FluMist Quadrivalent: Package Insert and Label Information (Page 2 of 4)

6.2 Postmarketing Experience

The following events have been spontaneously reported during post approval use of FluMist. 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 vaccine exposure.

Cardiac disorders: Pericarditis

Congenital, familial, and genetic disorders: Exacerbation of symptoms of mitochondrial encephalomyopathy (Leigh syndrome)

Gastrointestinal disorders: Nausea, vomiting, diarrhea

Immune system disorders: Hypersensitivity reactions (including anaphylactic reaction, facial edema, and urticaria)

Nervous system disorders: Guillain-Barré syndrome, Bell’s Palsy, meningitis, eosinophilic meningitis, vaccine-associated encephalitis

Respiratory, thoracic, and mediastinal disorders: Epistaxis

Skin and subcutaneous tissue disorders: Rash

7 DRUG INTERACTIONS

7.1 Aspirin Therapy

Do not administer FluMist Quadrivalent to children and adolescents through 17 years of age who are receiving aspirin therapy or aspirin-containing therapy because of the association of Reye’s syndrome with aspirin and wild-type influenza [see Contraindications (4.2)]. Avoid aspirin-containing therapy in these age groups during the first 4 weeks after vaccination with FluMist Quadrivalent unless clearly needed.

7.2 Antiviral Agents Against Influenza A and/or B

Antiviral drugs that are active against influenza A and/or B viruses may reduce the effectiveness of FluMist Quadrivalent if administered within 48 hours before, or within 2 weeks after vaccination. The concurrent use of FluMist Quadrivalent with antiviral agents that are active against influenza A and/or B viruses has not been evaluated. If antiviral agents and FluMist Quadrivalent are administered concomitantly, revaccination should be considered when appropriate.

7.3 Concomitant Administration with Inactivated Vaccines

The safety and immunogenicity of FluMist Quadrivalent when administered concomitantly with inactivated vaccines have not been determined. Studies of FluMist and FluMist Quadrivalent excluded subjects who received any inactivated or subunit vaccine within two weeks of enrollment.

7.4 Concomitant Administration with Other Live Vaccines

Concomitant administration of the trivalent formulation of FluMist with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) and the Varicella Vaccine Live (manufactured by Merck & Co., Inc.) was studied in children 12 through 15 months of age [see Clinical Studies (14.5)]. Concomitant administration of the MMR and the varicella vaccine with the trivalent or quadrivalent FluMist formulations has not been studied in children older than 15 months of age.

7.5 Intranasal Products

There are no data regarding co-administration of FluMist Quadrivalent with other intranasal preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

FluMist Quadrivalent is not absorbed systemically following intranasal administration and maternal use is not expected to result in fetal exposure to the drug.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women infected with seasonal influenza are at increased risk of severe illness associated with influenza infection compared with 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 and reproductive toxicity study, female rats were administered FluMist Quadrivalent either three times (during the period of organogenesis) or six times (prior to gestation and during the period of organogenesis), 200 microliter/rat/occasion (approximately 150 human dose equivalents), by intranasal instillation revealing no evidence of impaired fertility or harm to the fetus due to FluMist Quadrivalent.

8.2 Lactation

Risk Summary

FluMist is not absorbed systemically by the mother following intranasal administration and breastfeeding is not expected to result in exposure of the child to FluMist.

8.4 Pediatric Use

Safety and effectiveness of FluMist Quadrivalent in children 24 months of age and older is based on data from FluMist clinical studies and a comparison of post-vaccination antibody titers between persons who received FluMist Quadrivalent and those who received FluMist [see Clinical Studies (14.1, 14.2)]. FluMist Quadrivalent is not approved for use in children younger than 24 months of age because use of FluMist in children 6 through 23 months has been associated with increased risks of hospitalization and wheezing in clinical trials [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

8.5 Geriatric Use

FluMist Quadrivalent is not approved for use in persons 65 years of age and older because in a clinical study (AV009), effectiveness of FluMist to prevent febrile illness was not demonstrated in adults 50 through 64 years of age [see Clinical Studies (14.3)]. In this study, solicited events among individuals 50 through 64 years of age were similar in type and frequency to those reported in younger adults. In a clinical study of FluMist in persons 65 years of age and older, subjects with underlying high-risk medical conditions (N = 200) were studied for safety. Compared to controls, FluMist recipients had a higher rate of sore throat.

11 DESCRIPTION

FluMist Quadrivalent (Influenza Vaccine Live, Intranasal) is a live quadrivalent vaccine for administration by intranasal spray. FluMist Quadrivalent contains four vaccine virus strains: an A/H1N1 strain, an A/H3N2 strain and two B strains. FluMist Quadrivalent contains B strains from both the B/Yamagata/16/88 and the B/Victoria/2/87 lineages. FluMist Quadrivalent is manufactured according to the same process as FluMist.

