Flumist Product Monograph

Recent Major Label Changes

Table of Contents

Recent Major Label Changes ..................................................................................................... 2

Table of Contents ........................................................................................................................ 2

Part 1: Healthcare Professional Information ............................................................................ 4

1. 1.

   Indications ............................................................................................................................ 4

   1.1. Pediatrics ................................................................................................................... 4

   1.2. Geriatrics ................................................................................................................... 4

2. 2. Contraindications ................................................................................................................ 4
3. 4.

   Dosage and Administration ................................................................................................ 4

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 4

   4.4. Administration ............................................................................................................ 5

4. 5. Overdose .............................................................................................................................. 6
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................ 6
6. 7.

   Warnings and Precautions ................................................................................................. 7

   General .................................................................................................................................. 7

   Febrile .................................................................................................................................... 7

   Immune .................................................................................................................................. 8

   Neurologic ............................................................................................................................. 8

   Respiratory ............................................................................................................................ 8

   7.1. Special Populations ................................................................................................... 8

   7.1.1. Pregnancy ......................................................................................................... 8

   7.1.2. Breastfeeding .................................................................................................... 9

   7.1.3. Pediatrics ........................................................................................................... 9

   7.1.4. Geriatrics ........................................................................................................... 9

7. 8.

   Adverse Reactions .............................................................................................................. 9

   8.1. Adverse Reaction Overview ...................................................................................... 9

   8.2. Clinical Trial Adverse Reactions ................................................................................ 9

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................. 11

   8.5. Post-Market Adverse Reactions .............................................................................. 13

8. 9.

   Drug Interactions ............................................................................................................... 13

   9.3. Drug-Behaviour Interactions .................................................................................... 13

   9.4. Drug-Drug Interactions ............................................................................................ 13

   9.5. Drug-Food Interactions ............................................................................................ 14

   9.6. Drug-Herb Interactions ............................................................................................ 14

   9.7. Drug-Laboratory Test Interactions ........................................................................... 14

9. 10.

   Clinical Pharmacology ...................................................................................................... 14

   10.1. Mechanism of Action ............................................................................................... 14

   10.2. Pharmacodynamics ................................................................................................. 15

   10.4. Immunogenicity ....................................................................................................... 15

10. 11. Storage, Stability, and Disposal ....................................................................................... 15
11. 12. Special Handling Instructions .......................................................................................... 16

Part 2: Scientific Information ................................................................................................... 17

1. 13. Pharmaceutical Information ............................................................................................. 17
2. 14.

   Clinical Trials ..................................................................................................................... 17

   14.1. Clinical Trials by Indication ...................................................................................... 17

   Active Immunization Against Influenza ........................................................................... 17

3. 15. Microbiology ...................................................................................................................... 21
4. 16. Non-Clinical Toxicology .................................................................................................... 21

Patient Medication Information ............................................................................................... 23

INSTRUCTIONS FOR USE ........................................................................................................ 28

Part 1: Healthcare Professional Information

1. Indications

FLUMIST [influenza vaccine (live, attenuated)] is indicated for the active immunization of individuals 2-59 years of age against influenza caused by virus subtypes A, and type B contained in the vaccine.

1.1. Pediatrics

Pediatrics (2 to < 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FLUMIST in pediatric recipients has been established. Therefore, Health Canada has authorized an indication for pediatric use (see 8.2.1 Clinical Trial Adverse Reactions – Pediatrics and 14 Clinical Trials).

1.2. Geriatrics

Geriatrics (> 59 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2. Contraindications

FLUMIST [influenza vaccine (live, attenuated)] is contraindicated in individuals with:

• a history of hypersensitivity, especially anaphylactic reactions, to gentamicin, gelatin, or arginine or to any other non-medicinal ingredient in the formulation, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• severe allergic reaction (e.g., anaphylaxis) to eggs or to egg proteins (e.g., ovalbumin).
• a history of hypersensitivity to previous influenza vaccination.

