Fluzone ® 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. Fluzone Quadrivalent is approved for use in persons 6 months of age and older.
For intramuscular use The dose and schedule for Fluzone Quadrivalent are presented in Table 1. Table 1: Dose and Schedule for Fluzone Quadrivalent Age Vaccination Status Dose Schedule "-" Indicates information is not applicable 6 months through 35 months Not previously vaccinated with influenza vaccine or unknown vaccination history Two doses, either 0.25 mL or 0.5 mL The schedule can be completed as two 0.25-mL d...
Single-dose, prefilled syringe (clear plunger rod), without needle, 0.5 mL (NDC 49281-926-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-926-50). Multi-dose vial, 5 mL (NDC 49281-541-78) (not made with natural rubber latex). Supplied as package of one (NDC 49281-541-15). A maximum of ten doses can be withdrawn from the multi-dose vial. Store all Fluzone Quadrivalent presentations re...
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vaers.hhs.govFluzone® 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.
Fluzone Quadrivalent is approved for use in persons 6 months of age and older.
For intramuscular use
The dose and schedule for Fluzone Quadrivalent are presented in Table 1.
| Age | Vaccination Status | Dose | Schedule |
|---|---|---|---|
| "-" Indicates information is not applicable | |||
| 6 months through 35 months | Not previously vaccinated with influenza vaccine or unknown vaccination history | Two doses, either 0.25 mL or 0.5 mL* | Administer at least 4 weeks apart |
| Previously vaccinated with influenza vaccine | One or two doses†, either 0.25 mL or 0.5 mL* | If two doses, administer at least 4 weeks apart | |
| 36 months through 8 years | Not previously vaccinated with influenza vaccine or unknown vaccination history | Two 0.5 mL doses | Administer at least 4 weeks apart |
| Previously vaccinated with influenza vaccine | One or two 0.5 mL doses† | If two doses, administer at least 4 weeks apart | |
| 9 years and older | - | One 0.5 mL dose | - |
* The 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 apart
† To determine if 1 or 2 doses are required, refer to Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines
Fluzone Quadrivalent is clear and slightly opalescent in color. Parenteral drug products should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit. If any of these defects or conditions exist, Fluzone Quadrivalent should not be administered.
Before administering a dose of vaccine, shake the prefilled syringe or multi-dose vial. A maximum of ten doses can be withdrawn from the multi-dose vial.
Administer each dose intramuscularly.
Fluzone Quadrivalent is an injectable suspension. For individuals 6 months through 35 months, a single dose is 0.25 mL or 0.5 mL.
For individuals 36 months and older, a single dose is 0.5 mL.
Do not administer Fluzone Quadrivalent to anyone with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see Description (11)], including egg protein, or to a previous dose of any influenza vaccine.
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.
The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. (1)
Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of Fluzone Quadrivalent.
If Fluzone Quadrivalent is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.
Vaccination with Fluzone Quadrivalent may not protect all recipients.
Syncope (fainting) has been reported following vaccination with Fluzone Quadrivalent. Procedures should be in place to avoid injury from fainting.
In children 6 months through 35 months of age, the most common (≥10%) injection-site adverse reactions were pain (57%) or tenderness (47%– 54%), erythema (23%–37%), and swelling (13%–22%); the most common solicited systemic adverse reactions were irritability (47%– 54%), abnormal crying (33%–41%), malaise (38%), drowsiness (31%– 38%), appetite loss (27%–32%), myalgia (27%), vomiting (10%–15%), and fever (11%–14%).
In children 3 years through 8 years of age, the most common (≥10%) injection-site adverse 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 adverse 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 adverse reaction was pain (33%); the most common solicited systemic adverse reactions were myalgia (18%), headache (13%), and malaise (11%).
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trial(s) of another vaccine and may not reflect the rates observed in practice.
Children 6 Months Through 8 Years of Age
Study 1 (NCT01240746) 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.
