that appear to be related to vaccine use and for approximating the rates of these events. However, because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect rates observed in clinical practice. Adult and Geriatric Subjects

Safety data were collected in a total of 2768 adult and geriatric subjects (18 years of age and older) who have received FLUVIRIN® in 29 clinical studies since 1982.

In 9 clinical studies since 1997, among 1261 recipients of FLUVIRIN®, 745 (59%) were women; 1211 (96%) were White, 23 (2%) Asian, 15 (1%) Black and 12 (1%) other; 370 (29%) of subjects were elderly (≥65 years of age). All studies have been conducted in the UK, apart from a study run in the US in 2005-2006 where FLUVIRIN® was used as a comparator for an unlicensed vaccine.

After vaccination, the subjects were observed for 30 minutes for hypersensitivity or other immediate reactions. Subjects were instructed to complete a diary card for three days following immunization (i.e. Day 1 to 4) to collect local and systemic reactions (see Tables 2 and 3). All local and systemic adverse events were considered to be at least possibly related to the vaccine. Local and systemic reactions mostly began between day 1 and day 2. The overall adverse events reported in clinical trials since 1998 in at least 5% of the subjects are summarized in Table 4.



TABLE 2 Solicited Adverse Events in the First 72-96 Hours After Administration of FLUVIRIN® in

Adult (18-64 years of age) and Geriatric (≥65 years of age) Subjects.

1998-1999*§ 1999-2000*§ 2000-2001*§ 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs

N = 66 N = 44 N = 76 N = 34 N = 75 N = 35 Local Adverse Events

Pain 16 (24%) 4 (9%) 16 (21%) - 9 (12%) - Mass 7 (11%) 1 (2%) 4 (5%) - 8 (11%) 1 (3%) Inflammation 5 (8%) 2 (5%) 6 (8%) - 7 (9%) 1 (3%) Ecchymosis 4 (6%) 1 (2%) 3 (4%) 1 (3%) 4 (5%) - Edema 2 (3%) 1 (2%) 1 (1%) 2 (6%) 3 (4%) 1 (3%) Reaction 2 (3%) - 2 (3%) - 4 (5%) 1 (3%) Hemorrhage - - 1 (1%) - - -


Headache 7 (11%) 1 (2%) 17 (22%) 3 (9%) 4 (5%) - Fatigue 3 (5%) 2 (5%) 4 (5%) 1 (3%) 3 (4%) - Malaise 2 (3%) 1 (2%) 2 (3%) 1 (3%) 1 (1%) - Myalgia 1 (2%) - 2 (3%) - - - Fever 1 (2%) - 1 (1%) - - - Arthralgia - 1 (2%) - 1 (3%) - - Sweating - - 3 (4%) - 1 (1%) 1 (3%)

2001-2002*^ 2002-2003*^ 2004-2005*^

18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs N = 75 N = 35 N = 107 N = 88 N = 74 N = 61

Local Adverse Events Pain 12 (16%) 1 (3%) 14 (13%) 7 (8%) 15 (20%) 9 (15%) Mass 4 (5%) 1 (3%) - - - - Ecchymosis 2 (3%) - 3 (3%) 3 (3%) 2 (3%) 1 (2%) Edema 2 (3%) 1 (3%) 6 (6%) 2 (2%) - - Erythema 5 (7%) - 11 (10%) 5 (6%) 16 (22%) 5 (8%) Swelling - - - - 11 (15%) 4 (7%) Reaction - - 2 (2%) - - - Induration - - 14 (13%) 3 (3%) 11 (15%) 1 (2%) Pruritus - - 1 (1%) - - -


Headache 8 (11%) 1 (3%) 12 (11%) 9 (10%) 14 (19%) 3 (5%) Fatigue 1 (1%) 1 (3%) - - 5 (7%) 2 (3%) Malaise 3 (4%) - 3 (3%) 4 (5%) 1 (1%) 1 (2%) Myalgia 3 (4%) - 5 (5%) 3 (3%) 8 (11%) 1 (2%) Fever - - - 1 (1%) - - Arthralgia - - 2 (2%) - 1 (1%) - Sweating 3 (4%) 1 (3%) - 2 (2%) - - Shivering - - - 1 (1%) - -

Results reported to the nearest whole percent; Fever defined as >38°C – not reported * Solicited adverse events in the first 72 hours after administration of FLUVIRIN® § Solicited adverse events reported by COSTART preferred term ^ Solicited adverse events reported by MEDDRA preferred term



TABLE 3

Solicited Adverse Events in the First 72 Hours After Administration of FLUVIRIN® in Adult Subjects (18-49 years of age).

2005-2006 US Trial

FLUVIRIN®

N = 304 Local Adverse Events

Pain 168 (55%) Erythema 48 (16%) Ecchymosis 22 (7%) Induration 19 (6%) Swelling 16 (5%)

Systemic Adverse Events Headache 91 (30%) Myalgia 64 (21%) Malaise 58 (19%) Fatigue 56 (18%) Sore throat 23 (8%) Chills 22 (7%) Nausea 21 (7%) Arthralgia 20 (7%) Sweating 17 (6%) Cough 18 (6%) Wheezing 4 (1%) Chest tightness 4 (1%) Other difficulties breathing 3 (1%) Facial edema -

Results reported to the nearest whole percent – not reported



TABLE 4 Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998

1998-1999§ 1999-2000§ 2000-2001§ 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs

N = 66 N = 44 N = 76 N = 34 N = 75 N = 35 Adverse Events Fatigue 8 (12%) 2 (5%) 8 (11%) 2 (6%) 5 (7%) - Back pain 4 (6%) 3 (7%) - - - - Cough increased 2 (3%) 2 (5%) - - - - Ecchymosis 4 (6%) 1 (2%) 4 (5%) 1 (3%) 5 (7%) - Fever 3 (5%) - - - - - Headache 12 (18%) 5 (11%) 22 (29%) 5 (15%) 14 (19%) 2 (6%) Infection 3 (5%) 2 (5%) - - - - Malaise 4 (6%) 4 (9%) 4 (5%) 1 (3%) - - Migraine 4 (6%) 1 (2%) - - - - Myalgia 4 (6%) 1 (2%) - - - - Sweating 5 (8%) 1 (2%) - - - - Rhinitis 3 (5%) 1 (2%) - - 5 (7%) 2 (6%) Pharingitis 6 (9%) 1 (2%) 10 (13%) - 6 (8%) - Arthralgia - - - 2 (6%) - - Injection site pain 16 (24%) 4 (9%) 16 (21%) - 9 (12%) - Injection site ecchymosis 4 (6%) 1 (2%) - - 4 (5%) - Injection site mass 7 (11%) 1 (2%) 4 (5%) - 8 (11%) 1 (3%) Injection site edema - - 1 (1%) 2 (6%) - - Injection site inflammation

5 (8%) 2 (5%) 6 (8%) - 7 (9%) 1 (3%)

Injection site reaction - - - - 4 (5%) 1 (3%)

2001-2002^ 2002-2003^ 2004-2005^ 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs 18-64 yrs ≥ 65 yrs

N = 75 N = 35 N = 107 N = 88 N = 74 N = 61 Adverse Events Fatigue 5 (7%) 4 (11%) 11 (10%) 8 (9%) 4 (5%) 2 (3%) Hypertension - - 1 (1%) 4 (5%) - - Rinorrhea - - 2 (2%) 5 (6%) - - Headache 20 (27%) 2 (6%) 35 (33%) 18 (20%) 12 (16%) 1 (2%) Malaise 6 (8%) 1 (3%) 13 (12%) 8 (9%) - - Myalgia 4 (5%) 1 (3%) 10 (9%) 4 (5%) - - Sweating 3 (4%) 3 (9%) 2 (2%) 5 (6%) - - Rhinitis 4 (5%) - - - - - Pharingitis - - - - 6 (8%) - Arthralgia - - 5 (5%) 4 (5%) - - Sore throat 4 (5%) 1 (3%) 5 (5%) 4 (5%) - - Injection site pain 13 (17%) 3 (9%) 14 (13%) 7 (8%) 6 (8%) 2 (3%) Injection site ecchymosis 4 (5%) 1 (3%) 4 (4%) 4 (5%) - - Injection site erythema 5 (7%) 2 (6%) 11 (10%) 5 (6%) 4 (5%) - Injection site mass 4 (5%) 1 (3%) - - - - Injection site edema - - 6 (6%) 2 (2%) 4 (5%) 1 (2%) Injection site induration - - 14 (13%) 3 (3%) 7 (9%) -

Results reported to the nearest whole percent; Fever defined as >38°C – not reaching the cut-off of 5% § Solicited adverse events reported by COSTART preferred term ^ Solicited adverse events reported by MEDDRA preferred term



Adults (18 to 64 years of age) In adult subjects, solicited local adverse events occurred with similar frequency in

all trials. The most common solicited adverse events occurring in the first 96 hours after administration (Tables 2 and 3) were associated with the injection site (such as pain, erythema, mass, induration and swelling) but were generally mild/moderate and transient. The most common solicited systemic adverse events were headache and myalgia.

The most common overall events in adult subjects (18-64 years of age) were headache, fatigue, injection site reactions (pain, mass, erythema, and induration) and malaise (Table 4). Geriatric Subjects (65 years of age and older)

In geriatric subjects, solicited local and systemic adverse events occurred less frequently than in adult subjects. The most common solicited local and systemic adverse events were injection site pain, and headache (Tables 2 and 3). All were considered mild/moderate and were transient.

The most common overall events in elderly subjects (≥65 years of age) were headache and fatigue.

Only 11 serious adverse events in adult and geriatric subjects (18 years and older) have been reported to date from all the trials performed. These serious adverse events were a minor stroke experienced by a 67 year old subject 14 days after vaccination (1990), death of an 82 year old subject 35 days after vaccination (1990) in very early studies; death of a 72 year old subject 19 days after vaccination (1998-1999), a hospitalization for hemorrhoidectomy of a 38 year old male subject (1999-2000), a severe respiratory tract infection experienced by a 74 year old subject 12 days after vaccination (2002-2003), a planned transurethral resection of the prostate in a subject with prior history of prostatism (2004-2005), two cases of influenza (2005-2006), a drug overdose (2005-2006), cholelithiasis (2005-2006) and a nasal septal operation (2005-2006). None of these events were considered causally related to vaccination. Clinical Trial Experience in Pediatric Subjects

In 1987 a clinical study was carried out in 38 ‘at risk’ children aged between 4 and 12 years (17 females and 21 males). To record the safety of FLUVIRIN®, participants recorded their symptoms on a diary card during the three days after vaccination and noted any further symptoms they thought were attributable to the vaccine. The only reactions recorded were tenderness at the site of vaccination in 21% of the participants on day 1, which was still present in 16% on day 2 and 5% on day 3. In one child, the tenderness was also accompanied by redness at the site of injection for two days. The reactions were not age-dependent and there was no bias towards the younger children.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6 - 47 months). Of these, 285 healthy subjects plus 41 ‘at risk’ subjects received FLUVIRIN®. No serious adverse events were reported.

FLUVIRIN® should only be used for the immunization of persons aged 4 years and over.



6.3 Postmarketing Experience The following additional adverse reactions have been reported during post-

approval use of FLUVIRIN®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Adverse events described here are included because: a) they represent reactions which are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) the frequency of reporting.

• Body as a whole: Local injection site reactions (including pain, pain limiting limb

movement, redness, swelling, warmth, ecchymosis, induration), hot flashes/flushes; chills; fever; malaise; shivering; fatigue; asthenia; facial edema.

• Immune system disorders: Hypersensitivity reactions (including throat and/or mouth edema). In rare cases, hypersensitivity reactions have lead to anaphylactic shock and death.

• Cardiovascular disorders: Vasculitis (in rare cases with transient renal involvement), presyncope, syncope shortly after vaccination.

• Digestive disorders: Diarrhea; nausea; vomiting; abdominal pain. • Blood and lymphatic disorders: Local lymphadenopathy; thrombocytopenia (some

very rare cases were severe with platelet counts less than 5,000 per mm3). • Metabolic and nutritional disorders: Loss of appetite. • Musculoskeletal: Arthralgia; myalgia; myasthenia. • Nervous system disorders: Headache; dizziness; neuralgia; paraesthesia; confusion;

febrile convulsions; Guillain-Barré Syndrome; myelitis (including encephalomyelitis and transverse myelitis); neuropathy (including neuritis); paralysis (including Bell’s Palsy).

