The following Structured Product Label (SPL) was submitted to the FDA by Sanofi Pasteur Inc. for the product Fluzone High Dose Northern Hemisphere (NDC 49281-125). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2 dosage and administration, 2.1 dose and schedule, 2.2 administration, 3 dosage forms and strengths, 4 contraindications, 5.1 guillain-barré syndrome, 5.2 preventing and managing allergic reactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Fluzone® High-Dose is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus contained in the vaccine.
Fluzone High-Dose is approved for use in persons 65 years of age and older.
For intramuscular use
Administer Fluzone High-Dose as a single 0.5 mL dose.
Fluzone High-Dose is a colorless opalescent liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exist, the vaccine should not be administered.
Before administering a dose of vaccine, shake the prefilled syringe.
Administer Fluzone High-Dose intramuscularly.
Fluzone High-Dose is an injectable suspension.
A single dose is 0.5 mL. .
Do not administer Fluzone High-Dose to anyone with a history of 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 High-Dose should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. (See references 1.)
Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of Fluzone High-Dose.
If Fluzone High-Dose is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.
Vaccination with Fluzone High-Dose may not protect all recipients.
Syncope (fainting) has been reported following vaccination with Fluzone High-Dose. Procedures should be in place to avoid injury from fainting.
In adults ≥65 years of age, the most common (>10%) injection-site adverse reaction was pain (>35.6%); the most common solicited systemic adverse reactions were myalgia (21.4%), malaise (18.0%), and headache (16.8%).
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. Two clinical studies have evaluated the safety of Fluzone High-Dose.
Study 1 (NCT00391053) was a multi-center, double-blind trial conducted in the US. In this study, adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2006–2007 formulation). The study compared the safety and immunogenicity of Fluzone High-Dose to those of Fluzone. The safety analysis set included 2573 Fluzone High-Dose recipients and 1260 Fluzone recipients.
Table 1 summarizes solicited injection-site reactions and systemic adverse reactions reported within 7 days post-vaccination via diary cards. Onset was usually within the first 3 days after vaccination and a majority of the reactions resolved within 3 days. Solicited injection-site reactions and systemic adverse reactions were more frequent after vaccination with Fluzone High-Dose compared to Fluzone.
| Fluzone High-Dose (N N is the number of vaccinated participants with available data for the reactions listed =2569–2572)Percentage | Fluzone (N Percentage | |||||
|---|---|---|---|---|---|---|
| Any | Moderate Moderate - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection- site erythema and Injection-site swelling: ≥2.5 cm to <5 cm; Fever: >100.4°F to ≤102.2°F; Myalgia, Malaise, and Headache: interferes with daily activities | Severe Severe - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema and Injection- site swelling: ≥5 cm; Fever: >102.2°F; Myalgia, Malaise, and Headache: prevents daily activities | Any | Moderate | Severe | |
| Injection-Site Pain | 35.6 | 3.7 | 0.3 | 24.3 | 1.7 | 0.2 |
| Injection-Site Erythema | 14.9 | 1.9 | 1.8 | 10.8 | 0.8 | 0.6 |
| Injection-Site Swelling | 8.9 | 1.6 | 1.5 | 5.8 | 1.3 | 0.6 |
| Myalgia | 21.4 | 4.2 | 1.6 | 18.3 | 3.2 | 0.2 |
| Malaise | 18.0 | 4.7 | 1.6 | 14.0 | 3.7 | 0.6 |
| Headache | 16.8 | 3.1 | 1.1 | 14.4 | 2.5 | 0.3 |
| Fever Fever - The percentage of temperature measurements that were taken by oral route or not recorded were 97.9% and 2.1%, respectively, for Fluzone High-Dose; and 98.6% and 1.4%, respectively, for Fluzone (≥99.5°F) | 3.6 | 1.1 | 0.0 | 2.3 | 0.2 | 0.1 |
Within 6 months post-vaccination, 156 (6.1%) Fluzone High-Dose recipients and 93 (7.4%) Fluzone recipients experienced a serious adverse event (SAE). No deaths were reported within 28 days post-vaccination. A total of 23 deaths were reported during Days 29 – 180 post-vaccination:
16 (0.6%) among Fluzone High-Dose recipients and 7 (0.6%) among Fluzone recipients. The majority of these participants had a medical history of cardiac, hepatic, neoplastic, renal, and/or respiratory diseases. These data do not provide evidence for a causal relationship between deaths and vaccination with Fluzone High-Dose.