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

FLUMIST [influenza vaccine (live, attenuated)] is a spray for nasal use. Do not inject FLUMIST parenterally. The recommended dose for previously vaccinated and unvaccinated children and adults is:

^a Administer as 0.1 mL per nostril

For children 2-8 years of age not previously vaccinated with seasonal influenza vaccine, 2 doses of FLUMIST, 4 weeks apart, is recommended.

Annual revaccination with influenza vaccine is recommended because immunity declines over time, and because circulating strains of influenza virus can change from year to year.

4.4. Administration

Do not use FLUMIST if damaged, for example if the plunger is loose or displaced from the sprayer or if there are any signs of leakage. Do not use FLUMIST if the liquid contents of the sprayer appears discoloured. Do not prime or attempt to remove bubbles from the sprayer.

A recipient, or their caregiver, may administer FLUMIST. In pediatric recipients (2 to under 18 years of age), FLUMIST should be administered by a caregiver. Self/caregiver-administration of FLUMIST must occur under the direct supervision of a healthcare professional and be monitored by a healthcare professional post-administration. Ensure the recipient or their caregiver has access to the INSTRUCTIONS FOR USE section for more detailed instructions on the preparation, administration and disposal of FLUMIST.

When administered by a healthcare professional, refer to the administration diagram (Figure 2) for step-by-step administration instructions. Each sprayer (shown in Figure 1) contains a single dose of FLUMIST; approximately one-half of the contents should be administered into each nostril. Once FLUMIST has been administered, the sprayer should be disposed of according to the standard procedures for medical waste (e.g., sharps container or biohazard container).

Figure 1

Figure 2

5. Overdose

No data are available relevant to overdose with FLUMIST [influenza vaccine (live, attenuated)] vaccine.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

Table 1 – Dosage Forms, Strengths, and Composition

Description

FLUMIST is supplied as a 0.2 mL pre-filled, single-use glass sprayer (see Figure 1) and is available as a package of 10 sprayers and a package of 1 sprayer.

Each 0.2 mL dose contains 10^6.5-7.5 FFU of live attenuated influenza virus reassortants of each of the three strains for the specific season. The three strains used for the 2026-2027 season are: A/Switzerland/6849/2025 (H1N1) (A/Missouri/11/2025 (H1N1)pdm09-like virus),

A/Darwin/1369/2025 (H3N2) (A/Darwin/1454/2025 (H3N2)-like virus) and B/Perth/115/2025

(Victoria lineage) (B/Tokyo/EIS13-175/2025 (Victoria lineage)-like virus).

FLUMIST [influenza vaccine (live, attenuated)] contains no preservatives (e.g., no thimerosal). The intranasal sprayer contains no latex.

7. Warnings and Precautions

General

Prior to administration of any dose of FLUMIST, the vaccine recipient should be asked about personal medical history, family medical history, recent and current health status, including immunization history, main allergies and any adverse events associated with previous immunizations (see 2 Contraindications).

As with most vaccines, supervision and treatment by an appropriately trained healthcare professional should always be readily available in case of an anaphylactic event following the administration of the vaccine.

Influenza virus is unpredictable in that significant antigenic changes may occur from time to time. At this time, current influenza virus vaccines are not effective against all possible influenza strains. Protection is highest against those strains of virus from which the vaccine is prepared or against closely related strains.

Febrile

As with other vaccines, vaccination with FLUMIST should be postponed in case of acute severe febrile illness until symptoms have abated. However, the presence of mild non-serious febrile illness (such as mild upper respiratory tract infections) should not result in the deferral of vaccination.

Immune

As with any vaccine, immunization with FLUMIST may not protect 100% of susceptible individuals.

Administration of FLUMIST, a live attenuated virus vaccine, to immunosuppressed persons should be based on careful consideration of potential benefits and risks. Data supporting the safety and efficacy of FLUMIST in immunocompromised individuals are limited. FLUMIST has been administered to approximately 170 children and adults with mild to moderate immunosuppression due to HIV infections and 10 children with mild to moderate immunosuppression due to cancer (see 14 Clinical Trials).

