2.1 Dose and Schedule

Fluzone High-Dose should be administered as a single 0.5 mL injection by the intramuscular route in adults 65 years and older.

2.2 Administration

Inspect Fluzone High-Dose syringes visually for particulate matter and/or discoloration prior to administration. If either of these conditions exist, the vaccine should not be administered.

Before administering a dose of vaccine, shake the prefilled syringe.

The preferred site for intramuscular injection is the deltoid muscle. 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 or subcutaneously.

Fluzone High-Dose vaccine should not be combined through reconstitution or mixed with any other 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. (1) If GBS has occurred within 6 weeks of previous influenza vaccination, the decision to give Fluzone High-Dose 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 the vaccine.

5.3 Altered Immunocompetence

If Fluzone High-Dose 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 High-Dose may not protect all recipients.

6.1 Clinical Trials Experience

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 of another vaccine, and may not reflect the rates observed in practice.

Adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (year 2006-2007 formulation) in a multi-center, double-blind trial conducted in the US. The safety analysis set included 2573 Fluzone High-Dose recipients and 1260 Fluzone recipients.

Table 1 summarizes solicited injection-site reactions and systemic adverse events 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 events were more frequent after vaccination with Fluzone High-Dose compared to Fluzone.

Within 6 months post-vaccination, 156 (6.1%) Fluzone High-Dose recipients and 93 (7.4%) Fluzone recipients experienced a serious adverse event. No deaths were reported within 28 days post-vaccination. A total of 23 deaths were reported during the period Day 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. No deaths were considered to be caused by vaccination.

6.2 Post-Marketing Experience

The following events have been spontaneously reported during the post-approval use of Fluzone or Fluzone High-Dose. 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 High-Dose.

Events Reported During Post-Approval Use of Fluzone.

• Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy
• Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema)
• Eye Disorders: Ocular hyperemia
• Nervous 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, paresthesia
• Vascular Disorders: Vasculitis, vasodilatation/flushing
• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis, cough, wheezing, throat tightness
• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
• General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in extremities, chest pain
• Gastrointestinal Disorders: Vomiting

Other Events Reported During Post-Approval Use of Fluzone High-Dose.

• Gastrointestinal Disorders: Nausea, diarrhea
• General Disorders and Administration Site Conditions: Chills

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Fluzone High-Dose. It is also not known whether Fluzone High-Dose can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fluzone High-Dose should be given to a pregnant woman only if clearly needed.

8.4 Pediatric Use

Safety and effectiveness of Fluzone High-Dose in persons <65 years of age have not been established.

8.5 Geriatric Use

Safety and immunogenicity of Fluzone High-Dose have been evaluated in adults 65 years of age and older. [See Adverse Reactions (6.1) and Clinical Studies (14)]

12.1 Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody 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 subjects. (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. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating in the US in the upcoming winter.

Annual vaccination with the current 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 High-Dose has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14.1 Immunogenicity of Fluzone High-Dose in Geriatric Adults

Adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (year 2006-2007 formulation) in a multi-center, double-blind trial conducted in the US. For immunogenicity analyses, 2,576 participants were randomized to Fluzone High-Dose and 1,275 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 Caucasian (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. There are no data demonstrating clinically relevant prevention of culture-confirmed influenza or its complications after vaccination with Fluzone High-Dose compared to Fluzone in individuals 65 years of age and older.

16.1 How Supplied

Single-dose, prefilled syringe, without needle, 0.5 mL, package of 10 (does not contain latex) NDC 49281-391-65.

16.2 Storage and Handling

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.