Study 2 (NCT01427309) was a multi-center, double-blind post- licensure efficacy trial conducted in the US and Canada over two influenza seasons. In this study, adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2011–2012 and 2012–2013 formulations). The study compared the efficacy and safety of Fluzone High-Dose to those of Fluzone. The safety analysis set included 15,992 Fluzone High-Dose recipients and 15,991 Fluzone recipients.
Within the study surveillance period (approximately 6 to 8 months post-vaccination), 1323 (8.3%) Fluzone High-Dose recipients and 1442 (9.0%) Fluzone recipients experienced an SAE. Within 30 days post-vaccination, 204 (1.3%) Fluzone High-Dose recipients and 200 (1.3%) Fluzone recipients experienced an SAE. The majority of these participants had one or more chronic comorbid illnesses. A total of 167 deaths were reported within 6 to 8 months post-vaccination: 83 (0.5%) among Fluzone High-Dose recipients and 84 (0.5%) among Fluzone recipients. A total of 6 deaths were reported within 30 days post-vaccination: 6 (0.04%) among Fluzone High-Dose recipients and 0 (0%) among Fluzone recipients. These data do not provide evidence for a causal relationship between deaths and vaccination with Fluzone High-Dose.
The following events have been spontaneously reported during the postmarketing use of Fluzone, Fluzone High-Dose, Fluzone Quadrivalent, or Fluzone High-Dose 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 the vaccine.
Fluzone High-Dose is not approved for use in persons <65 years of age.
There are limited human data and no animal data available to establish whether there is a vaccine-associated risk with use of Fluzone High-Dose in pregnancy.
Fluzone High-Dose is not approved for use in persons <65 years of age. No human or animal data are available to assess the effects of Fluzone High-Dose on the breastfed infant or on milk production/excretion.
Safety and effectiveness of Fluzone High-Dose in persons <65 years of age have not been established.
Safety, immunogenicity, and efficacy of Fluzone High-Dose have been evaluated in adults 65 years of age and older. [See Adverse Reactions (6.1) and Clinical Studies (14)]
Fluzone High-Dose (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 High-Dose process uses an additional concentration factor after the ultrafiltration step to obtain a higher HA antigen concentration. The purified split virus from the three strains included in the vaccine are produced separately and then combined to make the trivalent formulation.
Fluzone High-Dose is an injectable suspension and is a colorless opalescent liquid.
Neither antibiotics nor preservative are used in the manufacture of Fluzone High-Dose.
The Fluzone High-Dose prefilled syringe presentation is not made with natural rubber latex.
Fluzone High-Dose is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following three influenza strains recommended for the 2023-2024 influenza season: A/Victoria/4897/2022 IVR-238 (H1N1), A/Darwin/9/2021 SAN-010 (H3N2) 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 2.
| Ingredient | Quantity (per dose) |
|---|---|
| Fluzone High-Dose 0.5 mL Dose | |
| Active Substance: Split influenza virus, inactivated strains per United States Public Health Service (USPHS) requirement : | 180 mcg HA total |
| A (H1N1) | 60 mcg HA |
| A (H3N2) | 60 mcg HA |
| B | 60 mcg HA |
| Other: | |
| Sodium phosphate-buffered isotonic sodium chloride solution | QS Quantity Sufficient to appropriate volume |
| Formaldehyde | ≤100 mcg |
| Octylphenol ethoxylate | ≤250 mcg |
| Gelatin | None |
| Preservative | None |
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. (See references 2 and 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 High-Dose has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.