Vaccine recipients should be informed that FLUMIST is an attenuated live virus vaccine and has the potential for transmission to immunocompromised contacts. Vaccine recipients should attempt to avoid, whenever possible, close association with severely immunocompromised individuals (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination. Peak incidence of vaccine virus recovery occurred 2-3 days post-vaccination in clinical studies. In circumstances where contact with severely immunocompromised individuals is unavoidable, the potential risk of transmission of the influenza vaccine virus should be weighed against the risk of acquiring and transmitting wild-type influenza virus.

Those under the age of 18 years receiving aspirin therapy or aspirin-containing therapy should avoid vaccination with FLUMIST due to the association of Reye’s syndrome with aspirin and wild-type influenza infection.

Neurologic

If Guillain-Barré syndrome has occurred within 6 weeks of any prior influenza vaccination, the decision to give FLUMIST should be based on careful consideration of the potential benefits and potential risks (see 8 Adverse Reactions).

Respiratory

FLUMIST should not be administered to individuals with severe asthma (e.g. currently requiring therapy with oral glucocorticosteroids or high dose inhaled glucocorticosteroids) or active wheezing (medically attended wheezing in the seven days prior to vaccination) because these individuals have not been adequately studied in clinical trials.

7.1. Special Populations

7.1.1. Pregnancy

Studies in pregnant women have not been conducted with FLUMIST.

In the AstraZeneca Safety Pharmacovigilance Database, there were 329 case reports of live attenuated influenza vaccine (LAIV) administration to pregnant women. Pregnancy outcome was provided in 167 cases: 111/167 (66.1%) cases had healthy babies or live births; 26/167 (15.5%) cases with elective abortions; 23/167 (13.7%) cases with spontaneous abortions; and 7/167 (4.2%) cases with a non-healthy baby. A search of the US Vaccine Adverse Event Reporting System (VAERS) identified 27 case reports of LAIV administration to pregnant women. There were 3/27 (11%) cases with spontaneous abortions. The occurrence of spontaneous abortions reported is consistent with rates in the general population: approximately 10% to 20% of pregnancies result in clinically recognized spontaneous abortion.

The effects of FLUMIST on embryo-fetal and pre-weaning development were evaluated in developmental toxicity studies of pregnant rats and pregnant ferrets. No adverse effects on pregnancy, parturition, lactation or embryo-fetal development were observed in any of the studies and, in addition no adverse effects on pre-weaning development were observed in the rat studies. There were no fetal malformations or other evidence of teratogenesis observed (see 16 Non-Clinical Toxicology).

FLUMIST should be given to pregnant women only if clearly needed.

7.1.2. Breastfeeding

Studies in lactating women have not been conducted with FLUMIST.

There are very limited data from the use of FLUMIST in lactating women. Therefore, as some viruses are excreted in human milk caution should be exercised if FLUMIST is administered to nursing mothers.

No adverse effects on lactation were observed in developmental toxicity studies of pregnant rats and pregnant ferrets (see 7.1.1 Pregnancy).

7.1.3. Pediatrics

Pediatrics (< 2 years of age): Do not administer FLUMIST to children <24 months of age due to increased risk of wheezing (see 8 Adverse Reactions).

7.1.4. Geriatrics

Geriatrics (> 59 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of FLUMIST was evaluated in studies that enrolled 28,500 children and adolescents 2 to under 18 years of age and over 4,350 adults 18-59 years of age. The most common adverse reaction observed in FLUMIST clinical studies in all ages was nasal congestion/rhinorrhea.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Twelve placebo-controlled studies and three active controlled studies were pooled to evaluate solicited events in adults 18-59 years of age. Table 2 presents an analysis of solicited events occurring in at least 1% of FLUMIST recipients and includes rates for these solicited events from active controlled studies. A total of 3,301 adults 18-59 years of age received FLUMIST dosing and provided data for the pooled safety analysis in controlled studies. In these studies, solicited events were documented for 6 days post vaccination.