The influenza virus strains in FluMist Quadrivalent are (a) cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wild-type influenza viruses); (b) temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently); and (c) attenuated (att) (i.e., they do not produce classic influenza-like illness in the ferret model of human influenza infection).

No evidence of reversion has been observed in the recovered vaccine strains that have been tested (135 of possible 250 recovered isolates) using FluMist [see Clinical Pharmacology (12.2)]. For each of the four reassortant strains in FluMist Quadrivalent, the six internal gene segments responsible for ca , ts , and att phenotypes are derived from a master donor virus (MDV), and the two segments that encode the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant wild-type influenza viruses. Thus, the four viruses contained in FluMist Quadrivalent maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses. For the Type A MDV, at least five genetic loci in three different internal gene segments contribute to the ts and att phenotypes. For the Type B MDV, at least three genetic loci in two different internal gene segments contribute to both the ts and att properties; five genetic loci in three gene segments control the ca property.

Each of the reassortant strains in FluMist Quadrivalent express the HA and NA of wild- type viruses that are related to strains expected to circulate during the 2022-2023 influenza season. Three of the viruses (A/H1N1, A/H3N2 and one B strain) have been recommended by the United States Public Health Service (USPHS) for inclusion in the annual trivalent and quadrivalent influenza vaccine formulations. An additional B strain has been recommended by the USPHS for inclusion in the quadrivalent influenza vaccine formulation.

Specific pathogen-free (SPF) eggs are inoculated with each of the reassortant strains and incubated to allow vaccine virus replication. The allantoic fluid of these eggs is harvested, pooled, and then clarified by filtration. The virus is concentrated by ultracentrifugation and diluted with stabilizing buffer to obtain the final sucrose and potassium phosphate concentrations. The viral harvests are then sterile filtered to produce the monovalent bulks. Each lot is tested for ca , ts , and att phenotypes and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. Monovalent bulks from the four strains are subsequently blended and diluted as required to attain the desired potency with stabilizing buffers to produce the quadrivalent bulk vaccine. The bulk vaccine is then filled directly into individual sprayers for nasal administration.

Each pre-filled refrigerated FluMist Quadrivalent sprayer contains a single 0.2 mL dose. Each 0.2 mL dose contains 106.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants of each of the four strains: A/Victoria/1/2020 (H1N1) (an A/Victoria/2570/2019 (H1N1)pdm09 — like virus), A/Norway/16606/2021 (H3N2) (an A/Darwin/9/2021 (H3N2) — like virus), B/Phuket/3073/2013 (B/Yamagata lineage), and B/Austria/1359417/2021 (B/Victoria lineage). Each 0.2 mL dose also contains 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, and 0.96 mg/dose monobasic potassium phosphate. Each dose contains residual amounts of ovalbumin (< 0.024 mcg/dose), and may also contain residual amounts of gentamicin sulfate (< 0.015 mcg/mL), and ethylenediaminetetraacetic acid (EDTA) (< 2.3 mcg/dose). FluMist Quadrivalent contains no preservatives.

The tip attached to the sprayer is equipped with a nozzle that produces a fine mist that is primarily deposited in the nose and nasopharynx. FluMist Quadrivalent is a colorless to pale yellow suspension and is clear to slightly cloudy.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Immune mechanisms conferring protection against influenza following receipt of FluMist Quadrivalent vaccine are not fully understood; serum antibodies, mucosal antibodies, and influenza-specific T cells may play a role.

FluMist and FluMist Quadrivalent contain live attenuated influenza viruses that must infect and replicate in cells lining the nasopharynx of the recipient to induce immunity. Vaccine viruses capable of infection and replication can be cultured from nasal secretions obtained from vaccine recipients (shedding) [see Pharmacodynamics (12.2)].

12.2 Pharmacodynamics

Shedding Studies

Shedding of vaccine viruses within 28 days of vaccination with FluMist was evaluated in (1) multi-center Study MI‑CP129 which enrolled healthy individuals 6 through 59 months of age (N = 200); and (2) multi-center Study FM026 which enrolled healthy individuals 5 through 49 years of age (N = 344). In each study, nasal secretions were obtained daily for the first 7 days and every other day through either Day 25 and on Day 28 or through Day 28. In Study MI‑CP129, individuals with a positive shedding sample at Day 25 or Day 28 were to have additional shedding samples collected every 7 days until culture negative on 2 consecutive samples. Results of these studies are presented in Table 5.

Table 5: Characterization of Shedding with FluMist in Specified Age Groups by Frequency, Amount, and Duration (Study MI-CP129* and Study FM026)
*
NCT00344305; see www.clinicaltrials.gov
NCT00192140; see www.clinicaltrials.gov
Proportion of subjects with detectable virus at any time point during the 28 days.
§
Peak titer at any time point during the 28 days among samples positive for a single vaccine virus.
FluMist and FluMist Quadrivalent are not approved for use in children younger than 24 months of age [see Adverse Reactions (6.1)].
#
A single subject who shed previously on Days 1-3; TCID50 /mL was less than 1.5 log10 on Day 23.
Þ
A single subject who did not shed previously; TCID50 /mL was less than 1.5 log10 .
ß
A single subject who did not shed previously; TCID50 /mL was less than 1.0 log10 .

