NDC 49281-337 Fluzone Quadrivalent Southern Hemisphere

Influenza A Virus A/victoria/2570/2019 Ivr-215 (h1n1) Antigen (formaldehyde Inactivated), Influenza A Virus A/hong Kong/2671/2019 Ivr-208 (h3n2) Antigen (formaldehyde Inactivated), Influenza B Virus B/phuket/3073/2013 Antigen (formaldehyde Inactivated), And Influenza B Virus B/washington/02/2019 Antigen (formaldehyde Inactivated)

NDC Product Code 49281-337

NDC CODE: 49281-337

Proprietary Name: Fluzone Quadrivalent Southern Hemisphere What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Influenza A Virus A/victoria/2570/2019 Ivr-215 (h1n1) Antigen (formaldehyde Inactivated), Influenza A Virus A/hong Kong/2671/2019 Ivr-208 (h3n2) Antigen (formaldehyde Inactivated), Influenza B Virus B/phuket/3073/2013 Antigen (formaldehyde Inactivated), And Influenza B Virus B/washington/02/2019 Antigen (formaldehyde Inactivated) What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

  • 49281 - Sanofi Pasteur Inc.
    • 49281-337 - Fluzone Quadrivalent Southern Hemisphere

NDC 49281-337-15

Package Description: 10 VIAL, MULTI-DOSE in 1 PACKAGE > 5 mL in 1 VIAL, MULTI-DOSE (49281-337-78)

NDC Product Information

Fluzone Quadrivalent Southern Hemisphere with NDC 49281-337 is a a vaccine lable product labeled by Sanofi Pasteur Inc.. The generic name of Fluzone Quadrivalent Southern Hemisphere is influenza a virus a/victoria/2570/2019 ivr-215 (h1n1) antigen (formaldehyde inactivated), influenza a virus a/hong kong/2671/2019 ivr-208 (h3n2) antigen (formaldehyde inactivated), influenza b virus b/phuket/3073/2013 antigen (formaldehyde inactivated), and influenza b virus b/washington/02/2019 antigen (formaldehyde inactivated). The product's dosage form is injection, suspension and is administered via intramuscular form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 2479030, 2479034, 2479038, 2479041, 2479043 and 2479045.

Dosage Form: Injection, Suspension - A liquid preparation, suitable for injection, which consists of solid particles dispersed throughout a liquid phase in which the particles are not soluble. It can also consist of an oil phase dispersed throughout an aqueous phase, or vice-versa.

Product Type: Vaccine What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Fluzone Quadrivalent Southern Hemisphere Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • OCTOXYNOL-9 (UNII: 7JPC6Y25QS)
  • FORMALDEHYDE (UNII: 1HG84L3525)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)
  • SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F)
  • SODIUM PHOSPHATE, MONOBASIC, ANHYDROUS (UNII: KH7I04HPUU)
  • OCTOXYNOL-9 (UNII: 7JPC6Y25QS)
  • FORMALDEHYDE (UNII: 1HG84L3525)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)
  • SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F)
  • SODIUM PHOSPHATE, MONOBASIC, ANHYDROUS (UNII: KH7I04HPUU)
  • OCTOXYNOL-9 (UNII: 7JPC6Y25QS)
  • FORMALDEHYDE (UNII: 1HG84L3525)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)
  • SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F)
  • SODIUM PHOSPHATE, MONOBASIC, ANHYDROUS (UNII: KH7I04HPUU)
  • THIMEROSAL (UNII: 2225PI3MOV)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intramuscular - Administration within a muscle.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Sanofi Pasteur Inc.
Labeler Code: 49281
FDA Application Number: BLA103914 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-04-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 12-31-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Fluzone Quadrivalent Southern Hemisphere Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Fluzone® Quadrivalent Southern Hemisphere is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine.Fluzone Quadrivalent Southern Hemisphere is approved for use in persons 6 months of age and older.

2 Dosage And Administration

For intramuscular use only

2.1 Dose And Schedule

The dose and schedule for Fluzone Quadrivalent Southern Hemisphere are presented in Table 1.Prior to vaccination, always refer to the current Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza.Table 1: Dose and Schedule for Fluzone Quadrivalent Southern HemisphereAgeVaccination StatusDoseSchedule"-" Indicates information is not applicable6 months through 35 monthsNot previously vaccinated with influenza vaccine or unknown vaccination historyTwo doses, either 0.25 mL or 0.5 mLThe schedule can be completed as two 0.25-mL doses ≥4 weeks apart, two 0.5-mL doses ≥4 weeks apart, or any combination of 2 doses (either 0.25 mL or 0.5 mL) administered ≥4 weeks apartAdminister at least 4 weeks apartPreviously vaccinated with influenza vaccineOne or two dosesTo determine if 1 or 2 doses are required, refer to Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza, either 0.25 mL or 0.5 mLIf two doses, administer at least 4 weeks apart36 months through 8 yearsNot previously vaccinated with influenza vaccine or unknown vaccination historyTwo 0.5 mL dosesAdminister at least 4 weeks apartPreviously vaccinated with influenza vaccineOne or two 0.5 mL dosesIf two doses, administer at least 4 weeks apart9 years and older-One 0.5 mL dose-

2.2 Administration

Parenteral drug products should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit. If any of these defects or conditions exist, Fluzone Quadrivalent Southern Hemisphere should not be administered.Before administering a dose of vaccine, shake the prefilled syringe or multi-dose vial. Use a separate sterile needle and syringe for each dose withdrawn from the multi-dose vial.The preferred sites for intramuscular injection are the anterolateral aspect of the thigh in infants 6 months through 11 months of age, the anterolateral aspect of the thigh (or the deltoid muscle if muscle mass is adequate) in persons 12 months through 35 months of age, or the deltoid muscle in persons ≥36 months of age. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.Do not administer this product intravenously, intradermally, or subcutaneously.Fluzone Quadrivalent Southern Hemisphere should not be combined through reconstitution or mixed with any other vaccine.

