2.1 Dose and Schedule

Administer Fluzone High-Dose as a single 0.5 mL dose.

2.2 Administration

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.

5.1 Guillain-Barré Syndrome

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 reference 1.)

5.2 Preventing and Managing Allergic Reactions

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of Fluzone High-Dose.

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.

5.5 Syncope

Syncope (fainting) has been reported following vaccination with Fluzone High-Dose. Procedures should be in place to avoid injury from fainting.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trial(s) of a vaccine cannot be directly compared to rates in the clinical trial(s) of another vaccine and may not reflect the rates observed in practice. 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 within7 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.

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.

6.2 Postmarketing Experience

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 thefollowing factors: severity, frequency of reporting, or strength of evidence for a causal relationship to the vaccine.

• 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, oropharyngeal pain, rhinorrhea, 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, chills
• Gastrointestinal Disorders: Vomiting, nausea, diarrhea
• Musculoskeletal and Connective Tissue Disorders: Arthralgia

8.1 Pregnancy

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.

8.2 Lactation

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.

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, 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)]

12.1 Mechanism of Action

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.

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 Adults 65 Years of Age and Older

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 were75 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.

14.2 Efficacy of Fluzone High-Dose in Adults 65 Years of Age and Older

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).

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).

16.1 How Supplied

Single-dose, prefilled syringe, without needle, 0.5 mL (NDC 49281-124-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-124-65).

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.