Age

Number of Subjects

% Shedding

Peak Titer (TCID50 /mL) §

% Shedding After Day 11

Day of Last Positive Culture

6-23 months 24-59 months5-8 years9-17 years18-49 years

99100102126115

8969502920

< 5 log10 < 5 log10 < 5 log10 < 4 log10 < 3 log10

7.01.02.91.60.9

Day 23# Day 25Þ Day 23ß Day 28ß Day 17ß

The highest proportion of subjects in each group shed one or more vaccine strains on Days 2-3 post vaccination. After Day 11 among individuals 2 through 49 years of age (n = 443), virus titers did not exceed 1.5 log10 TCID50 /mL.

Studies in Immunocompromised Individuals

Safety and shedding of vaccine virus following FluMist administration were evaluated in 28 HIV-infected adults [median CD4 cell count of 541 cells/mm3 ] and 27 HIV-negative adults 18 through 58 years of age. No serious adverse events were reported during the one-month follow-up period. Vaccine strain (type B) virus was detected in 1 of 28 HIV-infected subjects on Day 5 only, and in none of the HIV-negative FluMist recipients.

Safety and shedding of vaccine virus following FluMist administration were also evaluated in children in a randomized (1:1), cross-over, double-blind, AF-SPG placebo-controlled trial in 24 HIV-infected children [median CD4 cell count of 1013 cells/mm3 ] and 25 HIV-negative children 1 through 7 years of age, and in a randomized (1:1), open-label, inactivated influenza vaccine-controlled trial in 243 HIV-infected children and adolescents 5 through 17 years of age receiving stable anti-retroviral therapy. Frequency and duration of vaccine virus shedding in HIV-infected individuals were comparable to that seen in healthy individuals. No adverse effects on HIV viral load or CD4 counts were identified following FluMist administration. In the 5 through 17 year old age group, one inactivated influenza vaccine recipient and one FluMist recipient experienced pneumonia within 28 days of vaccination (days 17 and 13, respectively). The effectiveness of FluMist and FluMist Quadrivalent in preventing influenza illness in HIV-infected individuals has not been evaluated.

Twenty mild to moderately immunocompromised children and adolescents 5 through 17 years of age (receiving chemotherapy and/or radiation therapy or who had received chemotherapy in the 12 weeks prior to enrollment) were randomized 1:1 to receive FluMist or AF-SPG placebo. Frequency and duration of vaccine virus shedding in these immunocompromised children and adolescents were comparable to that seen in healthy children and adolescents. The effectiveness of FluMist and FluMist Quadrivalent in preventing influenza illness in immunocompromised individuals has not been evaluated.

Transmission Study

A prospective, randomized, double-blind, placebo-controlled trial was performed in a daycare setting in children younger than 3 years of age to assess the transmission of vaccine viruses from a vaccinated individual to a non-vaccinated individual. A total of 197 children 8 through 36 months of age were randomized to receive one dose of FluMist (N = 98) or AF-SPG placebo (N = 99). Virus shedding was evaluated for 21 days by culture of nasal swab specimens. Wild-type A (A/H3N2) influenza virus was documented to have circulated in the community and in the study population during the trial, whereas Type A (A/H1N1) and Type B strains did not.

At least one vaccine strain was isolated from 80% of FluMist recipients; strains were recovered from 1-21 days post vaccination (mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca) and temperature-sensitive (ts) phenotypes were preserved in 135 tested of 250 strains isolated at the local laboratory. Ten influenza isolates (9 influenza A, 1 influenza B) were cultured from a total of seven placebo subjects. One placebo subject had mild symptomatic Type B virus infection confirmed as a transmitted vaccine virus by a FluMist recipient in the same playgroup. This Type B isolate retained the ca , ts , and att phenotypes of the vaccine strain and had the same genetic sequence when compared to a Type B virus cultured from a vaccine recipient within the same playgroup. Four of the influenza Type A isolates were confirmed as wild-type A/Panama (H3N2). The remaining isolates could not be further characterized.

Assuming a single transmission event (isolation of the Type B vaccine strain), the probability of a young child acquiring vaccine virus following close contact with a single FluMist vaccinee in this daycare setting was 0.58% (95% CI: 0, 1.7) based on the Reed-Frost model. With documented transmission of one Type B in one placebo subject and possible transmission of Type A viruses in four placebo subjects, the probability of acquiring a transmitted vaccine virus was estimated to be 2.4% (95% CI: 0.13, 4.6) using the Reed-Frost model.

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