| Fluzone Quadrivalent‡
,
§
(N¶=1223) | TIV-1§
,
#
(B Victoria) (N¶=310) | TIV-2§
,
♠
(B Yamagata) (N¶=308) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2♥
(%) | Grade 3♦
(%) | Any (%) | Grade 2♥
(%) | Grade 3♦
(%) | Any (%) | Grade 2♥
(%) | Grade 3♦
(%) | |
| Injection-site adverse reactions | |||||||||
| Pain♣ | 57.0 | 10.2 | 1.0 | 52.3 | 11.5 | 0.8 | 50.3 | 5.4 | 2.7 |
| Tenderness*2 | 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)†2 | 14.3 | 5.5 | 2.1 | 16.0 | 6.6 | 1.7 | 13.0 | 4.1 | 2.0 |
| Malaise♣ | 38.1 | 14.5 | 4.6 | 35.2 | 14.8 | 4.7 | 32.4 | 12.8 | 6.8 |
| Myalgia♣ | 26.7 | 6.6 | 1.9 | 26.6 | 9.4 | 1.6 | 25.0 | 6.8 | 2.7 |
| Headache♣ | 8.9 | 2.5 | 0.6 | 9.4 | 3.9 | 0.0 | 12.2 | 4.7 | 0.0 |
| Irritability*2 | 54.0 | 26.4 | 3.2 | 52.8 | 20.1 | 3.1 | 53.5 | 22.9 | 2.8 |
| Crying abnormal*2 | 41.2 | 12.3 | 3.3 | 36.5 | 8.2 | 1.9 | 29.9 | 10.4 | 2.1 |
| Drowsiness*2 | 37.7 | 8.4 | 1.3 | 32.1 | 3.8 | 0.6 | 31.9 | 5.6 | 0.7 |
| Appetite loss*2 | 32.3 | 9.1 | 1.8 | 33.3 | 5.7 | 1.9 | 25.0 | 8.3 | 0.7 |
| Vomiting*2 | 14.8 | 6.2 | 1.0 | 11.3 | 4.4 | 0.6 | 13.9 | 6.3 | 0.0 |
* The safety analysis set includes all persons who received at least one dose of study vaccine
† NCT01240746
‡ Fluzone 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
¶ N is the number of participants in the safety analysis set
# 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
♠ 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
♥ Grade 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 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
♣ Assessed in children 24 months through 35 months of age
*2 Assessed in children 6 months through 23 months of age
†2 Fever measured by any route
| Fluzone Quadrivalent‡
(N§=1669) | TIV-1¶
(B Victoria) (N§=424) | TIV-2#
(B Yamagata) (N§=413) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | |
| Injection-site adverse reactions | |||||||||
| Pain | 66.6 | 15.8 | 2.1 | 64.6 | 9.5 | 2.0 | 63.8 | 11.6 | 2.8 |
| Erythema | 34.1 | 2.9 | 1.8 | 36.8 | 3.4 | 1.2 | 35.2 | 2.5 | 1.8 |
| Swelling | 24.8 | 2.8 | 1.4 | 25.4 | 1.5 | 1.2 | 25.9 | 2.5 | 1.8 |
| Systemic adverse reactions | |||||||||
| Fever (≥100.4°F)♦ | 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 |
* The safety analysis set includes all persons who received at least one dose of study vaccine
† NCT01240746
‡ Fluzone 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)
§ N is the number of participants in the safety analysis set
¶ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
# Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
♠ Grade 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 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
♦ Fever measured by any route
Among children 6 months through 8 years of age, unsolicited non-serious adverse events were reported in 1360 (47.0%) recipients in the Fluzone Quadrivalent group, 352 (48.0%) recipients in the TIV-1 group, and 346 (48.0%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were cough, vomiting, and pyrexia. During the 28 days following vaccination, a total of 16 (0.6%) recipients in the Fluzone Quadrivalent group, 4 (0.5%) recipients in the TIV-1 group, and 4 (0.6%) recipients in the TIV-2 group, experienced at least one SAE. 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 Age
Study 2 (NCT02915302) 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.
| Fluzone Quadrivalent 0.25 mL‡ (N§=949) | Fluzone Quadrivalent 0.5 mL‡ (N§=992) | |||
|---|---|---|---|---|
| Any (%) | Grade 3¶
(%) | Any (%) | Grade 3¶
(%) | |
| Injection-site adverse reactions | ||||
| Tenderness | 47.3 | 1.7 | 50.4 | 1.2 |
| Redness | 23.1 | 0.0 | 24.3 | 0.2 |
| Swelling | 12.9 | 0.1 | 14.7 | 0.0 |
| Systemic adverse reactions | ||||
| Irritability | 47.4 | 3.6 | 48.6 | 4.0 |
| Abnormal Crying | 33.3 | 3.1 | 34.1 | 2.6 |
| Drowsiness | 31.9 | 2.1 | 31.3 | 1.6 |
| Loss of Appetite | 27.3 | 1.4 | 28.3 | 2.2 |
| Fever (≥100.4°F)# | 11.3 | 0.6 | 12.2 | 1.2 |
| Vomiting | 10.0 | 0.4 | 10.2 | 0.5 |
* The safety analysis set includes all persons who received at least one dose of study vaccine
† NCT02915302
‡ Participants received 1 or 2 doses according to ACIP recommendations
§ N is the number of participants in the safety analysis set
¶ Grade 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
# Fever measured by any route
The 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.