Study 1 was a multi-center, double-blind pre-licensure trial conducted in the US in which adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (2006–2007 formulation). The study compared the safety and immunogenicity of Fluzone High-Dose to those of Fluzone. For immunogenicity analyses, 2576 participants were randomized to Fluzone High-Dose and 1275 participants were randomized to Fluzone. Females accounted for 51.3% of participants in the Fluzone High-Dose group and 54.7% of participants in the Fluzone group. In both groups, the mean age was 72.9 years (ranged from 65 through 97 years in the Fluzone High-Dose group and 65 through 94 years in the Fluzone group); 35% of participants in the Fluzone High-Dose group and 36% of participants in the Fluzone group were 75 years of age or older. Most participants in the Fluzone High-Dose and Fluzone groups, respectively, were White (91.7% and 92.9%), followed by Hispanic (4.8% and 3.7%), and Black (2.7% and 2.7%).
The primary endpoints of the study were HI GMTs and seroconversion rates 28 days after vaccination. Pre-specified statistical superiority criteria required that the lower limit (LL) of the 2- sided 95% CI of the GMT ratio (Fluzone High-Dose/Fluzone) be greater than 1.50 for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>0.67), and that the lower limit of the 2-sided 95% CI of the seroconversion rate difference (Fluzone High-Dose minus Fluzone) be greater than 10% for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>-10%). As shown in Table 3, statistically superior HI GMTs and seroconversion rates after vaccination with Fluzone High-Dose compared to Fluzone were demonstrated for influenza A subtypes, A (H1N1) and A (H3N2), but not for influenza type B. For strain B, non-inferiority of Fluzone High-Dose compared to Fluzone was demonstrated for both the HI GMTs and seroconversion rates.
| Influenza Strain | GMT | GMT Ratio | Seroconversion % Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28) titer ≥1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 | Difference | Met Both Pre-defined Superiority Criteria Predefined superiority criterion for seroconversion: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (Fluzone High-Dose minus Fluzone) is >10%. Predefined superiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (Fluzone High-Dose divided by Fluzone) is >1.5 | ||
|---|---|---|---|---|---|---|---|
| Fluzone High-Dose N N is the number of vaccinated participants with available data for the immunologic endpoint listed =2542–2544 | Fluzone N | Fluzone High-Dose over Fluzone (95% CI) | Fluzone High-Dose N | Fluzone N | Fluzone High-Dose minus Fluzone (95% CI) | ||
| A (H1N1) | 115.8 | 67.3 | 1.7 (1.6; 1.8) | 48.6 | 23.1 | 25.4 (22.4; 28.5) | Yes |
| A (H3N2) | 608.9 | 332.5 | 1.8 (1.7; 2.0) | 69.1 | 50.7 | 18.4 (15.1; 21.7) | Yes |
| B | 69.1 | 52.3 | 1.3 (1.2; 1.4) | 41.8 | 29.9 | 11.8 (8.6; 15.0) | No |
Study 2 was a multi-center, double-blind post-licensure efficacy trial conducted in the US and Canada in which adults 65 years of age and older were randomized (1:1) to receive either Fluzone High-Dose or Fluzone. The study was conducted over two influenza seasons (2011–2012 and 2012–2013); 53% of participants enrolled in the first year of the study were re- enrolled and re-randomized in the second year. The per-protocol analysis set for efficacy assessments included 15,892 Fluzone High-Dose recipients and 15,911 Fluzone recipients. The majority (67%) of participants in the per-protocol analysis set for efficacy had one or more high- risk chronic comorbid conditions.
In the per-protocol analysis set, females accounted for 57.2% of participants in the Fluzone High- Dose group and 56.1% of participants in the Fluzone group. In both groups, the median age was 72.2 years (range 65 through 100 years). Overall, most participants in the study were White (95%); approximately 4% of study participants were Black, and approximately 6% reported Hispanic ethnicity.