• Respiratory disorders: Dyspnea; chest pain; cough; pharyngitis; rhinitis. • Skin and appendages: Stevens-Johnson syndrome; sweating; pruritus; urticaria; rash

(including non-specific, maculopapular, and vesiculobulbous). • General disorders and administration site conditions: Injection site cellulitis-like

reaction (very rare cases of swelling, pain, and redness were large and extended to the entire arm)

6.4 Other Adverse Reactions Associated with Influenza Vaccination

Anaphylaxis has been reported after administration of FLUVIRIN®. Although FLUVIRIN® contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS (4)].

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated.

Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy have been reported.

Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination.



7 DRUG INTERACTIONS 7.1 Concomitant Administration with Other Vaccines There are no data to assess the concomitant administration of FLUVIRIN® with other vaccines. If FLUVIRIN® is to be given at the same time as another injectable vaccine(s), the vaccines should always be administered at different injection sites.

FLUVIRIN® should not be mixed with any other vaccine in the same syringe or vial. 7.2 Concurrent Use with Immunosuppressive Therapies Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to FLUVIRIN®. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: A reproductive and developmental toxicity study has been performed in rabbits at a dose level that was approximately 15 times the human dose based on body weight. The study revealed no evidence of impaired fertility or harm to the fetus due to FLUVIRIN®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this vaccine should be used during pregnancy only if clearly needed. In a reproductive and developmental toxicity study, the effect of FLUVIRIN® on embryo-fetal and post-natal development was evaluated in pregnant rabbits. Animals were administered FLUVIRIN® by intramuscular injection twice prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (approximately 15-fold excess relative to the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, embryo-fetal development, or post-natal development were observed. There were no vaccine related fetal malformations or other evidence of teratogenicity. 8.3 Nursing Mothers

It is not known whether FLUVIRIN® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUVIRIN® is administered to a nursing woman. 8.4 Pediatric Use

The safety and immunogenicity of FLUVIRIN® have not been established in children under 4 years of age.

The safety and immunogenicity of FLUVIRIN® have been established in the age group 4 years to 16 years. The use of FLUVIRIN® in these age groups is supported by evidence from adequate and well controlled studies of FLUVIRIN® in adults that demonstrate the immunogenicity of FLUVIRIN® [see ADVERSE REACTIONS (6) and CLINICAL STUDIES (14)].

8.5 Geriatric Use

Since 1997, of the total number of geriatric subjects (n = 397) in clinical studies of FLUVIRIN®, 29% were 65 years and over, while 2.1% were 75 years and over.



Antibody responses were lower in the geriatric population than in younger subjects. Adverse events occurred less frequently in geriatric subjects (≥65 years) than in younger adults. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. [See ADVERSE REACTION (6) and CLINICAL STUDIES (14)]. 11 DESCRIPTION

FLUVIRIN® is a trivalent, sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with betapropiolactone. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of nonylphenol ethoxylate, a process which removes most of the internal proteins. The nonylphenol ethoxylate is removed from the surface antigen preparation.

FLUVIRIN® is a homogenized, sterile, slightly opalescent suspension in a phosphate buffered saline. FLUVIRIN® has been standardized according to USPHS requirements for the 2016-2017 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 viruses: A/Christchurch/16/2010, NIB-74 (H1N1) (an A/California/7/2009 pdm09-like virus); A/Hong Kong/4801/2014, NYMC X-263B (H3N2) (an A/Hong Kong/4801/2014-like virus); and B/Brisbane/60/2008, wild type (a B/Brisbane/60/2008-like virus).

The 0.5-mL prefilled syringe presentation is formulated without preservative. However, thimerosal, a mercury derivative used during manufacturing, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose).

The 5-mL multidose vial formulation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury.

Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), polymyxin (≤ 3.75 mcg), neomycin (≤ 2.5 mcg), betapropiolactone (not more than 0.5 mcg) and nonylphenol ethoxylate (not more than 0.015% w/v).

The tip caps of the FLUVIRIN® prefilled syringes may contain natural rubber latex. The multidose vial stopper and the syringe stopper/plunger do not contain latex. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some human studies, antibody titer of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects [see REFERENCES (15.1, 15.2)].



Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter. Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year [see REFERENCES (15.3)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility FLUVIRIN® has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. 14 CLINICAL STUDIES

Between 1982 and 1991, twelve clinical studies were conducted in healthy adult and geriatric subjects and one in children between 4 and 12 years of age who were considered to be ‘at risk’. Since 1991 an annual clinical study has been conducted in the UK in healthy adults aged 18 years or older. FLUVIRIN® was also used as a control in a US clinical trial in adults (18-49 years of age). In all the trials, blood samples were taken prior to vaccination and approximately three weeks after vaccination to assess the immunogenic response to vaccination by measurement of anti-HA antibodies.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 ‘at risk’ pediatric subjects received FLUVIRIN®.

FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. 14.1 Immunogenicity in Adults (18 to 64 years of age)

Tables 5 and 6 show the immunogenicity data for the adult age group. The seven clinical studies presented enrolled a total of 774 adult subjects. In the adult group, for all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 40%; the geometric mean titer (GMT) increase was >2.5; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 70%.



TABLE 5 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer

≥1:40 for Adult Subjects

Year/Strain No. of subjects

Seroconversion ∞ HI titer ≥1:40¥

N % 95% CIφ n % 95% CIφ

1998-1999 A/H1N1 48 73 (62, 83) 50 76 (65, 86) A/H3N2 66 43 65 (54, 77) 47 71 (60, 82) B 42 64 (52, 75) 62 94 (88, 100) 1999-2000 A/H1N1 45 59 (48, 70) 50 66 (55, 76) A/H3N2 76 51 67 (57, 78) 66 87 (79, 94) B 53 70 (59, 80) 75 99 (96, 100) 2000-2001 A/H1N1 41 55 (44, 67) 41 55 (44, 67) A/H3N2 74 45 61 (50, 72) 52 84 (75, 92) B 50 68 (57, 78) 73 99 (96, 100) 2001-2002 A/H1N1 44 59 (48, 70) 48 64 (53, 75) A/H3N2 75 46 61 (50, 72) 68 91 (84, 97) B 42 56 (45, 67) 66 88 (81, 95) 2002-2003 A/H1N1 62 58 (49, 68) 73 69 (60, 78) A/H3N2 106 72 68 (59, 77) 93 88 (81, 94) B 78 74 (65, 82) 101 95 (91, 99) 2004-2005 A/H1N1 52 70 (59, 80) 66 89 (80, 95) A/H3N2 74 60 81 (70, 89) 73 99 (93, 100) B 57 77 (66, 86) 69 93 (85, 98) 2005-2006 A/H1N1 191 63 (57, 68) 296 98 (95, 99) A/H3N2 303 273 90 (86, 93) 294 97 (94, 99) B 213 70 (65, 75) 263 87 (82, 90) ∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer. ¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥ 1:40. φ 95% CI: 95% confidence interval



TABLE 6 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers,

Pre- and Post-Immunization, for Adult Subjects


Geometric Mean Titer (GMT) Pre-

vaccination Post-

vaccination Fold Increase (95% CI)*

1998-1999 A/H1N1 7.26 160.87 22.16 (14.25, 34.46) A/H3N2 66 8.23 87.02 10.57 (6.91, 16.16) B 20.97 231.07 110.2 (6.90, 17.59) 1999-2000 A/H1N1 7.43 58.95 7.93 (5.73, 10.97) A/H3N2 76 15.29 122.83 8.03 (5.80, 11.13) B 25.70 254.76 9.91 (6.97, 14.10) 2000-2001 A/H1N1 5.42 33.80 6.24 (4.49, 8.69) A/H3N2 74 15.98 126.01 7.89 (5.61, 11.09) B 26.24 308.25 11.75 (7.73, 17.85) 2001-2002 A/H1N1 7.76 54.78 7.06 (5.24, 9.52) A/H3N2 75 23.67 153.81 6.50 (4.78, 8.84) B 19.91 107.53 5.40 (3.95, 7.38) 2002-2003 A/H1N1 7.78 60.39 7.77 (5.81, 10.39) A/H3N2 106 23.32 292.03 12.52 (8.77, 17.87) B 30.20 314.11 10.40 (7.54, 14.34) 2004-2005 A/H1N1 13 159 12 (8.39, 17) A/H3N2 74 37 658 18 (12, 26) B 15 156 11 (7.87, 14) 2005-2006 A/H1N1 29 232 8 (6.68, 9.59) A/H3N2 303 14 221 15 (14, 17) B 13 83 6.5 (5.73, 7.37) * 95% CI: 95% confidence interval 14.2 Immunogenicity in Geriatric Subjects (65 years of age and older)

Tables 7 and 8 show the immunogenicity of FLUVIRIN® in the geriatric age group. The six clinical studies presented enrolled a total of 296 geriatric subjects. For each of the influenza antigens, the percentage of subjects who achieved seroconversion and the percentage of subjects who achieved HI titers of ≥1:40 are shown, as well as the fold increase in GMT.

For all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 30%; the geometric mean titer (GMT) increase was >2.0; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 60%. The pre-specified efficacy criteria were met in each study, although a relatively lower immunogenicity of A/H1N1 strain was seen in the last four studies (the same strain was in each of the formulations).



TABLE 7 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer

≥1:40 for Geriatric Subjects


Seroconversion ∞ HI titer ≥1:40¥

N % 95% CIφ N % 95% CIφ

1998-1999 A/H1N1 33 79 (66, 91) 38 90 (82, 99) A/H3N2 42 33 79 (66, 91) 36 86 (75, 96) B 13 31 (17, 45) 42 100 (100, 100) 1999-2000 A/H1N1 10 29 (14, 45) 23 68 (52, 83) A/H3N2 34 18 53 (36, 70) 31 91 (82, 100) B 9 26 (12, 41) 32 94 (86, 100) 2000-2001 A/H1N1 5 14 (3, 26) 10 29 (14, 44) A/H3N2 35 22 63 (47, 79) 31 89 (78, 99) B 13 37 (21, 53) 33 94 (87, 100) 2001-2002 A/H1N1 5 14 (3, 26) 14 40 (24, 56) A/H3N2 35 15 43 (26, 59) 33 94 (87, 100) B 6 17 (5, 30) 32 91 (82, 100) 2002-2003 A/H1N1 24 27 (18, 36) 52 58 (48, 69) A/H3N2 89 42 47 (37, 58) 85 96 (91, 100) B 41 46 (36, 56) 86 97 (93, 100) 2004-2005 A/H1N1 17 28 (17, 41) 46 75 (63, 86) A/H3N2 61 29 48 (35, 61) 60 98 (91, 100) B 38 62 (49, 74) 51 84 (72, 92) ∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer ¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥1:40 φ 95% CI: 95% confidence interval



TABLE 8 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers,

Pre- and Post-Immunization, for Geriatric Subjects


Geometric Mean Titer (GMT) Pre-

vaccination Post-

vaccination Fold Increase (95% CI)*

1998-1999 A/H1N1 13.92 176.65 12.69 (8.24, 19.56) A/H3N2 42 10.69 124.92 11.69 (7.02, 19.46) B 114.1 273.56 2.40 (1.82, 3.17) 1999-2000 A/H1N1 15.82 50.58 3.20 (2.13, 4.80) A/H3N2 34 28.00 133.19 4.76 (2.92, 7.76) B 57.16 127.86 2.24 (1.56, 3.20) 2000-2001 A/H1N1 6.66 18.85 2.83 (1.91, 4.18) A/H3N2 35 25.87 140.68 5.44 (3.72, 7.96) B 61.24 191.23 3.12 (2.13, 4.59) 2001-2002 A/H1N1 12.69 26.65 2.10 (1.55, 2.84) A/H3N2 35 47.33 114.26 2.41 (1.73, 3.38) B 45.49 91.89 2.02 (1.47, 2.78) 2002-2003 A/H1N1 13.29 31.92 2.40 (1.90, 3.03) A/H3N2 89 65.86 272.79 4.14 (3.09, 5.55) B 74.87 288.57 3.85 (2.89, 5.13) 2004-2005 A/H1N1 21 64 3.13 (2.33, 4.2) A/H3N2 61 72 320 4.43 (3.13, 6.27) B 20 114 5.69 (4.39, 7.38) * 95% CI: 95% confidence interval 14.3 Immunogenicity in Pediatric Subjects

A small-scale study, was conducted in 1987 to evaluate safety and immunogenicity of FLUVIRIN® in 38 ‘at risk’ children, with diabetes and/or asthma, or lymphoid leukemia. Thirty-eight participants aged between 4 and 12 years of age were assessed. Ten subjects had diabetes, 21 had asthma, two had both diabetes and asthma, and one had lymphoid leukemia. There were four healthy control subjects. All participants received a single 0.5-mL dose of FLUVIRIN®.