Adults
In Study 3 (NCT00988143), 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.
| Fluzone Quadrivalent‡
(N§=190) | TIV-1¶
(B Victoria) (N§=190) | TIV-2#
(B Yamagata) (N§=190) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | |
| Injection-site adverse reactions | |||||||||
| Pain | 47.4 | 6.8 | 0.5 | 52.1 | 7.9 | 0.5 | 43.2 | 6.3 | 0.0 |
| Erythema | 1.1 | 0.0 | 0.0 | 1.6 | 0.5 | 0.0 | 1.6 | 0.5 | 0.0 |
| Swelling | 0.5 | 0.0 | 0.0 | 3.2 | 0.5 | 0.0 | 1.1 | 0.0 | 0.0 |
| Induration | 0.5 | 0.0 | 0.0 | 1.6 | 0.5 | 0.0 | 0.5 | 0.0 | 0.0 |
| Ecchymosis | 0.5 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 |
| Systemic adverse reactions | |||||||||
| Myalgia | 23.7 | 5.8 | 0.0 | 25.3 | 5.8 | 0.0 | 16.8 | 5.8 | 0.0 |
| Headache | 15.8 | 3.2 | 0.5 | 18.4 | 6.3 | 0.5 | 18.0 | 4.2 | 0.0 |
| Malaise | 10.5 | 1.6 | 1.1 | 14.7 | 3.2 | 1.1 | 12.1 | 4.7 | 0.5 |
| Shivering | 2.6 | 0.5 | 0.0 | 5.3 | 1.1 | 0.0 | 3.2 | 0.5 | 0.0 |
| Fever (≥100.4°F)♦ | 0.0 | 0.0 | 0.0 | 0.5 | 0.5 | 0.0 | 0.5 | 0.5 | 0.0 |
* The safety analysis set includes all persons who received study vaccine
† NCT00988143
‡ Fluzone 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)
§ N is the number of participants in the safety analysis set
¶ 2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
# 2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed
♠ Grade 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 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
♦ Fever measured by any route
Unsolicited non-serious adverse events were reported in 33 (17.4%) recipients in the Fluzone Quadrivalent group, 45 (23.7%) recipients in the TIV-1 group, and 45 (23.7%) recipients in the TIV-2 group. The most commonly reported unsolicited non-serious adverse events were headache, cough, and oropharyngeal pain. In the follow-up period, there were two SAEs, 1 (0.5%) in the Fluzone Quadrivalent group and 1 (0.5%) in the TIV-2 group.
Geriatric Adults
In Study 4 (NCT01218646), 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.
| Fluzone Quadrivalent‡
(N§=225) | TIV-1¶
(B Victoria) (N§=225) | TIV-2#
(B Yamagata) (N§=225) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | Any (%) | Grade 2♠
(%) | Grade 3♥
(%) | |
| Injection-site adverse reactions | |||||||||
| Pain | 32.6 | 1.3 | 0.9 | 28.6 | 2.7 | 0.0 | 23.1 | 0.9 | 0.0 |
| Erythema | 2.7 | 0.9 | 0.0 | 1.3 | 0.0 | 0.0 | 1.3 | 0.4 | 0.0 |
| Swelling | 1.8 | 0.4 | 0.0 | 1.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Systemic adverse reactions | |||||||||
| Myalgia | 18.3 | 4.0 | 0.4 | 18.3 | 4.0 | 0.0 | 14.2 | 2.7 | 0.4 |
| Headache | 13.4 | 1.3 | 0.4 | 11.6 | 1.3 | 0.0 | 11.6 | 1.8 | 0.4 |
| Malaise | 10.7 | 4.5 | 0.4 | 6.3 | 0.4 | 0.0 | 11.6 | 2.7 | 0.9 |
| Fever (≥100.4°F)♦ | 1.3 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.9 | 0.4 | 0.4 |
* The safety analysis set includes all persons who received study vaccine
† NCT01218646
‡ Fluzone 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)
§ N is the number of participants in the safety analysis set
¶ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
# Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
♠ Grade 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 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
♦ Fever measured by any route
Unsolicited non-serious adverse events were reported in 28 (12.4%) recipients in the Fluzone Quadrivalent group, 22 (9.8%) recipients in the TIV-1 group, and 22 (9.8%) recipients in the TIV-2 group. The most commonly reported adverse events were oropharyngeal pain, rhinorrhea, injection-site induration, and headache. Three SAEs were reported during the follow-up period, 2 (0.9%) in the TIV-1 group and 1 (0.4%) in the TIV-2 group.
