Vaccine Information: FLUCELVAX QUADRIVALENT (PRE-FILLED SYRINGE) (Page 2 of 4)

6.2 Postmarketing Experience

The following additional adverse events have been identified during post-approval use of FLUCELVAX 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 the vaccine.

Immune system disorders: Allergic or immediate hypersensitivity reactions, including anaphylactic shock.

Nervous systems disorders: Syncope, presyncope, paresthesia.

Skin and subcutaneous tissue disorders: Generalized skin reactions including pruritus, urticaria or non-specific rash.

General disorders and administration site conditions: Extensive swelling of injected limb.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are insufficient data for FLUCELVAX QUADRIVALENT in pregnant women to inform vaccine-associated risks in pregnancy.

There were no developmental toxicity studies of FLUCELVAX QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUCELVAX (trivalent formulation) prior to mating and during gestation. The dose was 0.5 mL on each occasion (a single human dose is 0.5 mL). This study revealed no evidence of harm to the fetus due to FLUCELVAX (trivalent formulation).

Clinical Considerations

Disease-associated Maternal and/or Embryo-Fetal Risk

Pregnant women are at increased risk for severe illness due to influenza compared to non-pregnant women. Pregnant women with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.

Data

Animal Data

In a developmental toxicity study, female rabbits were administered FLUCELVAX (trivalent formulation) by intramuscular injection 1, 3, and 5 weeks prior to mating, and on gestation days 7 and 20. The dose was 0.5 mL on each occasion (a single human dose is 0.5 mL). No vaccine-related fetal malformations or variations and no adverse effects on pre-weaning development were observed in the study.

8.2 Lactation

Risk Summary

It is not known whether FLUCELVAX QUADRIVALENT is excreted in human milk. Data are not available to assess the effects of FLUCELVAX QUADRIVALENT on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLUCELVAX QUADRIVALENT and any potential adverse effects on the breastfed child from FLUCELVAX QUADRIVALENT or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine or the effects on milk production.

8.4 Pediatric Use

Safety and effectiveness have not been established in children less than 2 years of age.

8.5 Geriatric Use

Of the total number of adults who received one dose of FLUCELVAX QUADRIVALENT in clinical studies and included in the safety population (2493), 26% (660) were 65 years of age and older and 8% (194) were 75 years of age or older.

Antibody responses to FLUCELVAX QUADRIVALENT were lower in the geriatric (adults 65 years and older) population than in younger adults. [see Clinical Studies (14.3)]

11 DESCRIPTION

FLUCELVAX QUADRIVALENT (Influenza Vaccine) is a subunit influenza vaccine manufactured using cell derived candidate vaccine viruses (CVV) that are propagated in Madin Darby Canine Kidney (MDCK) cells, a continuous cell line. These cells were adapted to grow freely in suspension in culture medium. The virus is inactivated with β-propiolactone, disrupted by the detergent cetyltrimethylammonium bromide and purified through several process steps. Each of the 4 virus strains is produced and purified separately then pooled to formulate the quadrivalent vaccine.

FLUCELVAX QUADRIVALENT is a sterile, slightly opalescent suspension in phosphate buffered saline. FLUCELVAX QUADRIVALENT is standardized according to United States Public Health Service requirements for the 2021-2022 influenza season and is formulated to contain a total of 60 micrograms (mcg) hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following four influenza strains:

A/Washington/19/2020 (an A/Wisconsin/588/2019 (H1N1)pdm09-like virus);

A/Tasmania/503/2020 (an A/Cambodia/e0826360/2020 (H3N2)-like virus);

B/Darwin/7/2019 (a B/Washington/02/2019-like virus);

B/Singapore/INFTT-16-0610/2016 (a B/Phuket/3073/2013-like virus).

Each dose of FLUCELVAX QUADRIVALENT may contain residual amounts of MDCK cell protein (≤ 25.2 mcg), protein other than HA (≤ 240 mcg), MDCK cell DNA (≤ 10 ng), polysorbate 80 (≤ 1500 mcg), cetyltrimethylammonium bromide (≤ 18 mcg), and β-propiolactone (< 0.5 mcg), which are used in the manufacturing process.

FLUCELVAX QUADRIVALENT contains no egg protein or antibiotics.