Immunogenicity results were obtained for 19 of the 38 subjects enrolled in the study. The point estimate of the percentage of subjects achieving a titer of ≥ 1:40 was 84% for the A/H1N1 strain 79% for the B strain, and 53% for the A/H3N2 strain. The GMT fold increases were 5.8 for the A/H1N1 strain, 40 for the B strain and 17.7 for the A/H3N2 strain.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 ‘at risk’ pediatric subjects, received FLUVIRIN®.

In a 1995/1996 clinical study, 41 subjects (aged 6-36 months) at increased risk for influenza-related complications received two 0.25-mL doses of FLUVIRIN®. At least 49% of subjects showed a ≥4-fold increase in HI antibody titer to all three strains. HI



antibody titers of 1:40 or greater were seen in at least 71% of the subjects for all three influenza strains, with increases in geometric mean titer of 6.0-fold or greater to all three strains.

Two clinical studies (1999-2000 and 2004) indicated a lower immunogenicity profile for FLUVIRIN® compared with two commercial split vaccines; in a study in the age group 6-47 months the comparator was a US licensed vaccine, Fluzone®, and in another study in the age group 6-36 months the comparator was a non-US licensed inactivated influenza vaccine. Despite the small sample size (a total of 285 healthy subjects received FLUVIRIN® in these two clinical studies) the lower immunogenicity profile of FLUVIRIN® was greatest versus the comparator vaccines in children <36months but was also evident in those 36-47 months of age, though the differences were less.

FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. 15 REFERENCES 15.1 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of

influenza vaccination. Virus Res 2004; 103:133-138. 15.2 Hobson D, Curry RL, Beare A, et. al. The role of serum hemagglutinin-inhibiting

antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.

15.3 Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(33):1128-1132.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied

FLUVIRIN® product presentations are listed in Table 9 below:

TABLE 9 Fluvirin Product Presentations

Presentation Carton NDC Number

Components

Pre-filled syringe 70461-119-02 0.5 mL single dose pre-filled syringe, package of 10 syringes per carton (may contain latex) [NDC 70461-119-12]

Multi-dose vial 70461-119-10 5.0 mL multi-dose vial, individually packaged in a carton (contains no latex) [NDC 70461-119-11]


Store FLUVIRIN® refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Do not use after the expiration date. Between uses, return the multidose vial to the recommended storage conditions.

17 PATIENT COUNSELING INFORMATION Vaccine recipients and guardians should be informed by their health care provider of the potential benefits and risks of immunization with FLUVIRIN®. When educating



vaccine recipients and guardians regarding the potential side effects, clinicians should emphasize that (1) FLUVIRIN® contains non-infectious particles and cannot cause influenza and (2) FLUVIRIN® is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against all respiratory illness. Vaccine recipients and guardians should be instructed to report any severe or unusual adverse reactions to their healthcare provider. Vaccine recipients and guardians should be instructed that annual vaccination is recommended. FLUVIRIN® is a registered trademark of Seqirus Vaccines Limited. Manufactured by: Seqirus Vaccines Limited, Speke, Liverpool, UK An affiliate of: Seqirus, Inc., 475 Green Oaks Parkway, Holly Springs, NC 27540,

USA 1-855-358-8966

Sanofi Pasteur 16 February 2016 v0.1 372 Fluzone® High-Dose LE6868 HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Fluzone® High-Dose safely and effectively. See full prescribing information for Fluzone High-Dose. Fluzone High-Dose (Influenza Vaccine) Suspension for Intramuscular Injection 2016-2017 Formula Initial US Approval: 2009 ----------------------------INDICATIONS AND USAGE--------------------------------- Fluzone High-Dose is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus contained in the vaccine. (1) Fluzone High-Dose is approved for use in persons 65 years of age and older. (1) ----------------------------DOSAGE AND ADMINISTRATION------------------------ • For intramuscular use only A single 0.5 mL dose for intramuscular injection in adults 65 years of age and older. (2.1) ----------------------------DOSAGE FORMS AND STRENGTHS--------------------- Suspension for injection in prefilled syringe (gray plunger rod), 0.5 mL. (3)

----------------------------CONTRAINDICATIONS-------------------------------- Severe allergic reaction to any component of the vaccine, including egg protein, or after previous dose of any influenza vaccine. (4) ----------------------------WARNINGS AND PRECAUTIONS------------------- • If Guillain-Barré syndrome (GBS) has occurred within 6 weeks following

previous influenza vaccination, the decision to give Fluzone High-Dose should be based on careful consideration of the potential benefits and risks. (5.1)

-----------------------------ADVERSE REACTIONS------------------------------- • In adults >65 years of age, the most common injection-site reaction was

pain (>30%); the most common solicited systemic adverse events were myalgia, malaise, and headache (>10%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 at 1-800-822-2463 (1-800-VACCINE) or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. -------------------------USE IN SPECIFIC POPULATIONS------------------ Safety and effectiveness of Fluzone High-Dose has not been established in pregnant women. (8.1) See 17 PATIENT COUNSELING INFORMATION and FDA – approved patient labeling. Revised: XXXX XXXX

_______________________________________________________________________________________________________________________________________FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Dose and Schedule 2.2 Administration


5.1 Guillain-Barré Syndrome 5.2 Preventing and Managing Allergic Reactions 5.3 Altered Immunocompetence 5.4 Limitations of Vaccine Effectiveness

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.4 Pediatric Use 8.5 Geriatric Use


12.1 Mechanism of Action 13 NON-CLINICAL TOXICOLOGY


14.1 Immunogenicity of Fluzone High-Dose in Geriatric Adults 14.2 Efficacy of Fluzone High-Dose in Adults 65 Years of Age and Older

15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.


Sanofi Pasteur 16 February 2016 v0.1 372 Fluzone® High-Dose LE6868

Confidential/Propietary Information

Page 2 of 22

FULL PRESCRIBING INFORMATION: 1


Fluzone® High-Dose is a vaccine indicated for active immunization for the prevention of 3

influenza disease caused by influenza A subtype viruses and type B virus contained in the 4

vaccine. 5

6

Fluzone High-Dose is approved for use in persons 65 years of age and older. 7

8


• For intramuscular use only 10

2.1 Dose and Schedule 11

Fluzone High-Dose should be administered as a single 0.5 mL injection by the intramuscular 12

route in adults 65 years of age and older. 13

14

2.2 Administration 15

Inspect Fluzone High-Dose visually for particulate matter and/or discoloration prior to 16

administration. If either of these conditions exist, the vaccine should not be administered. 17

18

Before administering a dose of vaccine, shake the prefilled syringe. 19

20

The preferred site for intramuscular injection is the deltoid muscle. The vaccine should not be 21

injected into the gluteal area or areas where there may be a major nerve trunk. 22

23



Page 3 of 22

Do not administer this product intravenously or subcutaneously. 1

2

Fluzone High-Dose should not be combined through reconstitution or mixed with any other 3

vaccine. 4

5


Fluzone High-Dose is a suspension for injection. 7

8

Fluzone High-Dose is supplied in prefilled syringes (gray syringe plunger rod), 0.5 mL, for adults 9

65 years of age and older. 10

11


A severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see Description 13

(11)], including egg protein, or to a previous dose of any influenza vaccine is a contraindication to 14

administration of Fluzone High-Dose. 15

16



If Guillain-Barré syndrome (GBS) has occurred within 6 weeks following previous influenza 19

vaccination, the decision to give Fluzone High-Dose should be based on careful consideration of 20

the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated 21

risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; 22



Page 4 of 22

if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons 1

vaccinated. (See references 1 and 2.) 2

3

5.2 Preventing and Managing Allergic Reactions 4

Appropriate medical treatment and supervision must be available to manage possible anaphylactic 5

reactions following administration of the vaccine. 6

7


If Fluzone High-Dose is administered to immunocompromised persons, including those receiving 9

immunosuppressive therapy, the expected immune response may not be obtained. 10

11


Vaccination with Fluzone High-Dose may not protect all recipients. 13

14



Because clinical trials are conducted under widely varying conditions, adverse event rates 17

observed in the clinical trial(s) of a vaccine cannot be directly compared to rates in the clinical 18

trial(s) of another vaccine and may not reflect the rates observed in practice. 19

Two clinical studies have evaluated the safety of Fluzone High-Dose. 20

Study 1 (NCT00391053, see http://clinicaltrials.gov) was a multi-center, double-blind pre-21

licensure trial conducted in the US. In this study, adults 65 years of age and older were 22

http://clinicaltrials.gov/



Page 5 of 22

randomized to receive either Fluzone High-Dose or Fluzone (2006-2007 formulation). The study 1

compared the safety and immunogenicity of Fluzone High-Dose to those of Fluzone. The safety 2

analysis set included 2573 Fluzone High-Dose recipients and 1260 Fluzone recipients. 3

4

Table 1 summarizes solicited injection-site reactions and systemic adverse events reported within 5

7 days post-vaccination via diary cards. Onset was usually within the first 3 days after vaccination 6

and a majority of the reactions resolved within 3 days. Solicited injection-site reactions and 7

systemic adverse events were more frequent after vaccination with Fluzone High-Dose compared 8

to Fluzone. 9

10



Page 6 of 22

Table 1: Study 1a: Frequency of Solicited Injection-Site Reactions and Systemic Adverse 1 Events Within 7 Days After Vaccination with Fluzone High-Dose or Fluzone, Adults 65 2 Years of Age and Older 3

Fluzone High-Dose (Nb=2569-2572)

Percentage

Fluzone (Nb=1258-1260)

Percentage

Any Moderatec Severed Any Moderatec Severed

Injection-Site Pain 35.6 3.7 0.3 24.3 1.7 0.2 Injection-Site Erythema 14.9 1.9 1.8 10.8 0.8 0.6

Injection-Site Swelling 8.9 1.6 1.5 5.8 1.3 0.6

Myalgia 21.4 4.2 1.6 18.3 3.2 0.2 Malaise 18.0 4.7 1.6 14.0 3.7 0.6 Headache 16.8 3.1 1.1 14.4 2.5 0.3 Fevere (≥99.5°F) 3.6 1.1 0.0 2.3 0.2 0.1 a NCT00391053 4 b N is the number of vaccinated participants with available data for the events listed 5 c Moderate - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-6

site erythema and Injection-site swelling: ≥2.5 cm to <5 cm; Fever: >100.4°F to ≤102.2°F; Myalgia, Malaise, and 7 Headache: interferes with daily activities 8

d Severe - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema and Injection-9 site swelling: ≥5 cm; Fever: >102.2°F; Myalgia, Malaise, and Headache: prevents daily activities 10

e Fever - The percentage of temperature measurements that were taken by oral route or not recorded were 97.9% and 11 2.1%, respectively, for Fluzone High-Dose; and 98.6% and 1.4%, respectively, for Fluzone 12

13

Within 6 months post-vaccination, 156 (6.1%) Fluzone High-Dose recipients and 93 (7.4%) 14

Fluzone recipients experienced a serious adverse event (SAE). No deaths were reported within 28 15

days post-vaccination. A total of 23 deaths were reported during Days 29 – 180 post-vaccination: 16

16 (0.6%) among Fluzone High-Dose recipients and 7 (0.6%) among Fluzone recipients. The 17

majority of these participants had a medical history of cardiac, hepatic, neoplastic, renal, and/or 18

respiratory diseases. These data do not provide evidence for a causal relationship between deaths 19

and vaccination with Fluzone High-Dose. 20

21



Page 7 of 22

Study 2 (NCT01427309, see http://clinicaltrials.gov) was a multi-center, double-blind post-1

licensure efficacy trial conducted in the US and Canada over two influenza seasons. In this study, 2

adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone 3

(2011-2012 and 2012-2013 formulations). The study compared the efficacy and safety of Fluzone 4