^a Includes Studies AV001, AV003, AV004, AV005, AV009, D145-P501, D153-P001, D153-P003, D153-P004, D153-P507, D153-P510 and DMID 98-005.

^b Includes Studies AV003, D153-P003, and D153-P004.

^c Number of subjects evaluated for the specific solicited event. Range reflects differences in data collection between pooled studies.

^d Collected as decreased activity/tiredness/weakness/malaise.

Serious Adverse Events: In the pooled safety analysis for subjects 18 to 59 years of age, 0.18% (8/4,376) of subjects exposed to FLUMIST reported at least 1 SAE during Days 0 to 28 post dose. Two gastroenteritis events were reported; all other events occurred in 1 subject each. In placebo-controlled studies, 0.18% (6/3,315) of subjects who received FLUMIST and 0.29% (5/1,740) of subjects who received placebo reported at least 1 SAE during Days 0 to 28 post dose.

Death: Among the over 4,350 adults 18-59 years of age who received FLUMIST in clinical studies, there were 2 deaths reported within 180 days of FLUMIST dosing: one due to homicide and one due to drowning. In addition, 4 subjects died within 180 days of receipt of concurrent FLUMIST and injectable influenza vaccine in a study that enrolled subjects with stable chronic obstructive pulmonary disease (COPD): two due to COPD; one due to a gastrointestinal hemorrhage; and one due to an acute myocardial infarction.

None of the deaths described in adults were considered by the medical monitor or investigator to be related to FLUMIST.

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

Seven placebo-controlled studies and four active controlled studies were pooled to evaluate solicited events occurring in children and adolescents 2 to under 18 years of age. Table 3 presents an analysis of solicited events post dose 1 occurring in at least 1% of FLUMIST recipients and includes rates for these solicited events from active controlled studies. A total of 7,336 children and adolescents 2 to under 18 years of age received at least 1 dose of FLUMIST in Year 1 of dosing in controlled studies and provided data for the pooled safety analysis.

Solicited events were those about which parents/guardians were specifically queried after vaccination with FLUMIST. In these studies, solicited events were documented within 10 days post vaccination. Solicited events post dose 2 for FLUMIST were similar to those post dose 1 and were generally observed at a lower frequency.

^a Includes Studies D153-P002, D153-P501 Year 1, D153-P502 Year 1, D153-P504 Year 1, D153-P511, D153-P513, and D153-P526. Follow-up time for Study D153-P526 was Days 0-6 post dose.

^b Includes Studies MI-CP111, D153-P002, D153-P514, and D153-P515

^c Number of subjects evaluated for the specific solicited event. Range reflects differences in data collection between pooled studies.

^d Collected as decreased activity/tiredness/weakness/malaise.

In MI-CP111, an active-controlled study, an increased rate of wheezing through 42 days was observed in children 6-23 months of age (5.9% (117/1992) FLUMIST versus 3.8% (75/1975) injectable influenza vaccine) (see 7 Warnings and Precautions). The rate of wheezing was not increased in FLUMIST recipients 24 months and older (2.1% FLUMIST versus 2.5% injectable influenza vaccine).

In the same study, an increased rate of hospitalizations (for any cause) through 180 days after final vaccination dose was observed in children 6-11 months of age (6.1% (42/684) FLUMIST versus 2.6% (18/683) injectable influenza vaccine). The rate of hospitalizations was not increased in FLUMIST recipients 12 months and older (2.5% FLUMIST versus 2.9% injectable influenza vaccine).

