2.1 Dosage and Schedule

Administer FLUAD QUADRIVALENT as a single 0.5 mL intramuscular injection in adults 65 years of age and older.

2.2 Administration

• Gently shake each syringe. FLUAD QUADRIVALENT has a milky-white appearance. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit [see Description (11)]. If either condition exists, FLUAD QUADRIVALENT should not be administered.
• To use a pre-filled syringe fitted with a Luer Lok system, remove the tip cap by unscrewing it in a counter-clockwise direction. Once the tip cap is removed, attach a needle to the syringe by screwing it on in a clockwise direction until it locks. Once the needle is locked in place, remove the needle protector and administer the vaccine.
• The vaccine should be administered by intramuscular injection, preferably in the region of the deltoid muscle of the upper arm. Do not inject the vaccine in the gluteal region or areas where there may be a major nerve trunk.

5.1 Guillain-Barré Syndrome

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD 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. [see References (1)] Evidence for a causal relationship 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.

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

The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. [see Concurrent Use With Immunosuppressive Therapies (7.2)]

5.4 Syncope

Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope.

5.5 Limitations of Vaccine Effectiveness

Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against influenza disease.

6.1 Clinical Trials Experience

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

The safety of FLUAD QUADRIVALENT was evaluated in two clinical studies in 4269 elderly subjects 65 years of age and older. Study 1 (NCT02587221) was a multi-center, randomized, observer-blind, non-influenza comparator-controlled efficacy and safety study conducted in 12 countries during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons. In this study, 3381 subjects received FLUAD QUADRIVALENT and 3380 subjects received a US-licensed non-influenza comparator vaccine (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® [GlaxoSmithKline Biologicals]).

The mean age of subjects at enrollment was 72 years, 62% were female, 48% White, 34% Asian, 16% Other, 2% American Indian/Alaska Native, and 18% of Hispanic/Latino ethnicity.

Solicited local and systemic adverse reactions were collected for 7 days after vaccination in a subset of 665 subjects who received FLUAD QUADRIVALENT and 667 subjects who received the comparator vaccine. The percentages of subjects reporting solicited local adverse reactions are presented in Table 1a and systemic adverse reactions are presented in Table 1b. Onset usually occurred within the first 2 days after vaccination. The majority of solicited reactions resolved within 3 days.

Unsolicited adverse events (AEs) were collected for all subjects for 21 days after vaccination. Related unsolicited AEs were reported by 303 (9.0%) and by 261 (7.7%) of the subjects for FLUAD QUADRIVALENT and Boostrix, respectively. For FLUAD QUADRIVALENT, injection site pain and influenza-like illness were the only unsolicited adverse reactions reported in ≥ 1% of subjects (1.7% and 1.5%, respectively).

Serious adverse events (SAEs) and potentially immune-mediated adverse events of special interest (AESIs) were collected up to 366 days after vaccination. SAEs were reported by 238 (7.0%) FLUAD QUADRIVALENT recipients and 234 (6.9%) comparator recipients. There were no SAEs, AESIs or deaths in this study that were related to FLUAD QUADRIVALENT.

Study 2 (NCT03314662) was a multicenter, randomized, double-blind, comparator-controlled study conducted during the 2017-18 Northern Hemisphere influenza season. In this study, 888 subjects received FLUAD QUADRIVALENT, 444 subjects received the licensed adjuvanted trivalent vaccine (aTIV-1 - FLUAD® (trivalent formulation)) and 444 subjects received an adjuvanted trivalent influenza vaccine with an alternate B strain (aTIV-2).

The mean age of subjects at enrollment who received FLUAD QUADRIVALENT was 72.5 years. Female subjects represented 56.6% of the study population and the racial distribution of subjects was 91.6% Caucasian, 7.0% Black or African American, and ≤ 1% each for Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native or Other.

Solicited local and systemic adverse reactions reported within 7 days after vaccination were similar to those reported for Study 1. Unsolicited AEs were collected for 21 days after vaccination. Related unsolicited AEs were reported by 39 (4.4%) and by 17-19 (3.8%-4.3%) of subjects administered FLUAD QUADRIVALENT or aTIV, respectively. For FLUAD QUADRIVALENT, injection site bruising (1.0%) was the only unsolicited adverse reaction reported in ≥ 1% of subjects.

Serious AEs and AESIs were collected up to 181 days after vaccination. Within 6 months after vaccination, 37 (4.2%) FLUAD QUADRIVALENT recipients and 18-28 (4.1%-6.3%) aTIV recipients experienced an SAE. There were no SAEs, AESIs or deaths in this study that were related to the study vaccine. There were no AEs leading to withdrawal from the study.