3 Dosage Forms And Strengths

Fluzone Quadrivalent Southern Hemisphere is a suspension for injection.Fluzone Quadrivalent Southern Hemisphere is supplied in 3 presentations:1) Prefilled single-dose syringe (pink syringe plunger rod), 0.25 mL, for persons 6 months through 35 months of age.2) Prefilled single-dose syringe (clear syringe plunger rod), 0.5 mL, for persons 6 months of age and older.3) Multi-dose vial, 5 mL, for persons 6 months of age and older.

4 Contraindications

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

5.1 Guillain-Barré Syndrome

The 1976 swine influenza vaccine was associated with an elevated risk of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. (See ref. 1) If GBS has occurred within 6 weeks following previous influenza vaccination, the decision to give Fluzone Quadrivalent should be based on careful consideration of the potential benefits and risks.

5.2 Preventing And Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of Fluzone Quadrivalent Southern Hemisphere.

5.3 Altered Immunocompetence

If Fluzone Quadrivalent Southern Hemisphere is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.

5.4 Limitations Of Vaccine Effectiveness

Vaccination with Fluzone Quadrivalent Southern Hemisphere may not protect all recipients.

6 Adverse Reactions

Fluzone Quadrivalent Southern Hemisphere and Fluzone Quadrivalent are manufactured using the same process. This section summarizes data obtained from clinical studies with Fluzone Quadrivalent.In children 6 months through 35 months of age receiving a 0.25-mL dose of Fluzone Quadrivalent in Study 1 (NCT01240746, see http://clinicaltrials.gov), the most common (≥10%) injection-site reactions were pain (57%)Assessed in children 24 months through 35 months of age or tenderness (54%)Assessed in children 6 months through 23 months of age, 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%). In children 3 years through 8 years of age, the most common (≥10%) injection-site reactions were pain (67%), erythema (34%), and swelling (25%); the most common solicited systemic adverse reactions were myalgia (39%), malaise (32%), and headache (23%). In adults 18 years and older, the most common (≥10%) injection-site reaction was pain (47%); the most common solicited systemic adverse reactions were myalgia (24%), headache (16%), and malaise (11%). In adults 65 years of age and older, the most common (≥10%) injection-site reaction was pain (33%); the most common solicited systemic adverse reactions were myalgia (18%), headache (13%), and malaise (11%).

6.1 Clinical Trials Experience

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

Other

Children 6 Months Through 8 Years of AgeStudy 1 (NCT01240746, see http://clinicaltrials.gov) was a single-blind, randomized, active- controlled multi-center safety and immunogenicity study conducted in the US. In this study, children 6 months through 35 months of age received one or two 0.25 mL doses of either Fluzone Quadrivalent or one of two formulations of a comparator trivalent influenza vaccine (TIV-1 or TIV-2), and children 3 years through 8 years of age received one or two 0.5 mL doses of either Fluzone Quadrivalent, TIV-1, or TIV-2. Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). For participants who received two doses, the doses were administered approximately 4 weeks apart. The safety analysis set included 1841 children 6 months through 35 months of age and 2506 children 3 years through 8 years of age. Among participants 6 months through 8 years of age in the three vaccine groups combined, 49.3% were female (Fluzone Quadrivalent, 49.2%; TIV-1, 49.8%; TIV-2, 49.4%), 58.4% Caucasian (Fluzone Quadrivalent, 58.4%; TIV-1, 58.9%; TIV-2, 57.8%), 20.2% Black (Fluzone Quadrivalent, 20.5%; TIV-1, 19.9%; TIV-2, 19.1%), 14.1% Hispanic (Fluzone Quadrivalent, 14.3%; TIV-1, 13.2%; TIV-2, 14.7%), and 7.3% were of other racial/ethnic groups (Fluzone Quadrivalent, 6.8%; TIV-1, 8.0%; TIV-2, 8.5%). Table 2 and Table 3 summarize solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events for 28 days after each dose and serious adverse events (SAEs) during the 6 months following the last dose.Table 2: Study 1NCT01240746: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Children 6 Months Through 35 Months of Age (Safety Analysis Set)The safety analysis set includes all persons who received at least one dose of study vaccineFluzone QuadrivalentFluzone Quadrivalent (0.25 mL) containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage), Participants received 1 or 2 doses according to ACIP recommendations(NN is the number of participants in the safety analysis set=1223)TIV-1, 2010-2011 Fluzone TIV (0.25 mL) containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)(N=310)TIV-2, Investigational TIV (0.25 mL) containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)(N=308)Any(%)Grade 2Grade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site tenderness: cries and protests when injection-site is touched; Injection-site erythema, Injection-site swelling: ≥2.5 cm to <5 cm; Fever: >101.3°F to ≤103.1°F (6 months through 23 months); ≥101.2°F to ≤102.0°F (24 months through 35 months); Malaise, Myalgia, and Headache: some interference with activity; Irritability: requiring increased attention; Crying abnormal: 1 to 3 hours; Drowsiness: not interested in surroundings or did not wake up for a feed/meal; Appetite loss: missed 1 or 2 feeds/meals completely; Vomiting: 2 to 5 episodes per 24 hours(%)Grade 3Grade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site tenderness: cries when injected limb is moved, or the movement of the injected limb is reduced; Injection-site erythema, Injection-site swelling: ≥5 cm; Fever: >103.1°F (6 months through 23 months); ≥102.1°F (24 months through 35 months); Malaise, Myalgia, and Headache: Significant; prevents daily activity; Irritability: inconsolable; Crying abnormal: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite loss: refuses ≥3 feeds/meals or refuses most feeds/meals; Vomiting: ≥6 episodes per 24 hours or requiring parenteral hydration(%)Any(%)Grade 2(%)Grade 3(%)Any(%)Grade 2(%)Grade 3(%)Injection-site adverse reactionsPainAssessed in children 24 months through 35 months of age57.010.21.052.311.50.850.35.42.7TendernessAssessed in children 6 months through 23 months of age 54.111.31.948.48.21.949.710.30.0Erythema37.31.50.232.91.00.033.31.00.0Swelling21.60.80.219.71.00.017.30.00.0Systemic adverse reactionsFever (≥100.4°F)Fever measured by any route14.35.52.116.06.61.713.04.12.0Malaise38.114.54.635.214.84.732.412.86.8Myalgia26.76.61.926.69.41.625.06.82.7Headache8.92.50.69.43.90.012.24.70.0Irritability54.026.43.252.820.13.153.522.92.8Crying abnormal41.212.33.336.58.21.929.910.42.1Drowsiness37.78.41.332.13.80.631.95.60.7Appetite loss32.39.11.833.35.71.925.08.30.7Vomiting14.86.21.011.34.40.613.96.30.0Table 3: Study 1NCT01240746: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Children 3 Years Through 8 Years of Age (Safety Analysis Set)The safety analysis set includes all persons who received at least one dose of study vaccineFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)(NN is the number of participants in the safety analysis set=1669)TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)(N=424)TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)(N=413)Any(%)Grade 2Grade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site erythema, Injection-site swelling: ≥2.5 cm to <5 cm; Fever: ≥101.2°F to ≤102.0°F; Headache, Malaise, and Myalgia: some interference with activity(%)Grade 3Grade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema, Injection-site swelling: ≥5 cm; Fever: ≥102.1°F; Headache, Malaise, and Myalgia: Significant; prevents daily activity(%)Any(%)Grade 2(%)Grade 3(%)Any(%)Grade 2(%)Grade 3(%)Injection-site adverse reactionsPain66.615.82.164.69.52.063.811.62.8Erythema34.12.91.836.83.41.235.22.51.8Swelling24.82.81.425.41.51.225.92.51.8Systemic adverse reactionsFever(≥100.4°F)Fever measured by any route7.02.12.17.12.21.27.62.80.8Headache23.16.82.221.25.12.724.47.52.0Malaise31.911.25.532.811.45.633.410.85.0Myalgia38.612.23.334.19.02.738.411.12.8Among children 6 months through 8 years of age, unsolicited non-serious adverse events were reported in 1360 (47.0%) recipients in the Fluzone Quadrivalent group, 352 (48.0%) recipients in the TIV-1 group, and 346 (48.0%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were cough, vomiting, and pyrexia. During the 28 days following vaccination, a total of 16 (0.6%) recipients in the Fluzone Quadrivalent group, 4 (0.5%) recipients in the TIV-1 group, and 4 (0.6%) recipients in the TIV-2 group, experienced at least one SAE. Throughout the study period, a total of 41 (1.4%) recipients in the Fluzone Quadrivalent group, 7 (1.0%) recipients in the TIV-1 group, and 14 (1.9%) recipients in the TIV-2 group, experienced at least one SAE. Three SAEs were considered to be possibly related to vaccination: croup in a Fluzone Quadrivalent recipient and 2 episodes of febrile seizure, 1 each in a TIV-1 recipient and a TIV-2 recipient.