High-Dose to those of Fluzone. The safety analysis set included 15,992 Fluzone High-Dose 5

recipients and 15,991 Fluzone recipients. 6

7

Within the study surveillance period (approximately 6 to 8 months post-vaccination), 1323 (8.3%) 8

Fluzone High-Dose recipients and 1442 (9.0%) Fluzone recipients experienced an SAE. Within 9

30 days post-vaccination, 204 (1.3%) Fluzone High-Dose recipients and 200 (1.3%) Fluzone 10

recipients experienced an SAE. The majority of these participants had one or more chronic 11

comorbid illnesses. A total of 167 deaths were reported within 6 to 8 months post-vaccination: 83 12

(0.5%) among Fluzone High-Dose recipients and 84 (0.5%) among Fluzone recipients. A total of 13

6 deaths were reported within 30 days post-vaccination: 6 (0.04%) among Fluzone High-Dose 14

recipients and 0 (0 %) among Fluzone recipients. These data do not provide evidence for a causal 15

relationship between deaths and vaccination with Fluzone High-Dose. 16

17

6.2 Post-Marketing Experience 18

The following events have been spontaneously reported during the post-approval use of Fluzone 19

or Fluzone High-Dose. Because these events are reported voluntarily from a population of 20

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 21

relationship to vaccine exposure. Adverse events were included based on one or more of the 22




Page 8 of 22

following factors: severity, frequency of reporting, or strength of evidence for a causal 1

relationship to Fluzone or Fluzone High-Dose. 2

3

Events Reported During Post-Approval Use of Fluzone. 4

• Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy 5

• Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including 6

urticaria, angioedema) 7

• Eye Disorders: Ocular hyperemia 8

• Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile 9

convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy 10

(Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), 11

dizziness, paresthesia 12

• Vascular Disorders: Vasculitis, vasodilatation/flushing 13

• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis, cough, 14

wheezing, throat tightness 15

• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome 16

• General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in 17

extremities, chest pain 18

• Gastrointestinal Disorders: Vomiting 19

20

Other Events Reported During Post-Approval Use of Fluzone High-Dose. 21

• Gastrointestinal Disorders: Nausea, diarrhea 22

• General Disorders and Administration Site Conditions: Chills 23



Page 9 of 22


Data evaluating the concomitant administration of Fluzone High-Dose with other vaccines are not 2

available. 3

4


8.1 Pregnancy 6

Pregnancy Category C: Animal reproduction studies have not been conducted with Fluzone High-7

Dose. It is also not known whether Fluzone High-Dose can cause fetal harm when administered to 8

a pregnant woman or can affect reproduction capacity. Fluzone High-Dose should be given to a 9

pregnant woman only if clearly needed. 10

11


Safety and effectiveness of Fluzone High-Dose in persons <65 years of age have not been 13

established. 14

15


Safety, immunogenicity, and efficacy of Fluzone High-Dose have been evaluated in adults 65 17

years of age and older. [See Adverse Reactions (6.1) and Clinical Studies (14)] 18

19

11 DESCRIPTION 20

Fluzone High-Dose (Influenza Vaccine) for intramuscular injection is an inactivated influenza 21

vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-22

containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is 23



Page 10 of 22

concentrated and purified in a linear sucrose density gradient solution using a continuous flow 1

centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, octylphenol 2

ethoxylate (Triton® X-100), producing a “split virus”. The split virus is further purified and then 3

suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone High-4

Dose process uses an additional concentration factor after the ultrafiltration step in order to obtain 5

a higher hemagglutinin (HA) antigen concentration. 6

7

Fluzone High-Dose suspension for injection is clear and slightly opalescent in color. 8

9

Neither antibiotics nor preservative are used in the manufacture of Fluzone High-Dose. 10

11

The Fluzone High-Dose prefilled syringe presentation is not made with natural rubber latex. 12

13

Fluzone High-Dose is standardized according to United States Public Health Service requirements 14

and is formulated to contain HA of each of the following three influenza strains recommended for 15

the 2016-2017 influenza season: A/California/07/2009 X-179A (H1N1), A/Hong 16

Kong/4801/2014 X-263-B(H3N2), and B/Brisbane/60/2008(B Victoria Lineage). The amounts of 17

HA and other ingredients per dose of vaccine are listed in Table 2. 18



Page 11 of 22

Table 2: Fluzone High-Dose Ingredients 1

Ingredient

Quantity (per dose)

Fluzone High-Dose 0.5 mL Dose

Active Substance: Split influenza virus, inactivated strainsa:

180 mcg HA total

A (H1N1) 60 mcg HA A (H3N2) 60 mcg HA B 60 mcg HA Other: Sodium phosphate-buffered isotonic sodium chloride

solution QSb to appropriate volume

Formaldehyde ≤100 mcg Octylphenol ethoxylate ≤250 mcg

Gelatin None Preservative None a per United States Public Health Service (USPHS) requirement 2 b Quantity Sufficient 3 4



Influenza illness and its complications follow infection with influenza viruses. Global surveillance 7

of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of 8

influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. 9

Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with 10

inactivated influenza virus vaccines have not been correlated with protection from influenza virus 11

infection. In some human studies, antibody titers ≥1:40 have been associated with protection from 12

influenza illness in up to 50% of participants. (See references 3 and 4.) 13



Page 12 of 22

Antibodies against one influenza virus type or subtype confer limited or no protection against 1

another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect 2

against a new antigenic variant of the same type or subtype. Frequent development of antigenic 3

variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the 4

usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza 5

vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the 6

influenza viruses likely to be circulating in the US during the influenza season. 7

8

Annual vaccination with the current vaccine is recommended because immunity during the year 9

after vaccination declines and because circulating strains of influenza virus change from year to 10

year. 11

12

13 NON-CLINICAL TOXICOLOGY 13


Fluzone High-Dose has not been evaluated for carcinogenic or mutagenic potential or for 15

impairment of fertility. 16

17


14.1 Immunogenicity of Fluzone High-Dose in Adults 65 Years of Age and Older 19

Study 1 (NCT00391053) was a multi-center, double-blind pre-licensure trial conducted in the US 20

in which adults 65 years of age and older were randomized to receive either Fluzone High-Dose 21

or Fluzone (2006-2007 formulation). The study compared the safety and immunogenicity of 22

Fluzone High-Dose to those of Fluzone. For immunogenicity analyses, 2576 participants were 23



Page 13 of 22

randomized to Fluzone High-Dose and 1275 participants were randomized to Fluzone. Females 1

accounted for 51.3% of participants in the Fluzone High-Dose group and 54.7% of participants in 2

the Fluzone group. In both groups, the mean age was 72.9 years (ranged from 65 through 97 years 3

in the Fluzone High-Dose group and 65 through 94 years in the Fluzone group); 35% of 4

participants in the Fluzone High-Dose group and 36% of participants in the Fluzone group were 5

75 years of age or older. Most participants in the Fluzone High-Dose and Fluzone groups, 6

respectively, were White (91.7% and 92.9%), followed by Hispanic (4.8% and 3.7%), and Black 7

(2.7% and 2.7%). 8

9

The primary endpoints of the study were HI GMTs and seroconversion rates 28 days after 10

vaccination. Pre-specified statistical superiority criteria required that the lower limit (LL) of the 2-11

sided 95% CI of the GMT ratio (Fluzone High-Dose/Fluzone) be greater than 1.50 for at least two 12

of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated 13

(LL>0.67), and that the lower limit of the 2-sided 95% CI of the seroconversion rate difference 14

(Fluzone High-Dose minus Fluzone) be greater than 10% for at least two of the strains, and if one 15

strain failed, non-inferiority of that strain must be demonstrated (LL>-10%). As shown in Table 3, 16

statistically superior HI GMTs and seroconversion rates after vaccination with Fluzone High-17

Dose compared to Fluzone were demonstrated for influenza A subtypes, A (H1N1) and A 18

(H3N2), but not for influenza type B. For strain B, non-inferiority of Fluzone High-Dose 19

compared to Fluzone was demonstrated for both the HI GMTs and seroconversion rates. 20



Page 14 of 22

Table 3: Study 1a: Post-Vaccination HI Antibody GMTs and Seroconversion Rates and 1 Analyses of Superiority of Fluzone High-Dose Relative to Fluzone, Adults 65 Years of Age 2 and Older 3

Influenza Strain

GMT

GMT Ratio

Seroconversion %b

Difference

Met Both Pre-

defined Superiority

Criteriad

Fluzone

High-Dose

Nc=2542-2544

Fluzone

Nc=1252

Fluzone High-Dose

over Fluzone

(95% CI)

Fluzone

High-Dose

Nc=2529-2531

Fluzone

Nc=1248-1249

Fluzone High-Dose

minus Fluzone

(95% CI)

A (H1N1) 115.8

67.3

1.7 (1.6; 1.8)

48.6

23.1

25.4 (22.4; 28.5)

Yes

A (H3N2) 608.9

332.5

1.8 (1.7; 2.0)

69.1

50.7

18.4 (15.1; 21.7)

Yes

B 69.1

52.3

1.3 (1.2; 1.4)

41.8

29.9

11.8 (8.6; 15.0)

No

aNCT00391053 4 b Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28) titer ≥1:40 or a 5 minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 6

c N is the number of vaccinated participants with available data for the immunologic endpoint listed 7 d Predefined superiority criterion for seroconversion: the lower limit of the two-sided 95% CI of the difference of the 8 seroconversion rates (Fluzone High-Dose minus Fluzone) is >10%. Predefined superiority criterion for the GMT 9 ratio: the lower limit of the 95% CI of the GMT ratio (Fluzone High-Dose divided by Fluzone) is >1.5 10

11

14.2 Efficacy of Fluzone High-Dose in Adults 65 Years of Age and Older 12

Study 2 (NCT01427309) was a multi-center, double-blind post-licensure efficacy trial conducted 13

in the US and Canada in which adults 65 years of age and older were randomized (1:1) to receive 14

either Fluzone High-Dose or Fluzone. The study was conducted over two influenza seasons 15

(2011-2012 and 2012-2013); 53% of participants enrolled in the first year of the study were re-16

enrolled and re-randomized in the second year. The per-protocol analysis set for efficacy 17

assessments included 15,892 Fluzone High-Dose recipients and 15,911 Fluzone recipients. The 18



Page 15 of 22

majority (67%) of participants in the per-protocol analysis set for efficacy had one or more high-1

risk chronic comorbid conditions. 2

3

In the per-protocol analysis set, females accounted for 57.2% of participants in the Fluzone High-4

Dose group and 56.1% of participants in the Fluzone group. In both groups, the median age was 5

72.2 years (range 65 through 100 years). Overall, most participants in the study were White 6

(95%); approximately 4% of study participants were Black, and approximately 6% reported 7

Hispanic ethnicity. 8

9

The primary endpoint of the study was the occurrence of laboratory-confirmed influenza (as 10

determined by culture or polymerase chain reaction) caused by any influenza viral type/subtype in 11

association with influenza-like illness (ILI), defined as the occurrence of at least one of the 12

following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty 13

breathing; concurrent with at least one of the following systemic signs or symptoms: temperature 14

>99.0°F, chills, tiredness, headaches or myalgia. Participants were monitored for the occurrence 15

of a respiratory illness by both active and passive surveillance, starting 2 weeks post-vaccination 16

for approximately 7 months. After an episode of respiratory illness, nasopharyngeal swab 17

samples were collected for analysis; attack rates and vaccine efficacy were calculated (see Table 18

4). 19



Page 16 of 22

Table 4: Study 2a: Relative Efficacy Against Laboratory-Confirmed Influenzab Regardless 1

of Similarity to the Vaccine Components, Associated with Influenza-Like Illnessc, Adults 65 2

Years of Age and Older 3

Fluzone High-Dose Nd=15,892

ne (%)

Fluzone Nd=15,911

ne (%)

Relative Efficacy

% (95% CI)

