2.1. Dosage and Schedule

 The dose, schedule, and route of administration for Fluzone, Fluzone High-Dose and Fluzone Intradermal are presented in Table 1, Table 2 and Table 3.

2.2. Administration

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

Fluzone

Fluzone is supplied in 4 presentations:

1)

Prefilled syringe (pink syringe plunger rod), 0.25 mL, for persons 6 months through 35 months of age.

2)

Prefilled syringe (clear syringe plunger rod), 0.5 mL, for persons 36 months of age and older.

3)

Single-dose vial, 0.5 mL, for persons 36 months of age and older.

4)

Multi-dose vial, 5 mL, for persons 6 months of age and older.

Fluzone High-Dose

Fluzone High-Dose is supplied in prefilled syringes (gray syringe plunger rod), 0.5 mL, for adults 65 years of age and older.

Fluzone Intradermal

Fluzone Intradermal is supplied in a single-dose prefilled microinjection system, 0.1 mL, for adults 18 through 64 years of age.

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, Fluzone High-Dose or Fluzone Intradermal should be based on careful consideration of the potential benefits and risks.

5.2. Latex

 The prefilled syringe tip caps of Fluzone and Fluzone High-Dose may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals.

5.3. Preventing and Managing Allergic Reactions

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

5.4. Altered Immunocompetence

If Fluzone, Fluzone High-Dose, or Fluzone Intradermal are administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.

5.5. Limitations of Vaccine Effectiveness

Vaccination with Fluzone, Fluzone High-Dose, or Fluzone Intradermal 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.

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 strengh 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)
• 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
• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
• General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in extremities, chest pain

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

• Gastrointestinal Disorders: Nausea, vomiting, diarrhea

8.1. Pregnancy

8.3. Nursing Mothers

It is not known whether Fluzone or Fluzone Intradermal is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fluzone or Fluzone Intradermal is administered to a nursing woman.

8.4. Pediatric Use

8.5. Geriatric Use

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 (ie, typically two type A and one type B), 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. (4)

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluzone, Fluzone High-Dose, and Fluzone Intradermal have not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14.1. Immunogenicity of Fluzone in Children 6 Months through 8 Years of Age

In a multi-center study conducted in the US, 68 children 6 months through 35 months of age given two 0.25 mL doses of Fluzone and 120 children 3 years through 8 years of age given two 0.5 mL doses of Fluzone were included in the per-protocol analysis set. The two doses (year 2006-2007 formulation) were administered 26 to 30 days apart. Females accounted for 42.6% of the participants in the 6 months through 35 months age group and 53.3% of the participants in the 3 years through 8 years age group. Most participants in the 6 months through 35 months and 3 years through 8 years age groups, respectively, were Caucasian (70.6% and 79.2%), followed by Hispanic (19.1% and 13.3%), and Black (7.4% and 4.2%).

The percentage of participants who received influenza vaccination during the previous influenza season was 54.4% for the 6 months through 35 months age group and 27.5% for the 3 years through 8 years age group. Table 9 shows seroconversion rates and the percentage of participants with an HI titer ≥1:40 one month following the second dose of Fluzone.

14.2. Immunogenicity of Fluzone and Fluzone Intradermal in Adults

Adults 18 through 64 years of age were randomized to receive Fluzone Intradermal or Fluzone (year 2008-2009 formulation) in a multi-center trial conducted in the US. The trial was open-label for administration route. For immunogenicity analyses, there were 2581 participants who received Fluzone Intradermal and 1287 participants who received Fluzone in the per protocol analysis set. There were fewer males than females (36.1% and 35.8% males in the Fluzone Intradermal and Fluzone groups, respectively). In the Fluzone Intradermal group, the mean age was 42.7 years (ranged from 18.1 through 65.0 years), and in the Fluzone group, the mean age was 42.6 years (ranged from 18.2 through 65.0 years). Most participants in the Fluzone Intradermal and Fluzone groups, respectively, were Caucasian (79.6% and 80.0%), followed by Hispanic (10.2% and 11.0%), and Black (7.7% and 6.3%). HI antibody geometric mean titers (GMTs) following Fluzone Intradermal were non-inferior to those following Fluzone for all three strains. (See Table 10) Seroconversion rates following Fluzone Intradermal were non-inferior to those following Fluzone for strains A (H1N1) and A (H3N2), but not for strain B. (See Table 11) At 28 days following vaccination with either Fluzone or Fluzone Intradermal, the percentages of subjects with a serum HI antibody titer of at least 1:40 ranged from 87% to 92%, depending on the influenza strain.

14.3. Immunogenicity of Fluzone in Adults and Geriatric Adults

In two observational studies, the immunogenicity of a single dose of Fluzone (year 1999-2000 and year 2000-2001 formulation, respectively) was evaluated in adults 19 through 59 years of age (median age: 38 years) and adults 61 through 86 years of age (median age: 72 years). The percentages of subjects with post-vaccination HI titers ≥1:40 and a four-fold increase in titer from pre-vaccination to post-vaccination were analyzed. (See Table 12)

14.4. Immunogencity of Fluzone and 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 13, 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

The prefilled syringe tip caps of Fluzone and Fluzone High-Dose may contain natural rubber latex. Vial presentations of Fluzone and the Fluzone Intradermal microinjection system do not contain latex.

16.2. Storage and Handling

Store all Fluzone, Fluzone High-Dose, and Fluzone Intradermal 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.