Children and Adolescents 6 months through 17 years of age:

Study 1 (NCT 04074928) was a randomized, observer-blind, multicenter study in children 6 months through 3 years of age. The safety population included a total of 2402 children 6 months through 3 years of age who received FLUCELVAX QUADRIVALENT (N=1597) or a US-licensed quadrivalent influenza vaccine comparator, AFLURIA QUADRIVALENT (N=805). In the safety population, 894 subjects (37.2%) were 6 months through 23 months of age, and 1508 subjects (62.8%) were 24 months through 47 months of age. The solicited safety set consisted of 2348 subjects who received FLUCELVAX QUADRIVALENT (N=1564) or a US-licensed quadrivalent influenza vaccine comparator (N=784). Study subjects received one or two doses (separated by 4 weeks) of FLUCELVAX QUADRIVALENT or the comparator vaccine depending on the subject's prior influenza vaccination history. Data for FLUCELVAX QUADRIVALENT are relevant to FLUCELVAX because both vaccines are manufactured using the same process and have overlapping compositions.

In this study, solicited local injection site and systemic adverse reactions were collected on a symptom diary card for 7 days following vaccination.

In children 6 months through 3 years of age, the incidence of local and systemic solicited adverse reactions reported by children who received FLUCELVAX QUADRIVALENT and comparator are summarized in Table 2.

In children who received two doses, the rates of solicited local and systemic adverse reactions were generally similar or lower after the second dose compared to the first dose.

All unsolicited adverse events were collected for 28 days after last vaccination. In children 6 months through 3 years of age, unsolicited adverse events were reported in 26.2% of subjects who received FLUCELVAX QUADRIVALENT and 25.7% of subjects who received the US-licensed quadrivalent influenza vaccine comparator within 28 days after last vaccination.

In children 6 months through 3 years of age, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after last vaccination) and were reported by 0.9% of the subjects who received FLUCELVAX QUADRIVALENT and 0.9% of subjects who received the US-licensed quadrivalent influenza vaccine comparator. None of the SAEs were assessed as being related to study vaccine.

Information on the safety of FLUCELVAX administered to 3346 children and adolescents 4 through 17 years of age is available from two multinational, randomized, controlled clinical studies (Studies 2- NCT 00645411 and 3- NCT 01857206). In both studies, children 9 through 17 years of age received a single dose of FLUCELVAX or a US-licensed trivalent inactivated influenza vaccine (FLUVIRIN). In study 2, all children 4 through 8 years of age received two doses of study vaccine separated by 4 weeks. In study 3, children 4 through 8 years of age received one or two doses (separated by 4 weeks) of study vaccine based on determination of the subject's prior influenza vaccination history. Among subjects enrolled in these two studies, the mean age was 8.5 years, 49% were female, and 59% were Caucasian.

Solicited adverse reactions for FLUCELVAX and the comparator trivalent influenza vaccine (FLUVIRIN) for study 2 are summarized in Table 3. In children who received a second dose of FLUCELVAX or the comparator trivalent influenza vaccine (FLUVIRIN), the incidence of adverse reactions following the second dose of vaccine were similar to those observed with the first dose.

In studies 2 and 3 combined, the frequencies of unsolicited non-serious adverse events occurring within 28 days of vaccination were present in 32% of subjects who received FLUCELVAX and in 35% of subjects who received a comparator trivalent inactivated influenza vaccine.

One case of erythema multiforme considered related to vaccination with FLUCELVAX occurred in a 5 year old male.

In the two controlled studies in children and adolescents 4 through 17 years of age, serious adverse events were monitored for 6 months after last vaccination. Serious adverse events occurring within 28 days of any vaccination were reported in <1% of subjects (8 of 3345) who received FLUCELVAX, and in <1% of subjects (5 of 1828) who received a comparator trivalent influenza vaccine . No serious adverse events occurring within 6 months post-vaccination were considered related to the study vaccine.

Additional safety data are available from Study 4 (NCT 03165617). Study 4 was a multi-season, multi-national (Australia, Estonia, Finland, Lithuania, Philippines, Poland, Spain, Thailand), randomized, observer-blind study in children and adolescents 2 through 17 years of age. The solicited safety population included a total of 4509 children and adolescents 2 through 17 years of age who received FLUCELVAX QUADRIVALENT (N=2255) or a non-influenza (meningococcal (Groups A, C, Y, and W-135) oligosaccharide diphtheria CRM197 conjugate) comparator vaccine (N=2254).

Children 2 through 8 years of age received one or two doses (separated by 4 weeks) of FLUCELVAX QUADRIVALENT or comparator vaccine depending on the subject's prior influenza vaccination history. Children in the 2-dose comparator group received non-influenza comparator as the first dose and saline placebo as the second dose. Children and adolescents 9 through 17 years of age received a single dose of FLUCELVAX QUADRIVALENT or non-influenza comparator vaccine.

