Vaccine Information: FLUAD (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse events have been spontaneously reported during post-approval use of FLUAD in Europe and other regions since 1997. 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, paraesthesia, 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

There are no data to assess the concomitant administration of FLUAD with other vaccines. If FLUAD 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 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

FLUAD 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 in pregnancy.

A developmental toxicity study has been performed in female rabbits administered FLUAD prior to mating and during gestation. A 0.5 mL dose was injected on each occasion (a single human dose is 0.5 mL).

Animal Data

In a developmental toxicity study, the effect of FLUAD was evaluated in pregnant rabbits. Animals were administered FLUAD 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 is not approved for use in persons < 65 years of age. No human or animal data are available to assess the effects of FLUAD 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 in children 6 months to <72 months of age. The safety and effectiveness of FLUAD 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 have been evaluated in adults 65 years of age and older.

[See Adverse Reactions (6.1) and Clinical Studies (14)]

11 DESCRIPTION

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

FLUAD 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 three 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) and B/Victoria/705/2018 BVR-11 (a B/Washington/02/2019-like virus). FLUAD 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 is prepared by combining the three virus antigens with the MF59C.1 adjuvant. After combining, FLUAD 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 three 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 may contain trace amounts of neomycin (≤ 0.02 mcg by calculation), kanamycin (≤ 0.03 mcg by calculation) and hydrocortisone (≤ 0.0025 ng by calculation) which are used during the initial stages of manufacture, as well as residual egg proteins (˂ 0.4 mcg), formaldehyde (≤ 10 mcg), or CTAB (≤ 12 mcg).

FLUAD 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 trivalent influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains (two subtypes A and one type 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 has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. FLUAD did not affect female fertility in a rabbit developmental toxicity study [see Pregnancy (8.1)].

14 CLINICAL STUDIES

Study 1 (NCT01162122) evaluated the safety and immunogenicity of FLUAD in comparison to AGRIFLU. A total of 7,082 subjects were randomized and vaccinated with FLUAD (N=3,541) or AGRIFLU (N=3,541). The primary immunogenicity analyses were conducted on all vaccinated subjects with a blood sample collected at Day 22 (N=3,225-3,227 [91%] and 3,256- 3,259 [92%] in the FLUAD and AGRIFLU groups, respectively). Non-inferiority of FLUAD compared with AGRIFLU was demonstrated for all three vaccine strains based on pre-defined thresholds for seroconversion rate differences and GMT ratios (Table 2a & 2b).

Table 2a: Immune Responses to Each Antigen 22 Days after Vaccination with FLUAD or AGRIFLU in Adults 65 Years and Oldera

GMT = Geometric mean antibody titer; CI = Confidence Interval.

a Results obtained following vaccination with influenza vaccine formulated for the 2010-2011 season.

b N is the number of vaccinated participants with available data for the immunologic endpoint listed.

c FLUAD met non-inferiority criteria based on GMT ratios if the lower limit of the 95% CI [FLUAD:AGRIFLU] for each strain was > 0.67.

GMTs Against FLUAD and AGRIFLU Vaccine Strains FLUAD N b = 3225-3227 GMT (95% CI) AGRIFLU N b =3256-3259 GMT (95% CI) FLUAD and AGRIFLU GMT Ratio c (95% CI)
A/California/7/2009-like (H1N1) 99(93-106) 70(66-75) 1.4(1.32-1.49)
A/Perth/16/2009-like (H3N2) 272(257-288) 169(159-179) 1.61(1.52-1.7)
B/Brisbane/60/2008- like 28(26-29) 24(23-26) 1.15(1.08-1.21)
Table 2b: Immune Responses to Each Antigen 22 Days after Vaccination with FLUAD or AGRIFLU in Adults 65 Years and Oldera

a Results obtained following vaccination with influenza vaccine formulated for the 2010-2011 season.

b N is the number of vaccinated participants with available data for the immunologic endpoint listed.

d Seroconversion was defined as prevaccination HI titer <10 and postvaccination HI titer ≥ 40 or at least a 4-fold increase in HI from prevaccination HI titer ≥ 10.

e FLUAD met non-inferiority criteria based on seroconversion rate differences if the lower limit of the 95% CI

Seroconversion d for Vaccine Strains: FLUAD N b = 3225-3227 % of Subjects (95% CI) AGRIFLU N b =3256-3259 % of Subjects (95% CI) FLUAD and AGRIFLU Difference in Seroconversion Rate e (95% CI)
A/California/7/2009- like (H1N1) 69%(67%–70%) 58%(57%–60%) 9.8%(7.5%–12.1%)
A/Perth/16/2009-like (H3N2) 73%(71%–74%) 58%(56%–60%) 13.9%(11.7%–16.1%)
B/Brisbane/60/2008- like 33%(31%–35%) 29%(28%–31%) 3.2%(1.1%–5.3%)

[FLUAD -AGRIFLU] for each strain was >-10% .

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