The following events have been spontaneously reported during the post-approval use of Fluzone or Fluzone Quadrivalent. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Fluzone or Fluzone Quadrivalent.
Risk Summary
All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Available data with Fluzone Quadrivalent use in pregnant women are insufficient to inform vaccine-associated risk of adverse developmental outcomes.
A developmental toxicity study was performed in female rabbits administered Fluzone Quadrivalent prior to mating and during gestation. The dose was 0.5 mL on each of five occasions (a single human dose is 0.5 mL). This study revealed no adverse effects to the fetus or pre-weaning development and no evidence of impaired female fertility due to Fluzone Quadrivalent (see Data).
Data
Animal Data: A developmental toxicity study was performed in female rabbits administered a Fluzone Quadrivalent by intramuscular injection on 24 and 10 days before insemination, and on Days 6, 12, and 27 of gestation. The dose was 0.5 mL on each occasion (a single human dose is 0.5 mL). This study revealed no vaccine related fetal malformations and no adverse effects on pre-weaning development or female fertility.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Pregnant 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 Summary
It 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.
Safety and effectiveness of Fluzone Quadrivalent in children below the age of 6 months have not been established. Safety and effectiveness of Fluzone Quadrivalent in children 9 through 17 years of age is based on safety and effectiveness in children 6 months through 8 years of age and adults 18 years of age and older.
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.
Fluzone Quadrivalent (Influenza Vaccine) for intramuscular use 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 containing hemagglutinin (HA) antigen 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. The purified split virus from the four strains included in the vaccine are produced separately and then combined to make the quadrivalent formulation.
Fluzone Quadrivalent is an injectable suspension and is clear and slightly opalescent in color.
Antibiotics are not used in the manufacture of Fluzone Quadrivalent.
The Fluzone Quadrivalent prefilled syringe and multi-dose vial presentations are not made with natural rubber latex.
Fluzone Quadrivalent is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following four influenza strains recommended for the 2025–2026 influenza season: A/Victoria/4897/2022 IVR-238 (H1N1), A/Croatia/10136RV/2023 X-425A (H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and B/Michigan/01/2021 (a B/Austria/1359417/2021-like virus, B Victoria lineage).
The amounts of HA and other ingredients per dose of vaccine are listed in Table 7. The 0.5 mL single-dose, pre-filled syringe presentation is manufactured and formulated without thimerosal or any other preservative. The 5 mL multi-dose vial presentation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury. Each 0.25 mL dose from the multi-dose vial contains 12.5 mcg mercury.
| Ingredient | Quantity (per dose) | |
|---|---|---|
| Fluzone Quadrivalent 0.25 mL Dose | Fluzone Quadrivalent 0.5 mL Dose | |
| "-" Indicates information is not applicable | ||
| Active Substance: Split influenza virus, inactivated strains*: | 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 | QS† to appropriate volume | QS† to appropriate volume |
| Formaldehyde | ≤50 mcg | ≤100 mcg |
| Octylphenol ethoxylate | ≤125 mcg | ≤250 mcg |
| Preservative | ||
| Single-dose presentation | - | - |
| Multi-dose presentation (thimerosal) | 12.5 mcg mercury | 25 mcg mercury |
Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of participants. (2) (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.
Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility in males.
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.
Study 5 (NCT not available), 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.
| Fluzone† | Placebo‡ | Fluzone vs. Placebo | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Year | n§ | N¶ | Rate (n/N)# | (95% CI) | n§ | N¶ | Rate (n/N)# | (95% CI) | Relative Risk (95% CI) | Percent Relative Reduction♠
(95% CI) |
| Year 1♥
(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♦
(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) |
* The intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated
† Fluzone (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)
‡ Placebo: 0.4% NaCl
§ n is the number of participants with culture-confirmed influenza for the given year of study as listed in the first column
¶ N 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) * 100
♠ Relative reduction in vaccine efficacy was defined as (1-relative risk) × 100
♥ Includes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up)
♦ Includes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up)
Study 6 (NCT00538512), 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.
| Laboratory-Confirmed Symptomatic Influenza | Fluzone‡
(N=813)§ | Placebo¶
(N=325)§ | Fluzone vs. Placebo | |||||
|---|---|---|---|---|---|---|---|---|
| n# | Rate (%)♠ | (95% CI) | n# | Rate (%)♠ | (95% CI) | Relative Risk (95% CI) | Percent Relative Reduction♥
(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) |
* The intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated
† NCT00538512
‡ Fluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (Victoria lineage)
§ N is the number of participants randomly assigned to receive Fluzone or placebo
¶ Placebo: 0.9% NaCl
# n is the number of participants satisfying the criteria listed in the first column
♠ Rate (%) = (n/N) * 100
♥ Relative reduction in vaccine efficacy was defined as (1 - relative risk) × 100
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).
