Vaccine Information: FLUAD QUADRIVALENT (Page 2 of 3)

6.2. Postmarketing Experience

There are no postmarketing data available for FLUAD QUADRIVALENT. However, the post-marketing experience with FLUAD (trivalent formulation) is relevant to FLUAD QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions.

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 the vaccine.

Blood and lymphatic system disorders:

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

General disorders and administration site conditions:

Extensive swelling of injected limb lasting more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week)

Immune system disorders:

Allergic reactions including anaphylactic shock, anaphylaxis, and angioedema

Musculoskeletal and connective tissue disorders:

Muscular weakness

Nervous system disorders:

Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, parasthesia, syncope, presyncope

Skin and subcutaneous tissue disorders:

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

Vascular disorders:

Vasculitis, renal vasculitis

7 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

Risk Summary

FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. There are insufficient human data to establish whether there is a vaccine-associated risk with use of FLUAD QUADRIVALENT in pregnancy.

There were no developmental toxicity studies of FLUAD QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUAD (trivalent formulation) prior to mating and during gestation. A 0.5 mL dose was injected on each occasion (a single human dose is 0.5 mL). (see 8.1 Animal Data).

Animal Data

In a developmental toxicity study, the effect of FLUAD (trivalent formulation) was evaluated in pregnant rabbits. Animals were administered FLUAD (trivalent formulation) by intramuscular injection twice prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL (45 mcg)/rabbit/occasion. No vaccine-related fetal malformations or variations and no adverse effects on pre-weaning development were observed in the study.

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)]

11 DESCRIPTION

FLUAD QUADRIVALENT (Influenza Vaccine, Adjuvanted), a sterile injectable emulsion for intramuscular use, is a quadrivalent, inactivated influenza vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus.

FLUAD QUADRIVALENT is standardized according to United States Public Health Service requirements and each 0.5 mL dose is formulated to contain 15 mcg of hemagglutinin (HA) from each of the following four influenza strains recommended for the 2020-2021 influenza season: A/Victoria/2454/2019 IVR-207 (an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus), A/Hong Kong/2671/2019 IVR-208 (an A/Hong Kong/2671/2019 (H3N2)-like virus), B/Victoria/705/2018 BVR-11 (a B/Washington/02/2019-like virus), B/Phuket/3073/2013 BVR-1B (a B/Phuket/3073/2013-like virus).

FLUAD QUADRIVALENT also contains MF59C.1 adjuvant (MF59®), a squalene based oil-in-water emulsion.

Each of the strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with formaldehyde. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of cetyltrimethylammonium bromide (CTAB). The antigen preparation is further purified.

FLUAD QUADRIVALENT is prepared by combining the four virus antigens with the MF59C.1 adjuvant. After combining, FLUAD QUADRIVALENT is a sterile, milky-white injectable emulsion supplied in single-dose pre-filled syringes containing 0.5 mL dose. Each 0.5 mL dose contains 15 mcg of hemagglutinin (HA) from each of the four recommended influenza strains and MF59C.1 adjuvant (9.75 mg squalene, 1.175 mg of polysorbate 80, 1.175 mg of sorbitan trioleate, 0.66 mg of sodium citrate dihydrate and 0.04 mg of citric acid monohydrate) at pH 6.9-7.7.

FLUAD QUADRIVALENT may contain trace amounts of neomycin (≤ 0.02 mcg by calculation), kanamycin (≤ 0.03 mcg by calculation) and hydrocortisone (≤ 0.005 ng by calculation) which are used during the initial stages of manufacture, as well as residual egg protein (ovalbumin) (≤ 1.0 mcg), formaldehyde (≤ 10 mcg) or CTAB (≤ 18 mcg).

FLUAD QUADRIVALENT does not contain a preservative. The syringe, syringe plunger stopper and tip caps are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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.

Table 2: Immune Responses 21 Days After Vaccination with FLUAD QUADRIVALENT or a Non-Influenza Comparator Vaccine in Elderly Subjects 65 years of Age and Older (Study 1)

Abbreviations: CI=Confidence Interval, N=number of subjects in full analysis immunogenicity set.

Non-Influenza Comparator Vaccine = combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® (GlaxoSmithKline Biologicals)

b Seroconversion is defined as a pre-vaccination HI titer <1:10 and post-vaccination HI titer ≥ 1:40 or at least a 4-fold increase in HI from pre-vaccination HI titer ≥ 1:10. Success criteria: the LB of the 95% CI for the SCR must be ≥30%.

Strain Proportion of subjects with HI titer ≥1:40 a (95% CI) Fluad QUADRIVALENT N=1324 Proportion of subjects with HI titer ≥1:40 a (95% CI) Non-Influenza Comparator Vaccine N=332 Seroconversion b (95% CI) Fluad QUADRIVALENT N=1324 Seroconversion b (95% CI) Non-Influenza Comparator Vaccine N=332
A/H1N1 96.2% (95.1%, 97.2%) 46.7%(41.2%, 52.2%) 78.0%(75.7%, 80.2%) 2.1%(0.9%, 4.3%)
A/H3N2 95.6%(94.4%, 96.7%) 41.7%(36.3%, 47.2%) 84.6%(82.5%, 86.5%) 3.9%(2.1%, 6.6%)
B/Yamagata 79.2%(77.0%, 81.4%) 21.5%(17.2%, 26.4%) 60.8%(58.1%, 63.4%) 3.6%(1.9%, 6.3%)
B/Victoria 81.6%(79.4%, 83.7%) 18.4%(14.4%, 23.0%) 65.5%(62.9%, 68.1%) 2.1%(0.9%, 4.3%)

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