Any type/subtypef 227 (1.43) 300 (1.89) 24.2 (9.7; 36.5)g

Influenza A 190 (1.20) 249 (1.56) 23.6 (7.4; 37.1) A (H1N1) 8 (0.05) 9 (0.06) 11.0 (-159.9; 70.1) A (H3N2) 171 (1.08) 222 (1.40) 22.9 (5.4; 37.2)

Influenza Bh 37 (0.23) 51 (0.32) 27.4 (-13.1; 53.8) aNCT01427309 4 bLaboratory-confirmed: culture- or polymerase-chain-reaction-confirmed 5 cOccurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, 6 or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature 7 >99.0°F, chills, tiredness, headaches or myalgia 8 dN is the number of vaccinated participants in the per-protocol analysis set for efficacy assessments 9 en is the number of participants with protocol-defined influenza-like illness with laboratory confirmation 10 fPrimary endpoint 11 gThe pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95% CI of the 12 vaccine efficacy of Fluzone High-Dose relative to Fluzone > 9.1%) was met. 13 hIn the first year of the study the influenza B component of the vaccine and the majority of influenza B cases were of 14 the Victoria lineage; in the second year the influenza B component of the vaccine and the majority of influenza B 15 cases were of the Yamagata lineage 16 17 A secondary endpoint of the study was the occurrence of culture-confirmed influenza caused by 18

viral types/subtypes antigenically similar to those contained in the respective annual vaccine 19

formulations in association with a modified CDC-defined ILI, defined as the occurrence of a 20

temperature > 99.0°F (> 37.2°C) with cough or sore throat. The efficacy of Fluzone High-Dose 21

relative to Fluzone for this endpoint was 51.1% (95% CI: 16.8; 72.0). 22

23



Page 17 of 22

15 REFERENCES 1

2

1 Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 3

and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797-802. 4

2 Baxter, R, et al. Lack of Association of Guillain-Barré Syndrome with Vaccinations. Clin 5

Infect Dis 2013;57(2):197-204. 6

3 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 7

vaccination. Virus Res 2004;103:133-138. 8

4 Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-9

inhibiting antibody in protection against challenge infection with influenza A2 and B 10

viruses. J Hyg Camb 1972;70:767-777. 11

12



Page 18 of 22

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied

Single-dose, prefilled syringe, without needle, 0.5 mL (NDC 49281-399-88) (not made with

natural rubber latex). Supplied as package of 10 (NDC 49281-399-65).


Store Fluzone High-Dose refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if

vaccine has been frozen.

Do not use after the expiration date shown on the label.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

• Inform the patient or caregiver that Fluzone High-Dose contains killed viruses and cannot

cause influenza.

• Among persons aged 65 years and older, Fluzone High-Dose stimulates the immune system to

produce antibodies that help protect against influenza.

• Among persons aged 65 years and older, Fluzone High-Dose offers better protection against

influenza as compared to Fluzone.

• Annual influenza vaccination is recommended.

• Instruct vaccine recipients and caregivers to report adverse reactions to their healthcare

provider and/or to Vaccine Adverse Event Reporting System (VAERS).



Page 19 of 22

Fluzone is a registered trademark of Sanofi Pasteur Inc.

Manufactured by:

Sanofi Pasteur Inc.

Swiftwater PA 18370 USA 6868



Page 20 of 22

Patient Information Sheet Fluzone® High-Dose

Influenza Vaccine

Please read this information sheet before getting Fluzone High-Dose vaccine. This summary is

not intended to take the place of talking with your healthcare provider. If you have questions or

would like more information, please talk with your healthcare provider.

What is Fluzone High-Dose vaccine? Fluzone High-Dose is a vaccine that helps protect against influenza illness (flu).

Fluzone High-Dose vaccine is for people 65 years of age and older.

Vaccination with Fluzone High-Dose vaccine may not protect all people who receive the vaccine.

Who should not get Fluzone High-Dose vaccine? You should not get Fluzone High-Dose vaccine if you:

• ever had a severe allergic reaction to eggs or egg products.

• ever had a severe allergic reaction after getting any flu vaccine.

• are younger than 65 years of age.

Tell your healthcare provider if you have or have had:

• Guillain-Barré syndrome (severe muscle weakness) after getting a flu vaccine.

• problems with your immune system as the immune response may be diminished.

How is Fluzone High-Dose vaccine given? Fluzone High-Dose vaccine is a shot given into the muscle of the arm.



Page 21 of 22

What are the possible side effects of Fluzone High-Dose vaccine? The most common side effects of Fluzone High-Dose vaccine are:

• pain, redness, and swelling where you got the shot

• muscle ache

• tiredness

• headache

These are not all of the possible side effects of Fluzone High-Dose vaccine. You can ask your

healthcare provider for a list of other side effects that is available to healthcare professionals.

Call your healthcare provider for advice about any side effects that concern you. You may report

side effects to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 or

http://vaers.hhs.gov.

Why should I get Fluzone High-Dose vaccine instead of Fluzone vaccine? An efficacy study in adults 65 years of age and older has demonstrated that Fluzone High-Dose

vaccine offers better protection against influenza than Fluzone vaccine.

What are the ingredients in Fluzone High-Dose vaccine? Fluzone High-Dose vaccine contains 3 killed flu virus strains.

Inactive ingredients include formaldehyde and octylphenol ethoxylate.

http://vaers.hhs.gov/



Page 22 of 22

Manufactured by: Sanofi Pasteur Inc.

Swiftwater, PA 18370 USA

Sanofi Pasteur 10 May 2016 v0.4 450/477 Fluzone® Quadrivalent LE6872, 6879, 6883

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Fluzone® Quadrivalent safely and effectively. See full prescribing information for Fluzone Quadrivalent. Fluzone Quadrivalent (Influenza Vaccine) Suspension for Intramuscular Injection 2016-2017 Formula Initial US Approval (Fluzone Quadrivalent): 2013 ----------------------------INDICATIONS AND USAGE--------------------------------- 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. (1) Fluzone Quadrivalent is approved for use in persons 6 months of age and older. (1) ----------------------------DOSAGE AND ADMINISTRATION------------------------ • For intramuscular use only (2)

Age Dose Schedule 6 months through 35 months

One or two doses a, 0.25 mL each

If 2 doses, administer at least 4 weeks apart

36 months through 8 years

One or two doses a, 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 ----------------------------DOSAGE FORMS AND STRENGTHS--------------------- Suspension for injection supplied in 4 presentations: prefilled single-dose syringe (yellow plunger rod), 0.25 mL; prefilled single-dose syringe (purple plunger rod), 0.5 mL; single-dose vial, 0.5 mL; multi-dose vial, 5 mL. (3)

----------------------------CONTRAINDICATIONS-------------------------------- Severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or after previous dose of any influenza vaccine. (4) ----------------------------WARNINGS AND PRECAUTIONS------------------- • If Guillain-Barré syndrome (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. (5.1)

-----------------------------ADVERSE REACTIONS------------------------------- • In children 6 months through 35 months of age, the most common

(≥10%) injection-site reactions were pain (57%) or tenderness (54%), erythema (37%), and swelling (22%); the most common solicited systemic adverse reactions were irritability (54%), abnormal crying (41%), malaise (38%), drowsiness (38%), appetite loss (32%), myalgia (27%), vomiting (15%), and fever (14%). (6.1)

• 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%). (6.1)

• 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%). (6.1)

• 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%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., at 1-800-822-2463 (1-800-VACCINE) or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. -------------------------USE IN SPECIFIC POPULATIONS------------------ • Safety and effectiveness of Fluzone Quadrivalent have not been

established in pregnant women or children less than 6 months of age. (8.4)

• Pregnancy: Pregnancy registry available. Call Sanofi Pasteur Inc. at 1-800-822-2463.

• Antibody responses to Fluzone Quadrivalent are lower in persons ≥65 years of age than in younger adults. (8.5)

See 17 FOR PATIENT COUNSELING INFORMATION and FDA - approved patient labeling. Revised: XXXX XXXX

_______________________________________________________________________________________________________________________________________FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Dose and Schedule 2.2 Administration


5.1 Guillain-Barré Syndrome 5.2 Preventing and Managing Allergic Reactions 5.3 Altered Immunocompetence 5.4 Limitations of Vaccine Effectiveness

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience


11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Efficacy of Fluzone (Trivalent Influenza Vaccine) in Children 6 through 24 Months of Age 14.2 Efficacy of Fluzone (Trivalent Influenza Vaccine) in Adults

14.3 Immunogenicity of Fluzone Quadrivalent in Children 6 Months through 8 Years of Age 14.4 Immunogenicity of Fluzone Quadrivalent in Adults ≥18 years of age 14.5 Immunogenicity of Fluzone Quadrivalent in Geriatric Adults ≥65

years of age 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.



Confidential/Proprietary Information Page 2 of 37

FULL PRESCRIBING INFORMATION: 1


Fluzone® Quadrivalent is a vaccine indicated for active immunization for the prevention of 3

influenza disease caused by influenza A subtype viruses and type B viruses contained in the 4

vaccine. 5

6

Fluzone Quadrivalent is approved for use in persons 6 months of age and older. 7

8


• For intramuscular use only 10

Dose and Schedule 2.111

The dose and schedule for Fluzone Quadrivalent are presented in Table 1. 12

Table 1: Dose and Schedule for Fluzone Quadrivalent 13

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 14 recommendations on prevention and control of influenza with vaccines 15 "-" Indicates information is not applicable 16

17

Administration 2.218



Parenteral drug products should be inspected visually for particulate matter and/or discoloration 1

prior to administration, whenever solution and container permit. If any of these defects or 2

conditions exist, Fluzone Quadrivalent should not be administered. 3

4

Before administering a dose of vaccine, shake the prefilled syringe or vial. Withdraw one dose of 5

vaccine from the single-dose vial using a sterile needle and syringe. Use a separate sterile needle 6

and syringe for each dose withdrawn from the multi-dose vial. 7

8

The preferred sites for intramuscular injection are the anterolateral aspect of the thigh in infants 6 9

months through 11 months of age, the anterolateral aspect of the thigh (or the deltoid muscle if 10

muscle mass is adequate) in persons 12 months through 35 months of age, or the deltoid muscle in 11

persons ≥36 months of age. The vaccine should not be injected into the gluteal area or areas 12

where there may be a major nerve trunk. 13

14


16

Fluzone Quadrivalent should not be combined through reconstitution or mixed with any other 17

vaccine. 18

19


Fluzone Quadrivalent is a suspension for injection. 21

22

Fluzone Quadrivalent is supplied in 4 presentations: 23



1) Prefilled single-dose syringe (yellow syringe plunger rod), 0.25 mL, for persons 6 months 1

through 35 months of age. 2

2) Prefilled single-dose syringe (purple syringe plunger rod), 0.5 mL, for persons 36 months of 3

age and older. 4

3) Single-dose vial, 0.5 mL, for persons 36 months of age and older. 5

4) Multi-dose vial, 5 mL, for persons 6 months of age and older. 6

7


Do not administer Fluzone Quadrivalent to anyone with a history of a severe allergic reaction 9

(e.g., anaphylaxis) to any component of the vaccine [see Description (11)], including egg protein, 10

or to a previous dose of any influenza vaccine. 11

12


Guillain-Barré Syndrome 5.114

The 1976 swine influenza vaccine was associated with an elevated risk of Guillain-Barré 15

syndrome (GBS). Evidence for a causal relation of GBS with other influenza vaccines is 16

inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 17

million persons vaccinated. (See ref. 1) If GBS has occurred within 6 weeks following previous 18

influenza vaccination, the decision to give Fluzone Quadrivalent should be based on careful 19

consideration of the potential benefits and risks. 20

21

Preventing and Managing Allergic Reactions 5.222



Appropriate medical treatment and supervision must be available to manage possible anaphylactic 1

reactions following administration of Fluzone Quadrivalent. 2

3

Altered Immunocompetence 5.34

If Fluzone Quadrivalent is administered to immunocompromised persons, including those 5

receiving immunosuppressive therapy, the expected immune response may not be obtained. 6

7

Limitations of Vaccine Effectiveness 5.48

Vaccination with Fluzone Quadrivalent may not protect all recipients. 9

10


In children 6 months through 35 months of age, the most common (≥10%) injection-site reactions 12

were pain (57%)a or tenderness (54%)b, erythema (37%), and swelling (22%); the most common 13

solicited systemic adverse reactions were irritability (54%)b, abnormal crying (41%)b, malaise 14