0.5-mL Dose of Fluzone Quadrivalent in Children 6 Months through 35 Months of AgeStudy 2 (NCT02915302 see http://clinicaltrials.gov) was a randomized, observer-blinded, 2-arm, multi-center safety and immunogenicity study conducted in the US. In this study, 1950 children 6 months through 35 months of age were randomly assigned to receive Fluzone Quadrivalent administered in either a volume of 0.25 mL (Group 1) or 0.5 mL (Group 2). For participants recommended to receive two doses of influenza vaccine as per Advisory Committee on Immunization Practices guidance, the same dose was administered 4 weeks after the first. The safety analysis set included 1941 participants who received at least 1 dose of study vaccine. Of these participants, 49.7% were female, 74.3% were Caucasian, 19.2% were Black, 6.5% were of other racial groups, and 22.0% were Hispanic/Latino.Table 4 summarizes solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards for the 0.25 mL and 0.5 mL volumes of Fluzone Quadrivalent in children 6 months through 35 months of age.Table 4: Study 2NCT02915302: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Children 6 Months Through 35 Months of Age (Safety Analysis Set)The safety analysis set includes all persons who received at least one dose of study vaccineFluzone Quadrivalent0.25 mLParticipants received 1 or 2 doses according to ACIP recommendations(NN is the number of participants in the safety analysis set=949)Fluzone Quadrivalent0.5 mL(N=992)Any(%)Grade 3Grade 3 - Injection-site tenderness: Cries when injected limb is moved, or the movement of the injected limb is reduced; Injection-site redness, Injection-site swelling: ≥50 mm; Irritability: inconsolable; Abnormal Crying: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Loss of Appetite: refuses ≥3 feeds/meals or refuses most feeds/meals; Fever: >103.1°F; Vomiting: ≥6 episodes per 24 hours or requiring parenteral hydration(%)Any(%)Grade 3(%)Injection-site adverse reactions Tenderness47.31.750.41.2 Redness23.10.024.30.2 Swelling12.90.114.70.0Systemic adverse reactionsIrritability47.43.648.64.0Abnormal Crying33.33.134.12.6Drowsiness31.92.131.31.6Loss of Appetite27.31.428.32.2Fever(≥100.4°F)Fever measured by any route11.30.612.21.2Vomiting10.00.410.20.5The difference in fever rate (Group 2 minus Group 1) was 0.84% (95% CI: -2.13%; 3.80%), meeting the prespecified non-inferiority criterion (upper limit of the 2-sided 95% CI of the difference in fever rates <5%). Participants were monitored for unsolicited adverse events and SAEs during the 28 days following vaccination. Unsolicited non-serious adverse events were reported in 417 (44%) participants in Group 1 and 394 (40%) participants in Group 2. The most commonly reported unsolicited non-serious adverse events in both groups were cough and rhinorrhea. Ten SAEs were reported during the 28-day follow-up period: 5 (0.5%) in Group 1 and 5 (0.5%) in Group 2.