| Antigen Strain | Fluzone Quadrivalent§
N¶=2339 | Pooled TIV# N¶=1181 | GMT Ratio (95% CI)♠ | |
| GMT | GMT | |||
| A (H1N1) | 1124 | 1096 | 1.03 (0.93; 1.14) | |
| A (H3N2) | 822 | 828 | 0.99 (0.91; 1.08) | |
| Fluzone Quadrivalent§
N¶=2339 | TIV-1♥
(B Victoria) N¶=582 | TIV-2♦
(B Yamagata) N¶=599 | GMT Ratio (95% CI)♠ | |
| GMT | GMT | GMT | ||
| B/Brisbane/60/2008 (B Victoria) | 86.1 | 64.3 | (19.5)♣ | 1.34 (1.20; 1.50) |
| B/Florida/04/2006 (B Yamagata) | 61.5 | (16.3)*2 | 58.3 | 1.06 (0.94; 1.18) |
* Participants 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 included all persons who had no study protocol deviations
‡ NCT01240746
§ Fluzone 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)
¶ N is the number of participants in the per-protocol analysis set
# Pooled TIV group includes participants vaccinated with either TIV-1 or TIV-2
♠ 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
♥ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
♦ Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
♣ TIV-2 did not contain B/Brisbane/60/2008
*2 TIV-1 did not contain B/Florida/60/2006
| Antigen Strain | Fluzone Quadrivalent§
N¶=2339 | Pooled TIV#
N¶=1181 | Difference of Seroconversion Rates (95% CI)♠ | |
| Seroconversion♥ (%) | ||||
| 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 Quadrivalent§
N¶=2339 | TIV-1♦
(B Victoria) N¶=582 | TIV-2♣
(B Yamagata) N¶=599 | Difference of Seroconversion Rates (95% CI)♠ | |
| Seroconversion♥ (%) | ||||
| B/Brisbane/60/2008 (B Victoria) | 71.8 | 61.1 | (20.0)*2 | 10.7 (6.4; 15.1) |
| B/Florida/04/2006 (B Yamagata) | 66.1 | (17.9)†2 | 64.0 | 2.0 (-2.2; 6.4) |
* Participants 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 included all persons who had no study protocol deviations
‡ NCT01240746
§ Fluzone 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)
¶ N is the number of participants in the per-protocol analysis set
# Pooled TIV group includes participants vaccinated with either TIV-1 or TIV-2
♠ 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%
♥ Seroconversion: 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
♦ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
♣ Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
*2 TIV-2 did not contain B/Brisbane/60/2008
†2 TIV-1 did not contain B/Florida/04/2006
Non-inferiority immunogenicity criteria based on HI antibody GMTs and seroconversion rates were also met when age subgroups (6 months to <36 months and 3 years to <9 years) were examined. In addition, HI antibody GMTs and seroconversion rates following Fluzone Quadrivalent were higher than those following TIV for the B strain not contained in each respective TIV based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [Fluzone Quadrivalent divided by TIV] >1.5 for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV and the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [Fluzone Quadrivalent minus TIV] >10% for each B strain in Fluzone Quadrivalent compared with the corresponding B strain not contained in each TIV).
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%).
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).
| Antigen Strain | Fluzone Quadrivalent‡
N§=190 | Pooled TIV¶
N§=375 | GMT Ratio (95% CI)# | |
| GMT | GMT | |||
| A (H1N1) | 161 | 151 | 1.06 (0.87; 1.31) | |
| A (H3N2) | 304 | 339 | 0.90 (0.70; 1.15) | |
| Fluzone Quadrivalent‡
N§=190 | TIV-1♠
(B Victoria) N§=187 | TIV-2♥
(B Yamagata) N§=188 | GMT Ratio (95% CI)# | |
| GMT | GMT | GMT | ||
| B/Brisbane/60/2008 (B Victoria) | 101 | 114 | (44.0)♦ | 0.89 (0.70; 1.12) |
| B/Florida/04/2006 (B Yamagata) | 155 | (78.1)♣ | 135 | 1.15 (0.93; 1.42) |
* Per-protocol analysis set included all persons who had no study protocol deviations
† NCT00988143
‡ Fluzone 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)
§ N is the number of participants in the per-protocol analysis set
¶ Pooled TIV group includes participants vaccinated with either TIV-1 or TIV-2
# 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 >2/3
♠ 2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
♥ 2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed
♦ TIV-2 did not contain B/Brisbane/60/2008
♣ TIV-1 did not contain B/Florida/04/2006
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).