(38%)a, drowsiness (38%)b, appetite loss (32%)b, myalgia (27%)a, vomiting (15%)b, and fever 15

(14%). In children 3 years through 8 years of age, the most common (≥10%) injection-site 16

reactions were pain (67%), erythema (34%), and swelling (25%); the most common solicited 17

systemic adverse reactions were myalgia (39%), malaise (32%), and headache (23%). In adults 18 18

years and older, the most common (≥10%) injection-site reaction was pain (47%); the most 19

a Assessed in children 24 months through 35 months of age

b Assessed in children 6 months through 23 months of age



common solicited systemic adverse reactions were myalgia (24%), headache (16%), and malaise 1

(11%). In adults 65 years of age and older, the most common (≥10%) injection-site reaction was 2

pain (33%); the most common solicited systemic adverse reactions were myalgia (18%), headache 3

(13%), and malaise (11%). 4

5

Clinical Trials Experience 6.16

Because clinical trials are conducted under widely varying conditions, adverse event rates 7

observed in the clinical trial(s) of a vaccine cannot be directly compared to rates in the clinical 8

trial(s) of another vaccine and may not reflect the rates observed in practice. 9

10

Children 6 Months Through 8 Years of Age 11

Study 1 (NCT01240746, see http://clinicaltrials.gov) was a single-blind, randomized, active-12

controlled multi-center safety and immunogenicity study conducted in the US. In this study, 13

children 6 months through 35 months of age received one or two 0.25 mL doses of either Fluzone 14

Quadrivalent or one of two formulations of a comparator trivalent influenza vaccine (TIV-1 or 15

TIV-2), and children 3 years through 8 years of age received one or two 0.5 mL doses of either 16

Fluzone Quadrivalent, TIV-1, or TIV-2. Each of the trivalent formulations contained an influenza 17

type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B 18

virus of the Victoria lineage or a type B virus of the Yamagata lineage). For participants who 19

received two doses, the doses were administered approximately 4 weeks apart. The safety analysis 20

set included 1841 children 6 months through 35 months of age and 2506 children 3 years through 21

8 years of age. Among participants 6 months through 8 years of age in the three vaccine groups 22

combined, 49.3% were female (Fluzone Quadrivalent, 49.2%; TIV-1, 49.8%; TIV-2, 49.4%), 23




58.4% Caucasian (Fluzone Quadrivalent, 58.4%; TIV-1, 58.9%; TIV-2, 57.8%), 20.2% Black 1

(Fluzone Quadrivalent, 20.5%; TIV-1, 19.9%; TIV-2, 19.1%), 14.1% Hispanic (Fluzone 2

Quadrivalent, 14.3%; TIV-1, 13.2%; TIV-2, 14.7%), and 7.3% were of other racial/ethnic groups 3

(Fluzone Quadrivalent, 6.8%; TIV-1, 8.0%; TIV-2, 8.5%). Table 2 and Table 3 summarize 4

solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via 5

diary cards. Participants were monitored for unsolicited adverse events for 28 days after each dose 6

and serious adverse events (SAEs) during the 6 months following the last dose. 7

Table 2: Study 1a: Percentage of Solicited Injection-site and Systemic Adverse Reactions 8 Within 7 Days After Vaccination in Children 6 Months Through 35 Months of Age (Safety 9 Analysis Set)b 10

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 - Irritabilityj 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 1 bThe safety analysis set includes all persons who received at least one dose of study vaccine 2 c Fluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 3 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 4 d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 5 B/Brisbane/60/2008 (Victoria lineage), licensed 6 eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 7 (Yamagata lineage), non-licensed 8 fN is the number of participants in the safety analysis set 9 gGrade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site 10 tenderness: cries and protests when injection-site is touched; Injection-site erythema, Injection-site swelling: ≥2.5 cm 11 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 12 months); Malaise, Myalgia, and Headache: some interference with activity; Irritability: requiring increased attention; 13 Crying abnormal: 1 to 3 hours; Drowsiness: not interested in surroundings or did not wake up for a feed/meal; 14 Appetite loss: missed 1 or 2 feeds/meals completely; Vomiting: 2 to 5 episodes per 24 hours 15 hGrade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site tenderness: cries when 16 injected limb is moved, or the movement of the injected limb is reduced; Injection-site erythema, Injection-site 17 swelling: ≥5 cm; Fever: >103.1°F (6 months through 23 months); ≥102.1ºF (24 months through 35 months); Malaise, 18 Myalgia, and Headache: Significant; prevents daily activity; Irritability: inconsolable; Crying abnormal: >3 hours; 19 Drowsiness: sleeping most of the time or difficult to wake up; Appetite loss: refuses ≥3 feeds/meals or refuses most 20 feeds/meals; Vomiting: ≥6 episodes per 24 hours or requiring parenteral hydration 21 iAssessed in children 24 months through 35 months of age 22 jAssessed in children 6 months through 23 months of age 23 kFever measured by any route 24 25

Table 3: Study 1a: Percentage of Solicited Injection-site and Systemic Adverse Reactions 26 Within 7 Days After Vaccination in Children 3 Years Through 8 Years of Age (Safety 27 Analysis Set)b 28

Fluzone


TIV-1d


TIV-2e


Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%) Grade 3h

(%)


- 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 1 bThe safety analysis set includes all persons who received at least one dose of study vaccine 2 c Fluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 3 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 4 d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 5 B/Brisbane/60/2008 (Victoria lineage), licensed 6 eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 7 (Yamagata lineage), non-licensed 8 fN is the number of participants in the safety analysis set 9 gGrade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site 10 erythema, Injection-site swelling: ≥2.5 cm to <5 cm; Fever: ≥101.2°F to ≤102.0°F; Headache, Malaise, and Myalgia: 11 some interference with activity 12 hGrade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema, Injection-site 13 swelling: ≥5 cm; Fever: ≥102.1°F; Headache, Malaise, and Myalgia: Significant; prevents daily activity 14 iFever measured by any route 15 16

Among children 6 months through 8 years of age, unsolicited non-serious adverse events were 17

reported in 1360 (47.0%) recipients in the Fluzone Quadrivalent group, 352 (48.0%) recipients in 18

the TIV-1 group, and 346 (48.0%) recipients in the TIV-2 group. The most commonly reported 19

unsolicited non-serious adverse events were cough, vomiting, and pyrexia. During the 28 days 20

following vaccination, a total of 16 (0.6%) recipients in the Fluzone Quadrivalent group, 4 (0.5%) 21

recipients in the TIV-1 group, and 4 (0.6%) recipients in the TIV-2 group, experienced at least 22

one SAE; no deaths occurred. Throughout the study period, a total of 41 (1.4%) recipients in the 23

Fluzone Quadrivalent group, 7 (1.0%) recipients in the TIV-1 group, and 14 (1.9%) recipients in 24

the TIV-2 group, experienced at least one SAE. Three SAEs were considered to be possibly 25

related to vaccination: croup in a Fluzone Quadrivalent recipient and 2 episodes of febrile seizure, 26



1 each in a TIV-1 recipient and a TIV-2 recipient. One death occurred in the TIV-1 group (a 1

drowning 43 days post-vaccination). 2

3

Adults 4

In study 2 (NCT00988143, see http://clinicaltrials.gov), a multi-centered randomized, open-label 5

trial conducted in the US, adults 18 years of age and older received one dose of either Fluzone 6

Quadrivalent or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or TIV-7

2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one 8

of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type 9

B virus of the Yamagata lineage). The safety analysis set included 570 recipients, half aged 18-60 10

years and half aged 61 years or older. Among participants in the three vaccine groups combined, 11

67.2% were female (Fluzone Quadrivalent, 68.4%; TIV-1, 67.9%; TIV-2, 65.3%), 88.4% 12

Caucasian (Fluzone Quadrivalent, 91.1%; TIV-1, 86.8%; TIV-2, 87.4%), 9.6% Black (Fluzone 13

Quadrivalent, 6.8%; TIV-1, 12.1%; TIV-2, 10.0%), 0.4% Hispanic (Fluzone Quadrivalent, 0.0%; 14

TIV-1, 0.5%; TIV-2, 0.5%), and 1.7% were of other racial/ethnic groups (Fluzone Quadrivalent, 15

2.1%; TIV-1, 0.5%; TIV-2, 2.2%). Table 4 summarizes solicited injection-site and systemic 16

adverse reactions reported within 3 days post-vaccination via diary cards. Participants were 17

monitored for unsolicited adverse events and SAEs during the 21 days following vaccination. 18




Table 4: Study 2a: Percentage of Solicited Injection-site and Systemic Adverse Reactions 1 Within 3 Days After Vaccination in Adults 18 Years of Age and Older (Safety Analysis Set)b 2

Fluzone


TIV-1d


TIV-2e


Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%)

Grade 3h (%)


- 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 3 bThe safety analysis set includes all persons who received study vaccine 4 cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 5 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 6 d2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and 7 B/Brisbane/60/2008 (Victoria lineage), licensed 8 e2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and 9 B/Florida/04/2006 (Yamagata lineage), licensed 10 fN is the number of participants in the safety analysis set 11 gGrade 2 - Injection-site pain: Some interference with activity; Injection-site erythema, Injection-site swelling, 12 Injection-site induration, and Injection-site ecchymosis: ≥5.1 to ≤10 cm; Fever: ≥101.2°F to ≤102.0°F; Myalgia, 13 Headache, Malaise, and Shivering: some interference with activity 14 hGrade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema, Injection-site swelling, 15 Injection-site induration, and Injection-site ecchymosis: >10 cm; Fever: ≥102.1°F; Myalgia, Headache, Malaise, and 16 Shivering: Significant; prevents daily activity 17 iFever measured by any route 18 19



Unsolicited non-serious adverse events were reported in 33 (17.4%) recipients in the Fluzone 1

Quadrivalent group, 45 (23.7%) recipients in the TIV-1 group, and 45 (23.7%) recipients in the 2

TIV-2 group. The most commonly reported unsolicited non-serious adverse events were 3

headache, cough, and oropharyngeal pain. In the follow-up period, there were two SAEs, 1 (0.5%) 4

in the Fluzone Quadrivalent group and 1 (0.5%) in the TIV-2 group. No deaths were reported 5

during the trial period. 6

7

Geriatric Adults 8

In Study 3 (NCT01218646, see http://clinicaltrials.gov), a multi-center, randomized, double-blind 9

trial conducted in the US, adults 65 years of age and older received one dose of either Fluzone 10

Quadrivalent, or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or 11

TIV-2). Each of the trivalent formulations contained an influenza type B virus that corresponded 12

to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or 13

a type B virus of the Yamagata lineage). The safety analysis set included 675 recipients. Among 14

participants in the three vaccine groups combined, 55.7% were female (Fluzone Quadrivalent, 15

57.3%; TIV-1, 56.0%; TIV-2, 53.8%), 89.5% Caucasian (Fluzone Quadrivalent, 87.6%; TIV-1, 16

89.8%; TIV-2, 91.1%), 2.2% Black (Fluzone Quadrivalent, 4.0%; TIV-1, 1.8%; TIV-2, 0.9%), 17

7.4% Hispanic (Fluzone Quadrivalent, 8.4%; TIV-1, 7.6%; TIV-2, 6.2%) and 0.9% were of other 18

racial/ethnic groups (Fluzone Quadrivalent, 0.0%; TIV-1, 0.9%; TIV-2, 1.8%). 19

20

Table 5 summarizes solicited injection-site and systemic adverse reactions reported within 7 days 21

post-vaccination via diary cards. Participants were monitored for unsolicited adverse events and 22

SAEs during the 21 days following vaccination. 23




1

Table 5: Study 3a: Percentage of Solicited Injection-site and Systemic Adverse Reactions 2 Within 7 Days After Vaccination in Adults 65 Years of Age and Older (Safety Analysis Set)b 3

Fluzone


TIV-1d


TIV-2e


Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%) Grade 3h

(%) Any (%)

Grade 2g

(%) Grade 3h

(%)