FLUCELVAX QUADRIVALENT 0.5 mL pre-filled syringes contain no preservative.

FLUCELVAX QUADRIVALENT 5 mL multi-dose vials contain thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury.

The tip caps and plungers of the pre-filled syringes and the multi-dose vial stopper 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 and analysis of influenza virus isolates permits identification of yearly antigenic variants. 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 studies, HI antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of adults.2,3

Antibody against one influenza virus type or subtype confers little 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 strains in each year’s influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains representing the influenza viruses likely to circulate in the United States in the upcoming winter.

Annual influenza vaccination is recommended by the Advisory Committee on Immunization Practices because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.4

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

FLUCELVAX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals.

FLUCELVAX (trivalent formulation) administered to female rabbits had no effect on fertility. [see Use in Specific Population (8.1)]

14 CLINICAL STUDIES

14.1 Efficacy against Culture-Confirmed Influenza

The efficacy experience with FLUCELVAX is relevant to FLUCELVAX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions.

A multinational (US, Finland, and Poland), randomized, observer-blind, placebo-controlled trial was performed to assess clinical efficacy and safety of FLUCELVAX during the 2007-2008 influenza season in adults aged 18 through 49 years (Study 3). A total of 11,404 adults were enrolled to receive FLUCELVAX (N=3828), AGRIFLU (N=3676) or placebo (N=3900) in a 1:1:1 ratio. Among the overall study population enrolled, the mean age was 33 years, 55% were female, 84% were Caucasian, 7% were Black, 7% were Hispanic, and 2% were of other ethnic origin.

FLUCELVAX efficacy was assessed by the prevention of culture-confirmed symptomatic influenza illness caused by viruses antigenically matched to those in the vaccine and prevention of influenza illness caused by all influenza viruses compared to placebo. Influenza cases were identified by active and passive surveillance of influenza-like illness (ILI). ILI was defined as a fever (oral temperature ≥ 100.0°F / 38°C) and cough or sore throat. Nose and throat swab samples were collected for analysis within 120 hours of onset of an influenza-like illness in the period from 21 days to 6 months after vaccination. Overall vaccine efficacy against all influenza viral subtypes and vaccine efficacy against individual influenza viral subtypes were calculated (Tables 4 and 5, respectively).

Table 4: Vaccine Efficacy against Culture-Confirmed Influenza in Participants aged 18 through 49 years (Study 3)

1 Efficacy against influenza was evaluated over a 9-month period in 2007/2008

2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 — Relative Risk) x 100 %

3 VE success criterion: the lower limit of the one-sided 97.5% CI for the estimate of the VE relative to placebo is >40%

Study 3: NCT00630331

Number of participants per protocol Number of participants with influenza Attack Rate (%) Vaccine Efficacy (VE) 1,2
% Lower Limit of One- Sided 97.5% CI of VE 2, 3
Antigenically Matched Strains
FLUCELVAX 3776 7 0.19 83.8 61.0
Placebo 3843 44 1.14
All Culture-Confirmed Influenza
FLUCELVAX 3776 42 1.11 69.5 55.0
Placebo 3843 140 3.64
Table 5: Efficacy of FLUCELVAX against Culture-Confirmed Influenza by Influenza Viral Subtype in Participants aged 18 through 49 years (Study 3)

1 No VE success criterion was prespecified in the protocol for each individual influenza virus subtype.

2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 — Relative Risk) x 100 %;

3 There were too few cases of influenza due to vaccine-matched influenza A/H3N2 or B to adequately assess vaccine efficacy.

Study 3: NCT00630331.

FLUCELVAX (N=3776) Placebo (N=3843) Vaccine Efficacy (VE) 2
Attack Rate (%) Number of Participants with Influenza Attack Rate (%) Number of Participants with Influenza % Lower Limit of One-Sided 97.5% CI of VE 1,2
Antigenically Matched Strains
A/H3N23 0. 05 2 0 0
A/H1N1 0.13 5 1.12 43 88.2 67.4
B3 0 0 0.03 1
All Culture-Confirmed Influenza
A/H3N2 0.16 6 0.65 25 75.6 35.1
A/H1N1 0.16 6 1.48 57 89.3 73.0
B 0.79 30 1.59 61 49.9 18.2

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