| Antigen Strain | Fluzone Quadrivalent‡
N§=220 | Pooled TIV¶
N§=440 | GMT Ratio (95% CI)# | |
| GMT | GMT | |||
| A (H1N1) | 231 | 270 | 0.85 (0.67; 1.09) | |
| A (H3N2) | 501 | 324 | 1.55 (1.25; 1.92) | |
| Fluzone Quadrivalent‡
N§=220 | TIV-1♠
(B Victoria) N§=219 | TIV-2♥
(B Yamagata) N§=221 | GMT Ratio (95% CI)# | |
| GMT | GMT | GMT | ||
| B/Brisbane/60/2008 (B Victoria) | 73.8 | 57.9 | (42.2)♦ | 1.27 (1.05; 1.55) |
| B/Florida/04/2006 (B Yamagata) | 61.1 | (28.5)♣ | 54.8 | 1.11 (0.90; 1.37) |
* Per-protocol analysis set included all persons who had no study protocol deviations
† NCT01218646
‡ Fluzone 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)
§ N is the number of participants in the per-protocol analysis set
¶ Pooled TIV group includes participants vaccinated with either TIV-1 or TIV-2
# 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
♠ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
♥ Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
♦ TIV-2 did not contain B/Brisbane/60/2008
♣ TIV-1 did not contain B/Florida/04/2006
| Antigen Strain | Fluzone Quadrivalent‡
N§=220 | Pooled TIV¶
N§=440 | Difference of Seroconversion Rates (95% CI)# | |
| Seroconversion♠(%) | ||||
| 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 Quadrivalent‡
N§=220 | TIV-1♥
(B Victoria) N§=219 | TIV-2♦
(B Yamagata) N§=221 | Difference of Seroconversion Rates (95% CI)# | |
| Seroconversion♠(%) | ||||
| B/Brisbane/60/2008 (B Victoria) | 28.64 | 18.72 | (8.60)♣ | 9.91 (1.96; 17.70) |
| B/Florida/04/2006 (B Yamagata) | 33.18 | (9.13)*2 | 31.22 | 1.96 (-6.73; 10.60) |
* Per-protocol analysis set included all persons who had no study protocol deviations
† NCT01218646
‡ Fluzone 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)
§ N is the number of participants in the per-protocol analysis set
¶ Pooled TIV group includes participants vaccinated with either TIV-1 or TIV-2
# 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%
♠ Seroconversion: 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
♥ 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
♦ Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
♣ TIV-2 did not contain B/Brisbane/60/2008
*2 TIV-1 did not contain B/Florida/04/2006
Single-dose, prefilled syringe (clear plunger rod), without needle, 0.5 mL (NDC 49281-926-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-926-50).
Multi-dose vial, 5 mL (NDC 49281-541-78) (not made with natural rubber latex). Supplied as package of one (NDC 49281-541-15). A maximum of ten doses can be withdrawn from the multi-dose vial.
Store all Fluzone Quadrivalent presentations refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen.
Between uses, return the multi-dose vial to the recommended storage conditions at 2° to 8°C (35° to 46°F).
Do not use after the expiration date shown on the label.
See FDA-approved patient labeling (Patient Information). Inform the vaccine recipient or guardian:
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).
Fluzone is a registered trademark of Sanofi Pasteur Inc.
Manufactured by:
Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
This product's labeling may have been updated. For the most recent prescribing information, please visit dailymed.nlm.nih.gov/dailymed.
Fluzone® Quadrivalent
Influenza Vaccine
Please read this information sheet before getting Fluzone Quadrivalent. 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?
Fluzone Quadrivalent is a vaccine that helps protect against influenza illness (flu).
Fluzone Quadrivalent is for people who are 6 months of age and older.
Vaccination with Fluzone Quadrivalent may not protect all people who receive the vaccine.
Who should not get Fluzone Quadrivalent?
You should not get Fluzone Quadrivalent if you:
Tell your healthcare provider if you or your child have or have had:
How is the Fluzone Quadrivalent given?
Fluzone Quadrivalent is given as an injection into the muscle.
What are the possible side effects of Fluzone Quadrivalent?
The most common side effects of Fluzone Quadrivalent are:
These are not all of the possible side effects of Fluzone Quadrivalent. You can ask your healthcare provider about other side effects.
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 vaers.hhs.gov.
What are the ingredients in Fluzone Quadrivalent?
Fluzone Quadrivalent contains 4 killed influenza virus strains.
Other ingredients include formaldehyde and octylphenol ethoxylate. The preservative thimerosal is only in the multi-dose vial of Fluzone Quadrivalent.