- 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 4 bThe safety analysis set includes all persons who received study vaccine 5 c Fluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 6 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 7 d2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 8 B/Brisbane/60/2008 (Victoria lineage), licensed 9 eInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 10 (Yamagata lineage), non-licensed 11 fN is the number of participants in the safety analysis set 12 gGrade 2 - Injection-site pain: some interference with activity; Injection-site erythema and Injection-site swelling: 13 ≥5.1 to ≤10 cm; Fever: ≥101.2°F to ≤102.0°F; Myalgia, Headache, and Malaise: some interference with activity 14 hGrade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema and Injection-site swelling: 15 >10 cm; Fever: ≥102.1°F; Myalgia, Headache, and Malaise: Significant; prevents daily activity 16 iFever measured by any route 17 18

Unsolicited non-serious adverse events were reported in 28 (12.4%) recipients in the Fluzone 19

Quadrivalent group, 22 (9.8%) recipients in the TIV-1 group, and 22 (9.8%) recipients in the TIV-20



2 group. The most commonly reported adverse events were oropharyngeal pain, rhinorrhea, 1

injection-site induration, and headache. Three SAEs were reported during the follow-up period, 2 2

(0.9%) in the TIV-1 group and 1 (0.4%) in the TIV-2 group. No deaths were reported during the 3

trial period. 4

5

Post-Marketing Experience 6.26

Currently, there are no post-marketing data available for Fluzone Quadrivalent vaccine. 7

8

The following events have been spontaneously reported during the post-approval use of the 9

trivalent formulation of Fluzone. Because these events are reported voluntarily from a population 10

of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 11

relationship to vaccine exposure. Adverse events were included based on one or more of the 12

following factors: severity, frequency of reporting, or strength of evidence for a causal 13

relationship to Fluzone. 14

15

• Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy 16

• Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including 17

urticaria, angioedema) 18

• Eye disorders: Ocular hyperemia 19

• Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile 20

convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy 21

(Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), 22

dizziness, paresthesia 23



• Vascular Disorders: Vasculitis, vasodilatation/flushing 1

• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis, cough, 2

wheezing, throat tightness 3

• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome 4

• General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in 5

extremities, chest pain 6

• Gastrointestinal Disorders: Vomiting 7

8


Pregnancy 8.110

Pregnancy Category B: A developmental and reproductive toxicity study has been performed in 11

female rabbits at a dose approximately 20 times the human dose (on a mg/kg basis) and has 12

revealed no evidence of impaired female fertility or harm to the fetus due to Fluzone 13

Quadrivalent. There are, however, no adequate and well-controlled studies in pregnant women. 14

Because animal reproduction studies are not always predictive of human response, Fluzone 15

Quadrivalent should be given to a pregnant woman only if clearly needed. 16

17

In the developmental and reproductive toxicity study, female rabbits were administered Fluzone 18

Quadrivalent or control saline (each 0.5 mL/dose) by intramuscular injection 24 and 10 days 19

before insemination, and on Days 6, 12, and 27 of gestation. The administration of Fluzone 20

Quadrivalent did not result in systemic maternal toxicity (no adverse clinical signs and no change 21

in body weight or food consumption). In addition, no adverse effects on pregnancy, parturition, 22



lactation, or embryo-fetal or pre-weaning development were observed. There were no vaccine-1

related fetal malformations or other evidence of teratogenesis noted in this study. 2

Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on 3

pregnancy outcomes and newborn health status following vaccination with Fluzone Quadrivalent 4

during pregnancy. Healthcare providers are encouraged to enroll women who receive Fluzone 5

Quadrivalent during pregnancy in Sanofi Pasteur Inc.'s vaccination pregnancy registry by calling 6

1-800-822-2463. 7

8

Nursing Mothers 8.39

It is not known whether Fluzone Quadrivalent is excreted in human milk. Because many drugs are 10

excreted in human milk, caution should be exercised when Fluzone Quadrivalent is administered 11

to a nursing woman. 12

13

Pediatric Use 8.414

Safety and effectiveness of Fluzone Quadrivalent in children below the age of 6 months have not 15

been established. 16

17

Geriatric Use 8.518

Safety and immunogenicity of Fluzone Quadrivalent were evaluated in adults 65 years of age and 19

older. [See Clinical Studies (14.5).] Antibody responses to Fluzone Quadrivalent are lower in 20

persons ≥65 years of age than in younger adults. 21

22



11 DESCRIPTION 1

Fluzone Quadrivalent (Influenza Vaccine) for intramuscular injection is an inactivated influenza 2

vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-3

containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is 4

concentrated and purified in a linear sucrose density gradient solution using a continuous flow 5

centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, octylphenol 6

ethoxylate (Triton® X-100), producing a “split virus”. The split virus is further purified and then 7

suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone 8

Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order 9

to obtain a higher hemagglutinin (HA) antigen concentration. Antigens from the four strains 10

included in the vaccine are produced separately and then combined to make the quadrivalent 11

formulation. 12

13

Fluzone Quadrivalent suspension for injection is clear and slightly opalescent in color. 14

15

Antibiotics are not used in the manufacture of Fluzone Quadrivalent. 16

17

The Fluzone Quadrivalent prefilled syringe and vial presentations are not made with natural 18

rubber latex. 19

20

Fluzone Quadrivalent is standardized according to United States Public Health Service 21

requirements and is formulated to contain HA of each of the following four influenza strains 22

recommended for the 2016-2017influenza season: A/California/07/2009 X-179A (H1N1), 23



A/Hong Kong/4801/2014 X-263B(H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and 1

B/Brisbane/60/2008 (B Victoria lineage). The amounts of HA and other ingredients per dose of 2

vaccine are listed in Table 6. The single-dose, pre-filled syringe (0.25 mL and 0.5 mL) and the 3

single-dose vial (0.5 mL) are manufactured and formulated without thimerosal or any other 4

preservative. The 5 mL multi-dose vial presentation contains thimerosal, a mercury derivative, 5

added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury. 6

Each 0.25 mL dose from the multi-dose vial contains 12.5 mcg mercury. 7



Table 6: Fluzone Quadrivalent Ingredients 1

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 sodium chloride solution

QSb to appropriate volume

QSb to appropriate 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 2 bQuantity Sufficient 3 "-" Indicates information is not applicable 4

5


Mechanism of Action 12.17

Influenza illness and its complications follow infection with influenza viruses. Global surveillance 8

of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A 9

(H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, 10

two distinct lineages of influenza B (Victoria and Yamagata lineages) have co-circulated 11

worldwide. Protection from influenza virus infection has not been correlated with a specific level 12

of hemagglutination inhibition (HI) antibody titer post-vaccination. However, in some human 13



studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 1

50% of subjects. (See ref. 2) (See ref. 3) 2

3

Antibodies against one influenza virus type or subtype confer limited or no protection against 4

another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect 5

against a new antigenic variant of the same type or subtype. Frequent development of antigenic 6

variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the 7

usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza 8

vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the 9

influenza viruses likely to be circulating in the US during the influenza season. 10

11

Annual vaccination with the influenza vaccine is recommended because immunity during the year 12

after vaccination declines and because circulating strains of influenza virus change from year to 13

year. 14

13 NON-CLINICAL TOXICOLOGY 15

Carcinogenesis, Mutagenesis, Impairment of Fertility 13.116

Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential. A 17

reproductive study of female rabbits vaccinated with Fluzone Quadrivalent was performed and 18

revealed no evidence of impaired female fertility [see Pregnancy (8.1)]. 19

20


The effectiveness of Fluzone Quadrivalent was demonstrated based on clinical endpoint efficacy 22

data for Fluzone (trivalent influenza vaccine) and on an evaluation of serum HI antibody 23



responses to Fluzone Quadrivalent. Fluzone Quadrivalent, an inactivated influenza vaccine that 1

contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, 2

is manufactured according to the same process as Fluzone. 3

4

Efficacy of Fluzone (Trivalent Influenza Vaccine) in Children 6 through 24 14.15

Months of Age 6

A randomized, double-blind, placebo-controlled study was conducted at a single US center during 7

the 1999-2000 (Year 1) and 2000-2001 (Year 2) influenza seasons. The intent-to-treat analysis set 8

included a total of 786 children 6 through 24 months of age. Participants received two doses of 9

either Fluzone (N = 525) or a placebo (N = 261). Among all randomized participants in both 10

years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were 11

Black, and 7.2% were of other racial groups. Cases of influenza were identified through active 12

and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. 13

Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory 14

infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary 15

endpoint and is presented in Table 7. 16



Table 7: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Culture-1

Confirmed Influenza in Children Aged 6 through 24 Months during the 1999-2000 and 2

2000-2001 Influenza Seasons – Intent-to-Treat Analysis Seta 3

Fluzoneb Placeboc Fluzone vs. Placebo

Year nd Ne Rate (n/N)f (95% CI) nd Ne

Rate (n/N)f (95% CI)

Relative Risk (95% CI)

Percent Relative

Reductiong (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 2 i

(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 4 placebo and vaccinated 5

bFluzone: 1999-2000 formulation containing A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and 6 B/Yamanashi/166/98 (Yamagata lineage) and 2000-2001 formulation containing A/New Caledonia/20/99 (H1N1), 7 A/Panama/2007/99 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) 8

cPlacebo: 0.4% NaCl 9 dn is the number of participants with culture-confirmed influenza for the given year of study as listed in the first 10 column 11

eN is the number of participants randomly assigned to receive Fluzone or placebo for the given year of study as listed 12 in the column headers (intent-to-treat analysis set) 13

fRate (%) = (n/N) * 100 14 gRelative reduction in vaccine efficacy was defined as (1-relative risk) x 100 15 hIncludes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up) 16 iIncludes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up) 17

Efficacy of Fluzone (Trivalent Influenza Vaccine) in Adults 14.218

A randomized, double-blind, placebo-controlled study was conducted in a single US center during 19

the 2007-2008 influenza season. Participants received one dose of either Fluzone vaccine (N = 20

813), an active comparator (N = 814), or placebo (N = 325). The intent-to-treat analysis set 21

included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 22

years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% 23



were of other racial/ethnic groups. Cases of influenza were identified through active and passive 1

surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR). 2

Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal 3

congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). 4

Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 8. 5

Table 8: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Influenza in 6

Adults Aged 18 through 49 Years during the 2007-2008 Influenza Season – Intent-to-Treat 7

Analysis Setab 8

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)

Positive PCR 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 9 bThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or 10 placebo and vaccinated 11

cFluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and 12 B/Malaysia/2506/2004 (Victoria lineage) 13

dPlacebo: 0.9% NaCl 14 eN is the number of participants randomly assigned to receive Fluzone or placebo 15 fn is the number of participants satisfying the criteria listed in the first column 16 gRate (%) = (n/N) * 100 17 hRelative reduction in vaccine efficacy was defined as (1 - relative risk) x 100 18 19



Immunogenicity of Fluzone Quadrivalent in Children 6 Months through 8 14.31

Years of Age 2

In Study 1 (NCT01240746) [see Adverse Reactions (6.1)], 1419 children 6 months through 35 3

months of age and 2101 children 3 years through 8 years of age were included in the per-protocol 4

immunogenicity analysis. Participants received one or two 0.25 mL doses or one or two 0.5 mL 5

doses, respectively of Fluzone Quadrivalent, TIV-1, or TIV-2. For participants who received two 6

doses, the doses were administered approximately 4 weeks apart. The distribution of demographic 7

characteristics was similar to that of the safety analysis [see Adverse Reactions (6.1)]. 8

9

HI antibody geometric mean titers (GMTs) and seroconversion rates 28 days following 10

vaccination with Fluzone Quadrivalent were non-inferior to those following each TIV for all four 11

strains, based on pre-specified criteria (see Table 9 and Table 10). 12

Table 9: Study 1a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain 13 by HI Antibody GMTs at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of 14 Age (Per-protocol Analysis Set)b 15

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-1g (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)i 1.34 (1.20; 1.50)

B/Florida/04/2006 (B Yamagata) 61.5 (16.3)j 58.3 1.06 (0.94; 1.18)



aNCT01240746 1 bPer-protocol analysis set included all persons who had no study protocol deviations 2 cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 3 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 4 dN is the number of participants in the per-protocol analysis set 5 ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 6 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone 7 Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >0.66 8 g2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 9 B/Brisbane/60/2008 (Victoria lineage), licensed 10 hInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 11 (Yamagata lineage), non-licensed 12 iTIV-2 did not contain B/Brisbane/60/2008 13 jTIV-1 did not contain B/Florida/04/2006 14