6.2 Postmarketing Experience

In addition to the adverse reactions observed during clinical trials, the following adverse events were reported from postmarketing surveillance in individuals 65 years of age and older for FLUAD QUADRIVALENT and/or for FLUAD (trivalent formulation), which is relevant because both vaccines are manufactured using the same process and have overlapping compositions.Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish, for all events, a causal relationship to vaccine exposure.

Blood and lymphatic system disorders:

Thrombocytopenia (some cases were severe with platelet counts less than 5,000 per mm3), lymphadenopathy

Immune system disorders:

Allergic reactions including anaphylactic shock (in rare cases), anaphylaxis

Nervous system disorders:

Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, paresthesia, syncope, presyncope, dizziness

Vascular disorders:

Vasculitis which may be associated with transient renal involvement

Skin and subcutaneous tissue disorders:

Generalized skin reactions including erythema multiforme, urticaria, pruritis or non-specific rash, erythema, angioedema

Musculoskeletal and connective tissue disorders:

Muscular weakness, pain in extremity

General disorders and administration site conditions:

Extensive swelling of injected limb, injection site cellulitis-like reaction, injection site swelling, peripheral swelling, asthenia, malaise, pyrexia

7.1 Concomitant Use With Other Vaccines

No clinical data on concomitant administration of FLUAD QUADRIVALENT with other vaccines is available.

If FLUAD QUADRIVALENT is given at the same time as other injectable vaccine(s), the vaccine(s) should be administered at different injection sites.

Do not mix FLUAD QUADRIVALENT with any other vaccine in the same syringe.

7.2 Concurrent Use With Immunosuppressive Therapies

Immunosuppressive or corticosteroid therapies may reduce the immune response to FLUAD QUADRIVALENT.

8.1 Pregnancy

8.2 Lactation

FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. No human or animal data are available to assess the effects of FLUAD QUADRIVALENT on the breastfed infant or on milk production/excretion.

8.4 Pediatric Use

Safety and effectiveness of FLUAD and FLUAD QUADRIVALENT (same manufacturing process and overlapping composition with FLUAD) were evaluated in clinical trials conducted in children 6 months to <72 months of age. Data from these trials are inconclusive to demonstrate the safety and effectiveness of FLUAD QUADRIVALENT in children 6 months to <72 months of age. The safety and effectiveness of FLUAD QUADRIVALENT in infants less than 6 months of age and in children older than 72 months of age have not been evaluated.

8.5 Geriatric Use

Safety and immunogenicity of FLUAD QUADRIVALENT 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 titers induced by vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some human studies, HI antibody titers of 1:40 or greater have been associated with protection from influenza illness in up to 50% of subjects. [see References (2,3)]

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody 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, inactivated quadrivalent influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains (two subtypes A and two types B), representing the influenza viruses likely to be circulating in the United States in the upcoming influenza season.

Annual influenza vaccination is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

FLUAD QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. FLUAD (trivalent formulation) did not affect female fertility in a rabbit developmental toxicity study [see Pregnancy (8.1)].

14.1 Immunogenicity of FLUAD QUADRIVALENT

Immunogenicity of FLUAD QUADRIVALENT was evaluated in Study 1 (NCT02587221), a randomized, observer-blind, non-influenza comparator-controlled multicenter efficacy study conducted in 12 countries during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons. In this study, elderly subjects 65 years of age and older received one dose of either FLUAD QUADRIVALENT (N=3379) or a US-licensed non-influenza comparator vaccine (Boostrix; N=3382). Immunogenicity was evaluated 21 days after vaccination in a subgroup of subjects in a 4:1 ratio: FLUAD QUADRIVALENT (N=1324) and non-influenza control vaccines (N=332). In the immunogenicity set, the mean age across both vaccination groups was 72 years and females represented 59% of subjects. The racial distribution of subjects consisted of 89% Caucasian, 11% Asian and <1% American Indian or Alaska Native.

Immunogenicity endpoints measured 3 weeks after vaccination included percentage of subjects with HI titer ≥1:40 and percentage of subjects who achieved seroconversion. Success criteria required the lower bound of the 2-sided 95% CI for the proportion of subjects with an HI titer ≥1:40 to be ≥60% and for the lower bound of the 2-sided 95% CI for the proportion of subjects with seroconversion to be ≥30%. Antibody responses for all 4 strains are presented in Table 2.