Manufactured by:
Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
NDC 49281-541-78
5 mL Multi-Dose Vial
Influenza Vaccine
Fluzone® Quadrivalent
Rx only
2025-2026 Formula
Contains Preservative. DO NOT FREEZE. Store at 2° to 8°C (35° to 46°F).
SHAKE WELL. Contents: One 5 mL multi-dose vial.
0.25 mL or 0.5 mL dose for 6 – 35 months.
0.5 mL dose for 3 years of age and older.
For Intramuscular Use. See package insert for details.
US Govt License #1725
Mfg by: Sanofi Pasteur Inc.
NDC 49281-541-15
2025-2026
Formula
Influenza Vaccine
Fluzone® Quadrivalent
Rx only
For 6 months of age and older.
For Intramuscular Use.
5 mL multi-dose vial.
0.25 mL or 0.5 mL dose for 6 – 35 months.
0.5 mL dose for 3 years of age and older.
sanofi
NDC 49281-926-88
Influenza Vaccine
Fluzone® Quadrivalent
2025-2026 Formula
Rx only
0.5 mL Single-Dose
No Preservative
For IM Use
Mfd by: Sanofi Pasteur Inc.
NDC 49281-926-50
2025-2026
Formula
Influenza Vaccine
Fluzone® Quadrivalent
Rx only
For Intramuscular Use
For 6 months of age and older
10 single-dose prefilled syringes 0.5 mL each
sanofi
| RxCUI | RxNorm string | TTY | SPL version |
|---|---|---|---|
| 2719475 | Fluzone Quadrivalent 2025-2026 vaccine 0.5 ML Prefilled Syringe | PSN | 25 |
| 2719474 | Fluzone Quadrivalent 2025-2026 vaccine Injectable Suspension | PSN | 25 |
| 2709119 | influenza virus vaccine 2025 (quadrivalent - Croatia/Victoria/Michigan/Phuket) 0.5 ML Prefilled Syringe | PSN | 25 |
| 2709125 | influenza virus vaccine 2025 (quadrivalent - Croatia/Victoria/Michigan/Phuket) Injectable Suspension | PSN | 25 |
| 2719475 | 0.5 ML influenza A virus A/Croatia/10136RV/2023 (H3N2) antigen 0.03 MG/ML / influenza A virus A/Victoria/4897/2022 (H1N1) antigen 0.03 MG/ML / influenza B virus B/Michigan/01/2021 antigen 0.03 MG/ML / influenza B virus B/Phuket/3073/2013 antigen 0.03 MG/ML Prefilled Syringe [Fluzone Quadrivalent 2025-2026] | SBD | 25 |
| 2719474 | influenza A virus A/Croatia/10136RV/2023 (H3N2) antigen 0.03 MG/ML / influenza A virus A/Victoria/4897/2022 (H1N1) antigen 0.03 MG/ML / influenza B virus B/Michigan/01/2021 antigen 0.03 MG/ML / influenza B virus B/Phuket/3073/2013 antigen 0.03 MG/ML Injectable Suspension [Fluzone Quadrivalent 2025-2026] | SBD | 25 |
| 2709119 | 0.5 ML influenza A virus A/Croatia/10136RV/2023 (H3N2) antigen 0.03 MG/ML / influenza A virus A/Victoria/4897/2022 (H1N1) antigen 0.03 MG/ML / influenza B virus B/Michigan/01/2021 antigen 0.03 MG/ML / influenza B virus B/Phuket/3073/2013 antigen 0.03 MG/ML Prefilled Syringe | SCD | 25 |
| 2709125 | influenza A virus A/Croatia/10136RV/2023 (H3N2) antigen 0.03 MG/ML / influenza A virus A/Victoria/4897/2022 (H1N1) antigen 0.03 MG/ML / influenza B virus B/Michigan/01/2021 antigen 0.03 MG/ML / influenza B virus B/Phuket/3073/2013 antigen 0.03 MG/ML Injectable Suspension | SCD | 25 |
| 2719475 | Fluzone Quadrivalent 2025-2026 vaccine 0.5 ML Prefilled Syringe | SY | 25 |
| 2719474 | Fluzone Quadrivalent 2025-2026 vaccine Injectable Suspension | SY | 25 |
| 2709119 | influenza virus vaccine 2025 (quadrivalent - Croatia/Victoria/Michigan/Phuket) 0.5 ML Prefilled Syringe | SY | 25 |
| 2709125 | influenza virus vaccine 2025 (quadrivalent - Croatia/Victoria/Michigan/Phuket) Injectable Suspension | SY | 25 |
| Product concept | Relation | Version | Effective |
|---|---|---|---|
| 726062af-1135-4707-a1d7-57256991bbf9 | Product name | 2 | 20250226 |
| 19c71a3d-ed9c-166b-a7e5-38c250c35631 | Product name | 1 | 20140508 |
| Package NDC | Product | Description | Form | Quantity | Strength | SPL version |
|---|---|---|---|---|---|---|
| 49281-541-15 | Fluzone Quadrivalent Northern Hemisphere | 1 in 1 PACKAGE | INJECTION, SUSPENSION | 1 | 25 | |
| 49281-541-78 | Fluzone Quadrivalent Northern Hemisphere | 5 mL in 1 VIAL, MULTI-DOSE | INJECTION, SUSPENSION | 5 | 25 | |