In this study, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after last vaccination) and were reported by 1.1% of the children and adolescents who received FLUCELVAX QUADRIVALENT. None of the SAEs were assessed as being related to study vaccine.

Adults 18 years of age and older:

The safety of FLUCELVAX was evaluated in seven randomized, controlled studies conducted in the US, Europe and New Zealand (Study 5: NCT 00630331, Study 6: NCT 00492063, Study 7: NCT 00306527, Study 8: NCT 00264576, Study 9: NCT 00310804, Study 10: NCT number not assigned, Study 11: NCT number not assigned). The safety population includes 5709 adults 18 through 64 years of age and 572 adults 65 years of age and older administered FLUCELVAX.

In all studies, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination.

One of the seven clinical trials, Study 5 (NCT 00630331) was a randomized, double-blind, placebo-controlled study that evaluated three vaccines including: FLUCELVAX (N=3813), placebo (N=3894) and another influenza vaccine. The population was 18 through 49 years of age (mean 32.8 years), 55% were female and 84% were Caucasian. Solicited adverse reactions for FLUCELVAX and placebo are summarized in Table 4.

Study 6 (NCT 00492063) was a randomized, double-blind study comparing FLUCELVAX (N=1330) to AGRIFLU, a US-licensed trivalent inactivated influenza vaccine (N=1324) in adults 18 years of age or older. The mean age was 43.7 years of age for adults 18 through 64 years of age and 71.3 years of age for adults 65 years of age and older; 57% of subjects were female and 100% were Caucasian. The safety data observed are summarized in Table 5.

Unsolicited adverse events, including serious adverse events (SAEs), were collected for 21 days after vaccination in five studies. In adults 18 through 64 years of age (N=4038), 13% (284 out of 2266) of subjects who received FLUCELVAX and 13% (224 out of 1772) of subjects who received the comparator trivalent influenza vaccine (AGRIFLU) reported at least one unsolicited adverse event within 21 days after vaccination. The most commonly reported unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%), headache (2%) and oropharyngeal pain (2%). In adults 65 years of age and older (N=2013), 11% (110 out of 997) of subjects who received FLUCELVAX and 9% (95 out of 1016) of subjects who received the comparator trivalent influenza vaccine (AGRIFLU) reported at least one unsolicited adverse event within 21 days after vaccination. Within this age group, the most commonly reported unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%) and cough (2%). In both age groups, all other unsolicited adverse events were reported in 1% or fewer subjects.

In the seven controlled studies of FLUCELVAX, serious adverse events were collected for a duration of 21 days in two studies and for a duration of 6 to 9 months in five studies. Participants in Study 6 were revaccinated with FLUCELVAX or AGRIFLU in Study 7. Across the seven controlled studies, the rates per dose of serious adverse events among adults 18 through 64 years of age were 1% (84 out of 6388 doses) for FLUCELVAX, 1% (55 out of 5745 doses) for the comparator trivalent influenza vaccine (AGRIFLU) and 1% (37 out of 3894 doses) for placebo. The rates per dose of serious adverse events among adults 65 years of age and older were 4% (36 out of 997 doses) for FLUCELVAX and 4% (44 out of 1016 doses) for the comparator trivalent influenza vaccine (AGRIFLU).

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US 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. Data collected in a prospective Pregnancy Exposure Registry from 665 women vaccinated with FLUCELVAX QUADRIVALENT showed no evidence of a vaccine-associated increase in the risk of major birth defects and miscarriages when FLUCELVAX QUADRIVALENT is administered during any trimester of pregnancy (see Data). Data for FLUCELVAX QUADRIVALENT are relevant to FLUCELVAX because both vaccines are manufactured using the same process and have overlapping compositions.

A developmental toxicity study has been performed in female rabbits administered FLUCELVAX 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.

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

Human Data

Data from a prospective Pregnancy Exposure Registry in the US were collected from women vaccinated with FLUCELVAX QUADRIVALENT during 3 Northern Hemisphere influenza seasons (2017-18 through 2019-20) and there was no evidence of a vaccine-associated increase in the risk of major birth defects and miscarriages. A total of 665 pregnancy outcomes were reported, of which 27%, 42%, and 31% of the pregnancies were exposed to FLUCELVAX QUADRIVALENT during the 1st, 2nd, and 3rd trimester, respectively; 659 resulted in live births, 4 resulted in spontaneous pregnancy loss, 1 resulted in ectopic pregnancy, 1 resulted in elective pregnancy termination and there were no stillbirths. The prevalence rates for miscarriage and major birth defects assessed at time of birth were each 1.9% from the study. These rates of assessed outcomes in the prospective population were consistent with estimated background rates.

Animal Data

In a developmental toxicity study, female rabbits were administered FLUCELVAX 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 or on female fertility were observed in the study.

Risk Summary

It is not known whether FLUCELVAX is excreted in human milk. Data are not available to assess the effects of FLUCELVAX 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 and any potential adverse effects on the breastfed child from FLUCELVAX 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.