AdultsIn Study 3 (NCT00988143, see http://clinicaltrials.gov), a multi-centered randomized, open-label trial conducted in the US, adults 18 years of age and older received one dose of either Fluzone Quadrivalent or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or TIV-2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The safety analysis set included 570 recipients, half aged 18-60 years and half aged 61 years or older. Among participants in the three vaccine groups combined, 67.2% were female (Fluzone Quadrivalent, 68.4%; TIV-1, 67.9%; TIV-2, 65.3%), 88.4% Caucasian (Fluzone Quadrivalent, 91.1%; TIV-1, 86.8%; TIV-2, 87.4%), 9.6% Black (Fluzone Quadrivalent, 6.8%; TIV-1, 12.1%; TIV-2, 10.0%), 0.4% Hispanic (Fluzone Quadrivalent, 0.0%; TIV-1, 0.5%; TIV-2, 0.5%), and 1.7% were of other racial/ethnic groups (Fluzone Quadrivalent, 2.1%; TIV-1, 0.5%; TIV-2, 2.2%). Table 5 summarizes solicited injection-site and systemic adverse reactions reported within 3 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events and SAEs during the 21 days following vaccination.Table 5: Study 3NCT00988143: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 3 Days After Vaccination in Adults 18 Years of Age and Older (Safety Analysis Set)The safety analysis set includes all persons who received study vaccineFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)(NN is the number of participants in the safety analysis set=190)TIV-12009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)(N=190)TIV-22008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed(B Yamagata)(N=190)Any (%)Grade 2Grade 2 - Injection-site pain: Some interference with activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: ≥5.1 to ≤10 cm; Fever: ≥101.2°F to ≤102.0°F; Myalgia, Headache, Malaise, and Shivering: some interference with activity(%)Grade 3Grade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: >10 cm; Fever: ≥102.1°F; Myalgia, Headache, Malaise, and Shivering: Significant; prevents daily activity(%)Any (%)Grade 2(%)Grade 3(%)Any (%)Grade 2(%)Grade 3(%)Injection-site adverse reactions Pain47.46.80.552.17.90.543.26.30.0 Erythema1.10.00.01.60.50.01.60.50.0 Swelling0.50.00.03.20.50.01.10.00.0 Induration0.50.00.01.60.50.00.50.00.0 Ecchymosis0.50.00.00.50.00.00.50.00.0Systemic adverse reactions  Myalgia23.75.80.025.35.80.016.85.80.0 Headache15.83.20.518.46.30.518.04.20.0 Malaise10.51.61.114.73.21.112.14.70.5 Shivering2.60.50.05.31.10.03.20.50.0 Fever(≥100.4°F)Fever measured by any route0.00.00.00.50.50.00.50.50.0Unsolicited non-serious adverse events were reported in 33 (17.4%) recipients in the Fluzone Quadrivalent group, 45 (23.7%) recipients in the TIV-1 group, and 45 (23.7%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were headache, cough, and oropharyngeal pain. In the follow-up period, there were two SAEs, 1 (0.5%) in the Fluzone Quadrivalent group and 1 (0.5%) in the TIV-2 group.

Geriatric AdultsIn Study 4 (NCT01218646, see http://clinicaltrials.gov), a multi-center, randomized, double-blind trial conducted in the US, adults 65 years of age and older received one dose of either Fluzone Quadrivalent, or one of two formulations of comparator trivalent influenza vaccine (TIV-1 or TIV-2). Each of the trivalent formulations contained an influenza type B virus that corresponded to one of the two type B viruses in Fluzone Quadrivalent (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The safety analysis set included 675 recipients. Among participants in the three vaccine groups combined, 55.7% were female (Fluzone Quadrivalent, 57.3%; TIV-1, 56.0%; TIV-2, 53.8%), 89.5% Caucasian (Fluzone Quadrivalent, 87.6%; TIV-1, 89.8%; TIV-2, 91.1%), 2.2% Black (Fluzone Quadrivalent, 4.0%; TIV-1, 1.8%; TIV-2, 0.9%), 7.4% Hispanic (Fluzone Quadrivalent, 8.4%; TIV-1, 7.6%; TIV-2, 6.2%) and 0.9% were of other racial/ethnic groups (Fluzone Quadrivalent, 0.0%; TIV-1, 0.9%; TIV-2, 1.8%).Table 6 summarizes solicited injection-site and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Participants were monitored for unsolicited adverse events and SAEs during the 21 days following vaccination.Table 6: Study 4NCT01218646: Percentage of Solicited Injection-site and Systemic Adverse Reactions Within 7 Days After Vaccination in Adults 65 Years of Age and Older (Safety Analysis Set)The safety analysis set includes all persons who received study vaccineFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)(NN is the number of participants in the safety analysis set=225)TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)(N=225)TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)(N=225)Any (%)Grade 2Grade 2 - Injection-site pain: some interference with activity; Injection-site erythema and Injection-site swelling: ≥5.1 to ≤10 cm; Fever: ≥101.2°F to ≤102.0°F; Myalgia, Headache, and Malaise: some interference with activity(%)Grade 3Grade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema and Injection-site swelling: >10 cm; Fever: ≥102.1°F; Myalgia, Headache, and Malaise: Significant; prevents daily activity(%)Any (%)Grade 2(%)Grade 3(%)Any (%)Grade 2(%)Grade 3(%)Injection-site adverse reactions Pain32.61.30.928.62.70.023.10.90.0 Erythema2.70.90.01.30.00.01.30.40.0 Swelling1.80.40.01.30.00.00.00.00.0Systemic adverse reactions Myalgia18.34.00.418.34.00.014.22.70.4 Headache13.41.30.411.61.30.011.61.80.4 Malaise10.74.50.46.30.40.011.62.70.9 Fever(≥100.4°F)Fever measured by any route1.30.00.40.00.00.00.90.40.4Unsolicited non-serious adverse events were reported in 28 (12.4%) recipients in the Fluzone Quadrivalent group, 22 (9.8%) recipients in the TIV-1 group, and 22 (9.8%) recipients in the TIV-2 group. The most commonly reported adverse events were oropharyngeal pain, rhinorrhea, injection-site induration, and headache. Three SAEs were reported during the follow-up period, 2 (0.9%) in the TIV-1 group and 1 (0.4%) in the TIV-2 group.