| 49281-926-50 | Fluzone Quadrivalent Northern Hemisphere | 10 in 1 PACKAGE | INJECTION, SUSPENSION | 10 | 25 | |
| 49281-926-88 | Fluzone Quadrivalent Northern Hemisphere | 0.5 mL in 1 SYRINGE, GLASS | INJECTION, SUSPENSION | 0.5 | 25 |
| Ingredient | Type | UNII | SPL version | Uploaded |
|---|---|---|---|---|
| INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-179A (H1N1) ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE INGREDIENT | XQO8062U6R | 1 | |
| INFLUENZA A VIRUS A/SWITZERLAND/9715293/2013 NIB-88 (H3N2) ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE INGREDIENT | 0S33AL4WWP | 1 | |
| INFLUENZA B VIRUS B/BRISBANE/60/2008 ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE INGREDIENT | W45Z4CJE2J | 1 | |
| INFLUENZA B VIRUS B/PHUKET/3073/2013 ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE INGREDIENT | B93BQX9789 | 1 | |
| INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-179A (H1N1) HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE MOIETY | C8E791RO82 | 1 | |
| INFLUENZA A VIRUS A/SWITZERLAND/9715293/2013 NIB-88 (H3N2) HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE MOIETY | N5LV3U272G | 1 | |
| INFLUENZA B VIRUS B/BRISBANE/60/2008 HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE MOIETY | 166D8OWM7B | 1 | |
| INFLUENZA B VIRUS B/PHUKET/3073/2013 HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) | ACTIVE MOIETY | 9HB0XUS9TM | 1 | |
| FORMALDEHYDE | INACTIVE INGREDIENT | 1HG84L3525 | 1 | |
| OCTOXYNOL-9 | INACTIVE INGREDIENT | 7JPC6Y25QS | 1 | |
| THIMEROSAL | INACTIVE INGREDIENT | 2225PI3MOV | 1 |
Every source-derived product name is available through these pages.
| Product NDC | Package NDC |
|---|---|
| 49281-541 | 49281-541-78, 49281-541-15 |
| 49281-926 | 49281-926-88, 49281-926-50 |
Every source-derived ingredient row is available through these pages.
Inactive Ingredient Database values describe FDA-listed use contexts. The match method and ambiguity count are shown because ingredient names, routes, and dosage forms are not always unique. Browse recovered IID releases and source provenance.
| DailyMed ingredient | IID ingredient | UNII | Dosage form / route | Potency | Maximum daily exposure | Match |
|---|---|---|---|---|---|---|
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | INJECTION / INTRAVENOUS | 0.3 mg | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SOLUTION / NASAL | 0.01 mg/1ml | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | DROPS / NASAL | 0.01 mg/1ml | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | LOTION / TOPICAL | NA | ||
| OCTOXYNOL-9 | OCTOXYNOL-9 | 7JPC6Y25QS | GEL / TOPICAL | 2 mg | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SUSPENSION / OPHTHALMIC | NA | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | DROPS / AURICULAR (OTIC) | NA | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SOLUTION / AURICULAR (OTIC) | 0.01 %w/w | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | INJECTION / INTRAMUSCULAR | 0.3 mg | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SUSPENSION/ DROPS / OPHTHALMIC | 1 %v/v | ||
| OCTOXYNOL-9 | OCTOXYNOL-9 | 7JPC6Y25QS | LOTION / TOPICAL | 5 mg | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SUSPENSION / AURICULAR (OTIC) | 0.01 %w/v | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | INJECTION / SUBCUTANEOUS | NA | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SOLUTION/ DROPS / OPHTHALMIC | NA | ||
| OCTOXYNOL-9 | OCTOXYNOL-9 | 7JPC6Y25QS | SPONGE / TOPICAL | 5 %w/w | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | SOLUTION / OPHTHALMIC | 0.01 %w/v | ||
| THIMEROSAL | THIMEROSAL | 2225PI3MOV | CREAM / TOPICAL | NA |
Adverse event summaries are temporarily unavailable. Other product information remains available.