Table 10: Study 1a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain 15 by Seroconversion Rates at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years 16 of Age (Per-protocol Analysis Set)b 17


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 3.8 (1.4; 6.3) Fluzone


TIV-1h (B Victoria)

Nd=582

TIV-2i (B Yamagata)

Nd=599


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 18 bPer-protocol analysis set included all persons who had no study protocol deviations 19 cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 20 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 21

dN is the number of participants in the per-protocol analysis set 22 ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 23 fSeroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 4-24 fold increase for participants with pre-vaccination titer ≥1:10 25 gNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates 26 (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >-27 10% 28



h2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 1 B/Brisbane/60/2008 (Victoria lineage), licensed 2 iInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 3 (Yamagata lineage), non-licensed 4 jTIV-2 did not contain B/Brisbane/60/2008 5 kTIV-1 did not contain B/Florida/04/2006 6 7

Non-inferiority immunogenicity criteria based on HI antibody GMTs and seroconversion rates 8

were also met when age subgroups (6 months to <36 months and 3 years to <9 years) were 9

examined. In addition, HI antibody GMTs and seroconversion rates following Fluzone 10

Quadrivalent were higher than those following TIV for the B strain not contained in each 11

respective TIV based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio 12

of the GMTs [Fluzone Quadrivalent divided by TIV] >1.5 for each B strain in Fluzone 13

Quadrivalent compared with the corresponding B strain not contained in each TIV and the lower 14

limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone 15

Quadrivalent minus TIV] >10% for each B strain in Fluzone Quadrivalent compared with the 16

corresponding B strain not contained in each TIV). 17

18

Immunogenicity of Fluzone Quadrivalent in Adults ≥18 Years of Age 14.419

In Study 2 (NCT00988143) [see Adverse Reactions (6.1)], 565 adults 18 years of age and older 20

who had received one dose of Fluzone Quadrivalent, TIV-1, or TIV-2 were included in the per-21

protocol immunogenicity analysis. The distribution of demographic characteristics was similar to 22

that of the safety analysis [see Adverse Reactions (6.1)]. 23

24

HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to 25

those following each TIV for all four strains, based on pre-specified criteria (see Table11). 26



Table 11: Study 2a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain 1 by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 18 Years of Age and Older (Per-2 protocol Analysis Set)b 3


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


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)i 0.89 (0.70; 1.12)

B/Florida/04/2006 (B Yamagata)

155 (78.1)j 135 1.15 (0.93; 1.42)

aNCT00988143 4 bPer-protocol analysis set included all persons who had no study protocol deviations 5 cFluzone Quadrivalent containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), B/Brisbane/60/2008 6 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 7 dN is the number of participants in the per-protocol analysis set 8 ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 9 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone 10 Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >2/3 11 g2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and 12 B/Brisbane/60/2008 (Victoria lineage), licensed 13 h2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and 14 B/Florida/04/2006 (Yamagata lineage), licensed 15 iTIV-2 did not contain B/Brisbane/60/2008 16 jTIV-1 did not contain B/Florida/04/2006 17 18

Immunogenicity of Fluzone Quadrivalent in Geriatric Adults ≥65 Years of 14.519

Age 20

In Study 3 (NCT01218646) [see Adverse Reactions (6.1)], 660 adults 65 years of age and older 21

were included in the per-protocol immunogenicity analysis. The distribution of demographic 22

characteristics was similar to that of the safety analysis [see Adverse Reactions (6.1)]. 23



1

HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to 2

those following TIV for all four strains, based on pre-specified criteria (see Table 12). 3

Seroconversion rates 21 days following Fluzone Quadrivalent were non-inferior to those 4

following TIV for H3N2, B/Brisbane, and B/Florida, but not for H1N1 (see Table 13). The HI 5

antibody GMT following Fluzone Quadrivalent was higher than that following TIV-1 for 6

B/Florida but not higher than that following TIV-2 for B/Brisbane, based on pre-specified criteria 7

(the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by 8

TIV] >1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain 9

not contained in each TIV). Seroconversion rates following Fluzone Quadrivalent were higher 10

than those following TIV for the B strain not contained in each respective TIV, based on pre-11

specified criteria (the lower limit of the two 2-sided 95% CI of the difference of the 12

seroconversion rates [Fluzone Quadrivalent minus TIV] >10% for each B strain in Fluzone 13

Quadrivalent compared with the corresponding B strain not contained in each TIV). 14

Table 12: Study 3a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain 15 by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-16 protocol Analysis Set)b 17


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


TIV-1g (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)


61.1 (28.5)j 54.8 1.11 (0.90; 1.37)

aNCT01218646 1 bPer-protocol analysis set included all persons who had no study protocol deviations 2 cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 3 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 4 dN is the number of participants in the per-protocol analysis set 5 ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 6 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone 7 Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >0.66 8 g2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 9 B/Brisbane/60/2008 (Victoria lineage), licensed 10 hInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 11 (Yamagata lineage), non-licensed 12 iTIV-2 did not contain B/Brisbane/60/2008 13 jTIV-1 did not contain B/Florida/04/2006 14 15 16

Table 13: Study 3a: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain 17 by Seroconversion Rates at 21 Days Post-Vaccination, Adults 65 Years of Age and Older 18 (Per-protocol Analysis Set)b 19


Nd=220

Pooled TIVe

Nd=440


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


TIV-1h (B Victoria)

Nd=219

TIV-2i (B Yamagata)

Nd=221


Rate (95% CI)f

Seroconversiong(%) B/Brisbane/60/2008 (B Victoria)

28.64 18.72 (8.60)j 9.91 (1.96; 17.70)


33.18 (9.13)k 31.22 1.96 (-6.73; 10.60)

aNCT01218646 20 bPer-protocol analysis set included all persons who had no study protocol deviations 21



cFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 1 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage) 2 dN is the number of participants in the per-protocol analysis set 3 ePooled TIV group includes participants vaccinated with either TIV-1 or TIV-2 4 fNon-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates 5 (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >-6 10% 7 gSeroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 8

4-fold increase for participants with pre-vaccination titer ≥1:10 9 h2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and 10 B/Brisbane/60/2008 (Victoria lineage), licensed 11 iInvestigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 12 (Yamagata lineage), non-licensed 13 jTIV-2 did not contain B/Brisbane/60/2008 14 kTIV-1 did not contain B/Florida/04/2006 15 16 17

18



15 REFERENCES 1

2

1 Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 3

and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797-802. 4

2 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 5

vaccination. Virus Res 2004;103:133-138. 6

3 Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-7

inhibiting antibody in protection against challenge infection with influenza A2 and B 8

viruses. J Hyg Camb 1972;70:767-777. 9

10

11

12

13




How Supplied 16.12

Single-dose, prefilled syringe (yellow plunger rod), without needle, 0.25 mL 3

(NDC 49281-516-00) (not made with natural rubber latex). Supplied as package of 10 4

(NDC 49281- 516-25). 5

6

Single-dose, prefilled syringe (purple plunger rod), without needle, 0.5 mL (NDC 49281-416-88 ) 7

(not made with natural rubber latex). Supplied as package of 10 (NDC 49281-416-50 8

9

Single-dose vial, 0.5 mL (NDC 49281-416-58) (not made with natural rubber latex). Supplied as 10

package of 10 (NDC 49281-416-10). 11

12

Multi-dose vial, 5 mL (NDC 49281-625-78) (not made with natural rubber latex). Supplied as 13

package of 1 (NDC 49281- 625-15). A maximum of ten doses can be withdrawn from the multi-14

dose vial. 15

16

Storage and Handling 16.217

Store all Fluzone Quadrivalent presentations refrigerated at 2° to 8°C (35° to 46°F). DO NOT 18

FREEZE. Discard if vaccine has been frozen. 19

20

Do not use after the expiration date shown on the label. 21

22




See FDA-approved patient labeling (Patient Information). Inform the vaccine recipient or 1

guardian: 2

• Fluzone Quadrivalent contains killed viruses and cannot cause influenza. 3

• Fluzone Quadrivalent stimulates the immune system to protect against influenza, but does not 4

prevent other respiratory infections. 5

• Annual influenza vaccination is recommended. 6

• Report adverse reactions to their healthcare provider and/or to the Vaccine Adverse Event 7

Reporting System (VAERS) at 1-800-822-7967. 8

• Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on 9

pregnancy outcomes and newborn health status following vaccination with Fluzone 10

Quadrivalent during pregnancy. Women who receive Fluzone Quadrivalent during pregnancy 11

are encouraged to contact Sanofi Pasteur Inc. directly or have their healthcare provider contact 12

Sanofi Pasteur Inc. at 1-800-822-2463. 13

14

Vaccine Information Statements must be provided to vaccine recipients or their guardians, as 15

required by the National Childhood Vaccine Injury Act of 1986 prior to immunization. These 16

materials are available free of charge at the Centers for Disease Control and Prevention (CDC) 17

website (www.cdc.gov/vaccines). 18

19

20

http://www.cdc.gov/nip



Fluzone is a registered trademark of Sanofi Pasteur Inc. 1

2

Manufactured by: 3

Sanofi Pasteur Inc. 4

Swiftwater PA 18370 USA 6872, 6879, 6883 5

6

7

8



Patient Information Sheet 1

Fluzone® Quadrivalent 2

Influenza Vaccine 3 4

Please read this information sheet before getting Fluzone Quadrivalent vaccine. This summary is 5

not intended to take the place of talking with your healthcare provider. If you have questions or 6

would like more information, please talk with your healthcare provider. 7

8

What is Fluzone Quadrivalent vaccine? 9

Fluzone Quadrivalent is a vaccine that helps protect against influenza illness (flu). 10

Fluzone Quadrivalent vaccine is for people who are 6 months of age and older. 11

Vaccination with Fluzone Quadrivalent vaccine may not protect all people who receive the 12

vaccine. 13

14

Who should not get Fluzone Quadrivalent vaccine? 15

You should not get Fluzone Quadrivalent vaccine if you: 16

• ever had a severe allergic reaction to eggs or egg products. 17

• ever had a severe allergic reaction after getting any flu vaccine. 18

• are younger than 6 months of age. 19

20

Tell your healthcare provider if you or your child have or have had: 21

• Guillain-Barré syndrome (severe muscle weakness) after getting a flu vaccine. 22

• problems with your immune system as the immune response may be diminished. 23

24



How is the Fluzone Quadrivalent vaccine given? 1

Fluzone Quadrivalent vaccine is a shot given into the muscle of the arm. 2

For infants, Fluzone Quadrivalent vaccine is a shot given into the muscle of the thigh. 3

4

What are the possible side effects of Fluzone Quadrivalent vaccine? 5

The most common side effects of Fluzone Quadrivalent vaccine are: 6

• pain, redness, and swelling where you got the shot 7

• muscle aches 8

• tiredness 9

• headache 10

• fever 11

These are not all of the possible side effects of Fluzone Quadrivalent vaccine. You can ask your 12

healthcare provider for a list of other side effects that is available to healthcare professionals. 13

14

Call your healthcare provider for advice about any side effects that concern you. You may report 15

side effects to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 or 16

http://vaers.hhs.gov. Sanofi Pasteur Inc. is collecting information on pregnancy outcomes and the 17

health of newborns following vaccination with Fluzone Quadrivalent during pregnancy. Women 18

who receive Fluzone Quadrivalent during pregnancy are encouraged to contact Sanofi Pasteur Inc. 19

directly or have their healthcare provider contact Sanofi Pasteur Inc. at 1-800-822-2463. 20

21

What are the ingredients in Fluzone Quadrivalent vaccine? 22

Fluzone Quadrivalent vaccine contains 4 killed flu virus strains. 23

http://vaers.hhs.gov/



1

Inactive ingredients include formaldehyde and octylphenol ethoxylate. The preservative 2

thimerosal is only in the multi-dose vial of Fluzone Quadrivalent vaccine. 3

4 Manufactured by: 5

Sanofi Pasteur Inc. 6

Swiftwater, PA 18370 USA 7 8

9

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