Pregnancy Exposure RegistrySanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes following vaccination with Fluzone Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive Fluzone Quadrivalent during pregnancy in Sanofi Pasteur Inc.'s vaccination pregnancy registry by calling 1-800-822-2463.

Risk SummaryAll pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Available data with Fluzone Quadrivalent use in pregnant women are insufficient to inform vaccine-associated risk of adverse developmental outcomes.A developmental and reproductive toxicity study was performed in female rabbits given a 0.5 mL/dose of Fluzone Quadrivalent prior to mating and during gestation (a single human dose is 0.5 mL). This study revealed no adverse effects to the fetus or pre-weaning development due to Fluzone Quadrivalent [see Animal Data (8.1)].

Data

Animal Data: In a developmental and reproductive toxicity study female rabbits were administered a 0.5 mL/dose of Fluzone Quadrivalent by intramuscular injection 24 and 10 days before insemination, and on Days 6, 12, and 27 of gestation (a single human dose is 0.5 mL). There were no adverse effects on pre-weaning development or vaccine-related fetal malformations noted in this study.

Clinical Considerations

Disease-associated Maternal and/or Embryo/Fetal RiskPregnant women are at increased risk of complications associated with influenza infection compared to non-pregnant women. Pregnant women who contract influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.

Risk SummaryIt is not known whether Fluzone Quadrivalent is excreted in human milk. Data are not available to assess the effects of Fluzone Quadrivalent on the breastfed infant or on milk production/excretion.The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Fluzone Quadrivalent and any potential adverse effects on the breastfed child from Fluzone Quadrivalent or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to the disease prevented by the vaccine.

Fluzone is a registered trademark of Sanofi Pasteur Inc.Manufactured by:Sanofi Pasteur Inc.Swiftwater, PA 18370 USA

6.2 Post-Marketing Experience

  • The following events have been spontaneously reported during the post-approval use of Fluzone (trivalent) or Fluzone Quadrivalent Southern Hemisphere. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Fluzone (trivalent) or Fluzone Quadrivalent Southern Hemisphere.Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathyImmune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema)Eye Disorders: Ocular hyperemiaNervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell's palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paresthesiaVascular Disorders: Vasculitis, vasodilatation/flushingRespiratory, Thoracic and Mediastinal Disorders: Dyspnea, cough, wheezing, throat tightness, oropharyngeal pain, rhinorrheaSkin and Subcutaneous Tissue Disorders: Rash, pruritus, and Stevens-Johnson syndromeGeneral Disorders and Administration Site Conditions: Asthenia/fatigue, pain in extremities, chest painGastrointestinal Disorders: Vomiting

8 Use In Specific Populations

Fluzone Quadrivalent Southern Hemisphere and Fluzone Quadrivalent are manufactured using the same process. Data in this section were obtained in studies with Fluzone Quadrivalent.

8.4 Pediatric Use

Safety and effectiveness of Fluzone Quadrivalent Southern Hemisphere in children below the age of 6 months have not been established.

8.5 Geriatric Use

Safety and immunogenicity of Fluzone Quadrivalent were evaluated in adults 65 years of age and older. [See Clinical Studies (14.6).] Antibody responses to Fluzone Quadrivalent are lower in persons ≥65 years of age than in younger adults.

11 Description

Fluzone Quadrivalent Southern Hemisphere (Influenza Vaccine) for intramuscular injection is an inactivated influenza vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The virus- containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, octylphenol ethoxylate (Triton® X-100), producing a "split virus". The split virus is further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. Antigens from the four strains included in the vaccine are produced separately and then combined to make the quadrivalent formulation.Fluzone Quadrivalent Southern Hemisphere suspension for injection is clear and slightly opalescent in color.Antibiotics are not used in the manufacture of Fluzone Quadrivalent Southern Hemisphere.The Fluzone Quadrivalent Southern Hemisphere prefilled syringe and vial presentations are not made with natural rubber latex.Fluzone Quadrivalent Southern Hemisphere is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following four influenza strains recommended for the 2021 Southern Hemisphere influenza season: A/Victoria/2570/2019 IVR-215 (H1N1), A/Hong Kong/2671/2019 IVR-208 (H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and B/Washington/02/2019 (B Victoria lineage). The amounts of HA and other ingredients per dose of vaccine are listed in Table 7. The single-dose, pre-filled syringe (0.25 mL and 0.5 mL) is formulated without thimerosal or any other preservative. The 5 mL multi-dose vial presentation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury. Each 0.25 mL dose from the multi-dose vial contains 12.5 mcg mercury.Table 7: Fluzone Quadrivalent Southern Hemisphere IngredientsIngredientQuantity (per dose)Fluzone Quadrivalent0.25 mL DoseFluzone Quadrivalent0.5 mL Dose"-" Indicates information is not applicableActive Substance: Split influenza virus, inactivated strainsper United States Public Health Service recommendations:30 mcg HA total60 mcg HA total  A (H1N1)7.5 mcg HA15 mcg HA  A (H3N2)7.5 mcg HA15 mcg HA  B/(Victoria lineage)7.5 mcg HA15 mcg HA  B/(Yamagata lineage)7.5 mcg HA15 mcg HAOther:  Sodium phosphate-buffered isotonic sodium chloride solutionQSQuantity Sufficient to appropriate volumeQS to appropriate volume  Formaldehyde≤50 mcg≤100 mcg  Octylphenol ethoxylate≤125 mcg≤250 mcgPreservative  Single-dose presentations--  Multi-dose presentation (thimerosal)12.5 mcg mercury25 mcg mercury

12.1 Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have co-circulated worldwide. Protection from influenza virus infection has not been correlated with a specific level of hemagglutination inhibition (HI) antibody titer post-vaccination. However, in some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects. (See ref. 2) (See ref. 3)Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating during the influenza season in the hemisphere for which the vaccine is intended.Annual vaccination with the influenza vaccine is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rabbits with Fluzone Quadrivalent revealed no evidence of impaired female fertility [see Animal Data (8.1)].