Serious Adverse Events: In the pooled safety analysis for subjects 2 to under 18 years of age, 0.45% (129/28,873) of subjects exposed to FLUMIST reported at least 1 serious adverse event (SAE) during Days 0 to 42 post dose in the first year of dosing. The majority of these were either infectious (0.23%) or respiratory (0.05%) events, including gastroenteritis, pneumonia, otitis media, and asthma. Of the 2.22% (182/8,202) subjects who reported at least 1 SAE during Days 0 to 180 post dose in the first year of dosing, the majority reported infectious (1.52%), respiratory (0.28%) or gastrointestinal (0.23%) events, including pneumonia, gastroenteritis, asthma, and otitis media. During Days 0 to 42 post dosing, in studies with an active control, 0.75% (32/4,245) of subjects who received FLUMIST and 1.01% (43/4,278) subjects who received injectable influenza vaccine reported at least 1 SAE, and in placebo controlled studies, 0.49% (52/10,693) of subjects who received FLUMIST and 0.55% (31/5,677) of subjects who received placebo reported at least 1 SAE. During Days 0 to 180 post dosing, in studies with an active control, 2.28% (94/4,130) of subjects who received FLUMIST and 2.45% (102/4,163) of subjects who received injectable influenza vaccine reported at least 1 SAE, and in placebo controlled studies, 2.91% (70/2,408) of subjects who received FLUMIST and 2.72% (42/1,546) subjects who received placebo reported at least 1 SAE.

Death: Among the over 40,000 children and adolescents less than 18 years of age who received FLUMIST in clinical studies, there were eight deaths reported within 180 days of FLUMIST dosing. Of the 8 deaths, 4 occurred within 42 days after the last dose of FLUMIST due to escherichial septicaemia and protein-calorie malnutrition, bronchopneumonia, accidental drowning, and accident at home and 4 occurred between 43 and 180 days after FLUMIST dosing due to diarrhea and sepsis, encephalopathy, suffocation, and posterior fossa tumor and malignant hyperthermia.

None of the deaths described in children and adolescents were considered by the medical monitor or investigator to be related to FLUMIST.

8.5. Post-Market Adverse Reactions

The following adverse reactions have been identified during post-approval use of FLUMIST. Because these reactions 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.

Congenital, familial and genetic:

Exacerbation of symptoms of mitochondrial encephalomyopathy (Leigh syndrome)

Immune system:

Hypersensitivity reactions (including anaphylactic reaction, facial edema and urticaria)

Nervous system:

Guillain-Barré syndrome, Bell’s Palsy

Respiratory, thoracic and mediastinal:

Epistaxis

Skin and subcutaneous tissue:

Rash

9. Drug Interactions

9.3. Drug-Behaviour Interactions

The interaction of FLUMIST with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

Table 4 describes the established or potential Drug-Drug interaction studies with FLUMIST.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Immune mechanisms conferring protection against influenza following receipt of FLUMIST

[influenza vaccine (live, attenuated)] are not fully understood. Likewise, naturally acquired immunity to wild-type influenza has not been completely elucidated. Serum antibodies, mucosal antibodies and influenza-specific T cells may play a role in prevention and recovery from infection.

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. 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, influenza vaccines are standardized to the WHO recommendation (northern hemisphere) to contain the strains (i.e., typically two subtype A and a type B lineage) representing the influenza viruses likely to be circulating in North America in the upcoming winter.

10.2. Pharmacodynamics

FLUMIST is designed to induce a broad immune response that resembles the response generated by wild-type influenza infection without causing influenza illness. Immune mechanisms triggered include influenza-specific serum antibodies, mucosal antibodies and cell-mediated immunity, which may contribute to protection conferred by FLUMIST. Responses to FLUMIST vary depending on age of the individual and prior experience with influenza. Additionally, young, unprimed, seronegative children show more robust antibody responses compared to older children and adults. For further information see 14 Clinical Trials.