The primary endpoint of the study was the occurrence of laboratory-confirmed influenza (as determined by culture or polymerase chain reaction) caused by any influenza viral type/subtype in association with influenza-like illness (ILI), defined as the occurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature >99.0°F, chills, tiredness, headaches or myalgia. Participants were monitored for the occurrence of a respiratory illness by both active and passive surveillance, starting 2 weeks post-vaccination for approximately 7 months. After an episode of respiratory illness, nasopharyngeal swab samples were collected for analysis; attack rates and vaccine efficacy were calculated (see Table 4).
| Fluzone High-Dose N N is the number of vaccinated participants in the per-protocol analysis set for efficacy assessments =15,892n n is the number of participants with protocol-defined influenza-like illness with laboratory confirmation (%) | Fluzone N n | Relative Efficacy % (95% CI) | |
|---|---|---|---|
| Any type/subtype Primary endpoint | 227 (1.43) | 300 (1.89) | 24.2 (9.7; 36.5) The pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95% CI of the vaccine efficacy of Fluzone High-Dose relative to Fluzone > 9.1%) was met. |
| Influenza A | 190 (1.20) | 249 (1.56) | 23.6 (7.4; 37.1) |
| A (H1N1) | 8 (0.05) | 9 (0.06) | 11.0 (-159.9; 70.1) |
| A (H3N2) | 171 (1.08) | 222 (1.40) | 22.9 (5.4; 37.2) |
| Influenza B In the first year of the study the influenza B component of the vaccine and the majority of influenza B cases were of the Victoria lineage; in the second year the influenza B component of the vaccine and the majority of influenza B cases were of the Yamagata lineage | 37 (0.23) | 51 (0.32) | 27.4 (-13.1; 53.8) |
A secondary endpoint of the study was the occurrence of culture-confirmed influenza caused by viral types/subtypes antigenically similar to those contained in the respective annual vaccine formulations in association with a modified CDC-defined ILI, defined as the occurrence of a temperature >99.0°F (>37.2°C) with cough or sore throat. The efficacy of Fluzone High-Dose relative to Fluzone for this endpoint was 51.1% (95% CI: 16.8; 72.0).
Single-dose, prefilled syringe, without needle, 0.5 mL (NDC 49281-467-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-467-65).
Store Fluzone High-Dose refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen.
Do not use after the expiration date shown on the label.
See FDA-approved patient labeling (Patient Information).
Fluzone is a registered trademark of Sanofi Pasteur Inc.
Manufactured by:
Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
Patient Information Sheet
Fluzone® High-Dose
Influenza Vaccine
Please read this information sheet before getting Fluzone High-Dose vaccine. This summary is not intended to take the place of talking with your healthcare provider. If you have questions or would like more information, please talk with your healthcare provider.
What is Fluzone High-Dose vaccine?
Fluzone High-Dose is a vaccine that helps protect against influenza illness (flu).
Fluzone High-Dose vaccine is for people 65 years of age and older.
Vaccination with Fluzone High-Dose vaccine may not protect all people who receive the vaccine.
Who should not get Fluzone High-Dose vaccine?
You should not get Fluzone High-Dose vaccine if you:
Tell your healthcare provider if you have or have had:
How is Fluzone High-Dose vaccine given?
Fluzone High-Dose vaccine is given as an injection into the muscle.
What are the possible side effects of Fluzone High-Dose vaccine?
The most common side effects of Fluzone High-Dose vaccine are:
These are not all of the possible side effects of Fluzone High-Dose vaccine. 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 https://vaers.hhs.gov.
Why should I get Fluzone High-Dose vaccine instead of Fluzone vaccine?
An efficacy study in adults 65 years of age and older has demonstrated that Fluzone High-Dose vaccine offers better protection against influenza than Fluzone vaccine.
What are the ingredients in Fluzone High-Dose vaccine?
Fluzone High-Dose vaccine contains 3 killed influenza virus strains. There is no live influenza virus in Fluzone High-Dose. Fluzone High-Dose cannot cause influenza.
Other ingredients include formaldehyde and octylphenol ethoxylate.
Manufactured by: Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
NDC 49281-467-88
Influenza Vaccine
Fluzone® High-Dose
2023-2024 Formula
No Preservative
0.5 mL Single-Dose
For 65 yrs of age and older
Mfd by: Sanofi Pasteur Inc.
Rx only
For IM Use
Principal Display Panel (0.5 mL Syringe Label)
NDC 49281-467-65
FOR ADULTS
65+
Influenza Vaccine
Fluzone® High-Dose
2023-2024 Formula
Rx only
For Intramuscular Use
10 single-dose prefilled syringes 0.5 mL each
Principal Display Panel (0.5 mL Syringe Package)
* Please review the disclaimer below.