14 Clinical Studies

The effectiveness of Fluzone Quadrivalent was demonstrated based on clinical endpoint efficacy data for Fluzone (trivalent influenza vaccine) and on an evaluation of serum HI antibody responses to Fluzone Quadrivalent. Fluzone Quadrivalent, an inactivated influenza vaccine that contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, is manufactured according to the same process as Fluzone.Fluzone Quadrivalent Southern Hemisphere and Fluzone Quadrivalent are manufactured using the same process. Data in this section were obtained in studies with Fluzone Quadrivalent.

14.1 Efficacy Of Fluzone (Trivalent Influenza Vaccine) In Children 6 Through 24 Months Of Age

A randomized, double-blind, placebo-controlled study was conducted at a single US center during the 1999-2000 (Year 1) and 2000-2001 (Year 2) influenza seasons. The intent-to-treat analysis set included a total of 786 children 6 through 24 months of age. Participants received two 0.25 mL doses of either Fluzone (N=525) or a placebo (N=261). Among all randomized participants in both years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were Black, and 7.2% were of other racial groups. Cases of influenza were identified through active and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary endpoint and is presented in Table 8.Table 8: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Culture- Confirmed Influenza in Children Aged 6 through 24 Months during the 1999-2000 and 2000-2001 Influenza Seasons – Intent-to-Treat Analysis SetThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinatedFluzoneFluzone (0.25 mL): 1999-2000 formulation containing A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) and 2000-2001 formulation containing A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage)PlaceboPlacebo: 0.4% NaClFluzone vs. PlaceboYearnn is the number of participants with culture-confirmed influenza for the given year of study as listed in the first columnNN is the number of participants randomly assigned to receive Fluzone or placebo for the given year of study as listed in the column headers (intent-to-treat analysis set)Rate(n/N)Rate (%) = (n/N) * 100(95% CI)nNRate(n/N)(95% CI)Relative Risk(95% CI)Percent Relative ReductionRelative reduction in vaccine efficacy was defined as (1-relative risk) × 100 (95% CI)Year 1Includes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up)152735.5(3.1; 8.9)2213815.9(10.3; 23.1)0.34 (0.18; 0.64)66 (36; 82)(1999-2000)Year 2Includes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up)92523.6(1.6; 6.7)41233.3(0.9; 8.1)1.10 (0.34; 3.50)-10 (-250; 66)(2000-2001)

14.2 Efficacy Of Fluzone (Trivalent Influenza Vaccine) In Adults

A randomized, double-blind, placebo-controlled study was conducted in a single US center during the 2007-2008 influenza season. Participants received one dose of either Fluzone vaccine (N=813), an active comparator (N=814), or placebo (N=325). The intent-to-treat analysis set included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% were of other racial/ethnic groups. Cases of influenza were identified through active and passive surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR).Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 9.Table 9: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Influenza in Adults Aged 18 through 49 Years during the 2007-2008 Influenza Season – Intent-to-Treat Analysis SetNCT00538512,The intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinatedLaboratory- Confirmed Symptomatic InfluenzaFluzoneFluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (Victoria lineage)(N=813)N is the number of participants randomly assigned to receive Fluzone or placeboPlaceboPlacebo: 0.9% NaCl(N=325)Fluzone vs. Placebonn is the number of participants satisfying the criteria listed in the first column Rate(%)Rate (%) = (n/N) * 100(95% CI)nRate(%)(95% CI)Relative Risk(95% CI)Percent Relative ReductionRelative reduction in vaccine efficacy was defined as (1 - relative risk) × 100(95% CI)Positive culture212.6(1.6; 3.9)319.5(6.6; 13.3)0.27 (0.16; 0.46)73 (54; 84) Positive PCR283.4(2.3; 4.9)3510.8(7.6; 14.7)0.32 (0.20; 0.52)68 (48; 80) Positive culture, positive PCR, or both283.4(2.3; 4.9)3510.8(7.6; 14.7)0.32 (0.20; 0.52)68 (48; 80)