Safety Pharmacology

A safety pharmacology study was performed using a murine model to demonstrate a lack of neurovirulence of FLUMIST vaccine strains. A murine-adapted neurotropic virus strain, A/NWS-33, was used to establish the system to study viral transmission to the central nervous system and replication. Eighteen monovalent live attenuated FLUMIST vaccine strains and one trivalent FLUMIST vaccine were used to evaluate the neurovirulent potential of these vaccine strains. Mice were inoculated with 3 log₁₀ TCID₅₀ of the neurotropic virus control intranasally; brain tissue harvested 7 days later had evidence of influenza viral RNA ranging from 7.68 x 10² to 1.05 x 10⁵ copies/mg of viral RNA. In contrast, when mice were inoculated with 5 log₁₀ TCID₅₀ of any of the type A or type B vaccine strains viral RNA was not detected. Similarly, no viral RNA was detected in the mouse brain tissue following intranasal administration of trivalent FLUMIST consisting of A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/05 (H3N2) and B/Malaysia/2506/04.

FLUMIST vaccine viruses, either in monovalent or trivalent formulation, did not exhibit any neurotropism or neurovirulence in mice.

10.4. Immunogenicity

The immunogenicity of FLUMIST is described in 14.1 Clinical Trials by Indication.

1. 11. Storage, Stability, and Disposal

Store in a refrigerator (2°C – 8°C) upon receipt and until use. DO NOT FREEZE.

A single temperature excursion up to 25°C for 12 hours has been shown to have no adverse impact on the vaccine. After a temperature excursion, the vaccine should be returned immediately to the recommended storage condition (2°C – 8°C) and used as soon as feasible. Subsequent excursions are not permitted.

Keep the nasal sprayer in the outer carton in order to protect from light.

Use the product before the expiration date on the sprayer label.

See 12 Special Handling Instructions for more detailed safety disposal instructions.

12. Special Handling Instructions

Any unused vaccine or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Influenza vaccine (live, attenuated)

Physicochemical properties: The influenza virus strains in FLUMIST are:

1. (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);
2. (b) temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strain) or 39°C (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently);
3. (c) attenuated (att) (they do not produce classic influenza-like illness in the ferret model of human influenza infection). The cumulative effect of the antigenic properties and the ca, ts, and att phenotypes is that the attenuated vaccine viruses replicate in the nasopharynx and induce protective immunity.

Product Characteristics: The spray is a colourless to pale yellow, clear to opalescent liquid; small white particles may be present.

FLUMIST [influenza vaccine (live, attenuated)] is a live, trivalent vaccine for administration by intranasal spray. FLUMIST contains three vaccine virus strains: an A/H1N1 strain, an A/H3N2 strain and a B strain. FLUMIST contains a B strain from the B/Victoria lineage. Each pre-filled FLUMIST sprayer contains a single 0.2 mL dose that contains 10 ^6.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants of each of three strains propagated in specific pathogen-free (SPF) eggs from SPF chicken flocks. The three strains used for the 2026-2027 season are: A/Switzerland/6849/2025 (H1N1) (A/Missouri/11/2025 (H1N1)pdm09-like virus), A/Darwin/1369/2025 (H3N2) (A/Darwin/1454/2025 (H3N2)-like virus) and B/Perth/115/2025 (Victoria lineage) (B/Tokyo/EIS13-175/2025 (Victoria lineage)-like virus). This influenza vaccine complies with the WHO recommendation (northern hemisphere) for the 2026-2027 influenza season.

14. Clinical Trials

14.1. Clinical Trials by Indication

Active Immunization Against Influenza

FLUMIST Clinical Studies

FLUMIST has been administered to over 30,000 subjects in controlled clinical studies over multiple years, in various regions and using different vaccine strains. Many clinical studies in the development of FLUMIST evaluated the efficacy endpoint of incidence of culture-confirmed influenza-like illness relative to placebo or injectable influenza vaccine.

Pediatric studies: The efficacy of FLUMIST has been demonstrated in 9 pediatric controlled studies comprising over 20,000 children, conducted during 7 influenza seasons. Four placebo-controlled studies included second season revaccination. FLUMIST demonstrated superiority in

3 active-controlled studies with injectable influenza vaccine. See Table 5 and Table 6 for a summary of FLUMIST efficacy results in children.

^a Number of study participants for year 1 efficacy analysis.

^b Reduction in culture-confirmed influenza-like illness relative to placebo.