14.3 Immunogenicity Of Fluzone Quadrivalent In Children 6 Months Through 8 Years Of Age

In Study 1 (NCT01240746) [see Adverse Reactions (6.1)], 1419 children 6 months through 35 months of age and 2101 children 3 years through 8 years of age were included in the per-protocol immunogenicity analysis. Participants 6 months through 35 months of age received one or two 0.25 mL doses and participants 3 years through 8 years of age received one or two 0.5 mL doses of Fluzone Quadrivalent, TIV-1, or TIV-2. For participants who received two doses, the doses were administered approximately 4 weeks apart. The distribution of demographic characteristics was similar to that of the safety analysis set [see Adverse Reactions (6.1)].HI antibody geometric mean titers (GMTs) and seroconversion rates 28 days following vaccination with Fluzone Quadrivalent were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (see Table 10 and Table 11).Table 10: Study 1NCT01240746: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of AgeParticipants 6-35 months old received 1 or 2 doses (0.25 mL) and participants 3-8 years old received 1 or 2 doses (0.5 mL) as per ACIP recommendation (Per-protocol Analysis Set)Per-protocol analysis set included all persons who had no study protocol deviationsAntigen StrainFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)NN is the number of participants in the per-protocol analysis set=2339Pooled TIVPooled TIV group includes participants vaccinated with either TIV-1 or TIV-2N=1181GMT Ratio (95% CI)Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >0.66 GMTGMTA (H1N1)112410961.03 (0.93; 1.14)A (H3N2)8228280.99 (0.91; 1.08)Fluzone QuadrivalentN=2339TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)N=582TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)N=599GMT Ratio (95% CI)GMTGMTGMTB/Brisbane/60/2008(B Victoria)86.164.3(19.5)TIV-2 did not contain B/Brisbane/60/20081.34 (1.20; 1.50)B/Florida/04/2006(B Yamagata)61.5(16.3)TIV-1 did not contain B/Florida/60/200658.31.06 (0.94; 1.18)Table 11: Study 1NCT01240746: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by Seroconversion Rates at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of AgeParticipants 6-35 months old received 1 or 2 doses (0.25 mL) and participants 3-8 years old received 1 or 2 doses (0.5 mL) as per ACIP recommendations (Per-protocol Analysis Set)Per-protocol analysis set included all persons who had no study protocol deviationsAntigen StrainFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)NN is the number of participants in the per-protocol analysis set=2339Pooled TIVPooled TIV group includes participants vaccinated with either TIV-1 or TIV-2N=1181Difference of Seroconversion Rates(95% CI)Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >-10%SeroconversionSeroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 (%)A (H1N1)92.491.40.9 (-0.9; 3.0)A (H3N2)88.084.23.8 (1.4; 6.3)Fluzone QuadrivalentN=2339TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)N=582TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)N=599Difference of Seroconversion Rates(95% CI)Seroconversion (%)B/Brisbane/60/2008(B Victoria)71.861.1(20.0)TIV-2 did not contain B/Brisbane/60/200810.7 (6.4; 15.1)B/Florida/04/2006(B Yamagata)66.1(17.9)TIV-1 did not contain B/Florida/04/200664.02.0 (-2.2; 6.4)Non-inferiority immunogenicity criteria based on HI antibody GMTs and seroconversion rates were also met when age subgroups (6 months to <36 months and 3 years to <9 years) were examined. In addition, HI antibody GMTs and seroconversion rates following Fluzone Quadrivalent were higher than those following TIV for the B strain not contained in each respective TIV based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by TIV] >1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV and the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone Quadrivalent minus TIV] >10% for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV).

14.4 Immunogenicity Of The 0.5 Ml Dose Of Fluzone Quadrivalent In Children 6 Months Through 35 Months Of Age

In Study 2 (NCT02915302) [see Adverse Reactions (6.1)], 1027 children, 6 months through 35 months of age, were included in the per-protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis set [see Adverse Reactions (6.1)].In this study, children 6 months through 35 months of age received one or two doses of either 0.25 mL or 0.5 mL of Fluzone Quadrivalent. Non-inferiority of the 0.5 mL dose(s) relative to the 0.25 mL dose(s) of Fluzone Quadrivalent was demonstrated for all four strains based on pre- specified criteria (lower limit of the 2-sided 95% CI of the ratio of GMTs between groups >0.667; lower limit of the 2-sided 95% CI of the difference in seroconversion rates >-10%). GMT ratios (GMT0.5-mL dose divided by GMT0.25-mL dose) for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 1.42 (95% CI: 1.16; 1.74), 1.48 (95% CI: 1.21; 1.82), 1.33 (95% CI: 1.09; 1.62), and 1.41 (95% CI: 1.17; 1.70), respectively. Seroconversion rate (SCR) differences (SCR0.5-mL dose minus SCR0.25-mL dose) for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 4.6% (95% CI: -0.4%; 9.6%), 5.1% (95% CI: 0.4%; 9.8%), 1.3% (95% CI: -2.9%; 5.6%), and 2.6% (95% CI: -1.4%; 6.5%).

14.5 Immunogenicity Of Fluzone Quadrivalent In Adults ≥18 Years Of Age

In Study 3 (NCT00988143) [see Adverse Reactions (6.1)], 565 adults 18 years of age and older who had received one dose of Fluzone Quadrivalent, TIV-1, or TIV-2 were included in the per- protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis set [see Adverse Reactions (6.1)].HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (see Table 12).Table 12: Study 3NCT00988143: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 18 Years of Age and Older (Per- protocol Analysis Set)Per-protocol analysis set included all persons who had no study protocol deviationsAntigen StrainFluzone QuadrivalentFluzone Quadrivalent containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)NN is the number of participants in the per-protocol analysis set=190Pooled TIVPooled TIV group includes participants vaccinated with either TIV-1 or TIV-2N=375GMT Ratio(95% CI)Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >2/3GMTGMTA (H1N1)1611511.06 (0.87; 1.31)A (H3N2)3043390.90 (0.70; 1.15)Fluzone QuadrivalentN=190TIV-12009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)N=187TIV-22008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed(B Yamagata)N=188GMT Ratio(95% CI)GMTGMTGMTB/Brisbane/60/2008(B Victoria)101114(44.0)TIV-2 did not contain B/Brisbane/60/20080.89 (0.70; 1.12)B/Florida/04/2006(B Yamagata)155(78.1)TIV-1 did not contain B/Florida/04/20061351.15 (0.93; 1.42)

14.6 Immunogenicity Of Fluzone Quadrivalent In Geriatric Adults ≥65 Years Of Age

In Study 4 (NCT01218646) [see Adverse Reactions (6.1)], 660 adults 65 years of age and older were included in the per-protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis set [see Adverse Reactions (6.1)].HI antibody GMTs 21 days following vaccination with Fluzone Quadrivalent were non-inferior to those following TIV for all four strains, based on pre-specified criteria (see Table 13).Seroconversion rates 21 days following Fluzone Quadrivalent were non-inferior to those following TIV for H3N2, B/Brisbane, and B/Florida, but not for H1N1 (see Table 14). The HI antibody GMT following Fluzone Quadrivalent was higher than that following TIV-1 for B/Florida but not higher than that following TIV-2 for B/Brisbane, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by TIV] >1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV). Seroconversion rates following Fluzone Quadrivalent were higher than those following TIV for the B strain not contained in each respective TIV, based on pre- specified criteria (the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone Quadrivalent minus TIV] >10% for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV).Table 13: Study 4NCT01218646: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-protocol Analysis Set)Per-protocol analysis set included all persons who had no study protocol deviationsAntigen StrainFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)NN is the number of participants in the per-protocol analysis set=220Pooled TIVPooled TIV group includes participants vaccinated with either TIV-1 or TIV-2N=440GMT Ratio (95% CI)Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (Fluzone Quadrivalent divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >0.66GMTGMTA (H1N1)2312700.85 (0.67; 1.09)A (H3N2)5013241.55 (1.25; 1.92)Fluzone QuadrivalentN=220TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)N=219TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)N=221GMT Ratio (95% CI)GMTGMTGMTB/Brisbane/60/2008(B Victoria)73.857.9(42.2)TIV-2 did not contain B/Brisbane/60/20081.27 (1.05; 1.55)B/Florida/04/2006(B Yamagata)61.1(28.5)TIV-1 did not contain B/Florida/04/200654.81.11 (0.90; 1.37)Table 14: Study 4NCT01218646: Non-inferiority of Fluzone Quadrivalent Relative to TIV for Each Strain by Seroconversion Rates at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-protocol Analysis Set)Per-protocol analysis set included all persons who had no study protocol deviationsAntigen StrainFluzone QuadrivalentFluzone Quadrivalent containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/04/2006 (Yamagata lineage)NN is the number of participants in the per-protocol analysis set=220Pooled TIVPooled TIV group includes participants vaccinated with either TIV-1 or TIV-2N=440Difference of Seroconversion Rate(95% CI)Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (Fluzone Quadrivalent minus pooled TIV for the A strains, or the TIV containing the corresponding B strain) was >-10%SeroconversionSeroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 (%)A (H1N1)65.9169.77-3.86 (-11.50; 3.56)A (H3N2)69.0959.329.77 (1.96; 17.20)Fluzone QuadrivalentN=220TIV-12010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed(B Victoria)N=219TIV-2Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed(B Yamagata)N=221Difference of Seroconversion Rate(95% CI)Seroconversion (%)B/Brisbane/60/2008(B Victoria)28.6418.72(8.60)TIV-2 did not contain B/Brisbane/60/20089.91 (1.96; 17.70)B/Florida/04/2006(B Yamagata)33.18(9.13)TIV-1 did not contain B/Florida/04/200631.221.96 (-6.73; 10.60)

15 References

  • 1Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797-802.2Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.3Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination- inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767-777.

16.1 How Supplied

Single-dose, prefilled syringe (pink plunger rod), without needle, 0.25 mL (NDC 49281-182-00) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-182-25).Single-dose, prefilled syringe (clear plunger rod), without needle, 0.5 mL (NDC 49281-321-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-321-50).Multi-dose vial, 5 mL (NDC 49281-337-78) (not made with natural rubber latex). Supplied as package of 1 (NDC 49281-337-15). A maximum of ten doses can be withdrawn from the multi- dose vial.

16.2 Storage And Handling

Store all Fluzone Quadrivalent Southern Hemisphere presentations refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen.Do not use after the expiration date shown on the label.

17 Patient Counseling Information

  • See FDA-approved patient labeling (Patient Information). Inform the vaccine recipient or guardian:Fluzone Quadrivalent Southern Hemisphere contains killed viruses and cannot cause influenza.Fluzone Quadrivalent Southern Hemisphere stimulates the immune system to protect against influenza, but does not prevent other respiratory infections.Annual influenza vaccination is recommended by the World Health Organization.Report adverse reactions to their healthcare provider and/or to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967.Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Fluzone Quadrivalent Southern Hemisphere during pregnancy. Women who receive Fluzone Quadrivalent Southern Hemisphere during pregnancy are encouraged to contact Sanofi Pasteur Inc. directly or have their healthcare provider contact Sanofi Pasteur Inc. at 1-800-822-2463.Vaccine Information Statements must be provided to vaccine recipients or their guardians, as required by the National Childhood Vaccine Injury Act of 1986 prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Patient Information Sheetfluzone® Quadrivalent Southern Hemisphere Influenza Vaccine

  • Please read this information sheet before getting Fluzone Quadrivalent Southern Hemisphere 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 Quadrivalent vaccine?Fluzone Quadrivalent Southern Hemisphere is a vaccine that helps protect against influenza illness (flu) caused by strains circulating in the southern hemisphere. Fluzone Quadrivalent Southern Hemisphere vaccine is for people who are 6 months of age and older.Vaccination with Fluzone Quadrivalent Southern Hemisphere vaccine may not protect all people who receive the vaccine.Who should not get Fluzone Quadrivalent vaccine?You should not get Fluzone Quadrivalent Southern Hemisphere 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 6 months of age.Tell your healthcare provider if you or your child 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 the Fluzone Quadrivalent Southern Hemisphere vaccine given?Fluzone Quadrivalent Southern Hemisphere vaccine is a shot given into the muscle of the arm.For infants, Fluzone Quadrivalent Southern Hemisphere vaccine is a shot given into the muscle of the thigh.What are the possible side effects of Fluzone Quadrivalent Southern Hemisphere vaccine?The most common side effects of Fluzone Quadrivalent Southern Hemisphere vaccine are:pain, redness, and swelling where you got the shotmuscle achestirednessheadachefeverThese are not all of the possible side effects of Fluzone Quadrivalent Southern Hemisphere 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. Sanofi Pasteur Inc. is collecting information on pregnancy outcomes and the health of newborns following vaccination with Fluzone Quadrivalent Southern Hemisphere during pregnancy. Women who receive Fluzone Quadrivalent Southern Hemisphere during pregnancy are encouraged to contact Sanofi Pasteur Inc. directly or have their healthcare provider contact Sanofi Pasteur Inc. at 1-800-822-2463.What are the ingredients in Fluzone Quadrivalent Southern Hemisphere vaccine?Fluzone Quadrivalent Southern Hemisphere vaccine contains 4 killed flu virus strains.Inactive ingredients include formaldehyde and octylphenol ethoxylate. The preservative thimerosal is only in the multi-dose vial of Fluzone Quadrivalent Southern Hemisphere vaccine.Manufactured by: Sanofi Pasteur Inc. Swiftwater, PA 18370 USA

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