^c Data presented for clinical trials AV006 and D153-P504 are for subjects who received two doses of study vaccine. In previously unvaccinated children who received one dose in year 1, efficacy was 88.8% (95% CI: 64.5, 96.5) and 88.8% (95% CI: 64.5, 96.5), respectively in AV006, and 57.7% (95% CI: 44.7, 67.9) and 56.3% (95% CI: 43.1, 66.7), respectively in D153-P504, thus supporting the need for two doses of vaccine in previously unvaccinated children.

^d In children who received 2 doses in year 1 and placebo in year 2, efficacy in year 2 was 57.0% (95% CI: 6.1, 81.7) and 35.3% (95% CI: -0.3, 58.7), respectively, in D153-P504 and 56.2% (95% CI: 30.5, 72.7) and 44.8% (95% CI: 18.2, 62.9), respectively, in D153-P501, thus supporting the need for second-season revaccination.

^e The primary circulating strain was antigenically dissimilar from the H3N2 strain represented in the vaccine; efficacy against the mismatched A/H3N2 strain was 85.9% (95% CI: 75.3, 91.9).

As presented in Table 5, FLUMIST consistently demonstrated high rates of efficacy against culture-confirmed influenza illness due to matched strains and against influenza illness due to all strains regardless of antigenic match compared to placebo. During the first seasonal outbreak following FLUMIST vaccination, absolute efficacy against matched strains ranged from 62% to 93%. In analyses for all strains regardless of antigenic match, FLUMIST absolute efficacy during the first season ranged from 49% to 93%. In clinical studies AV006 and D153-P504, 1 dose of FLUMIST in previously unvaccinated children demonstrated statistically significant efficacy; however, the efficacy of two doses was higher than the efficacy of 1 dose, thus supporting the need for two doses of vaccine in previously unvaccinated children. In the 4 studies that examined the efficacy of second-season revaccination, FLUMIST efficacy ranged from 74% to 100% for matched strains, and from 47% to 87% for all strains regardless of antigenic match. Efficacy against matched strains after second-season revaccination was either the same as, or higher than, efficacy after the primary (first season) vaccination, confirming the benefit of second-season FLUMIST revaccination. In two separate studies (D154-P501 and D154-P504), 2 doses of FLUMIST in Year 1 was associated with efficacy that persisted into the subsequent season however, annual revaccination with FLUMIST is recommended because protection is lower in the second year following vaccination, and because circulating strains of influenza virus can change from year to year.

^a Age range as described in the protocol for the study.

^b Number of study participants in the per-protocol population.

^c Reduction in culture-confirmed influenza-like illness relative to injectable influenza vaccine.

^d Vaccine efficacy was 55.7% (95% CI: 39.9, 67.6) in 3,686 children 6-23 months of age and 54.4% (95% CI: 41.8, 64.5) in 4,166 children 24-59 months of age.

^e Vaccine efficacy was 64.4% (95% CI: 1.4, 88.8) in 476 children 6-23 months of age and 48.2% (95% CI: 12.7, 70.0) in 1,609 children 24-71 months of age.

In three active comparator studies involving >12,000 children, FLUMIST consistently demonstrated statistically significant superior efficacy relative to injectable, trivalent inactivated influenza vaccine against culture confirmed influenza illness caused by wild-type virus strains antigenically matched to those in the vaccine, as well as against illness caused by all strains regardless of antigenic match.

Compared to injectable, trivalent inactivated influenza vaccine, FLUMIST reduced the number of cases of culture-confirmed influenza illness by 35% to 53% for illness due to matched strains and by 32% to 55% for illness due to all strains regardless of antigenic match (see Table 6).

Adult studies: Data supporting the efficacy of FLUMIST in adults comes from 3 controlled clinical studies, including a wild-type influenza challenge study.

A published study was conducted on University campuses in Michigan, USA to analyze the safety and efficacy of FLUMIST and an injectable, trivalent inactivated influenza vaccine in adults 18 to 49 years of age. The three-year study was randomized, placebo controlled, and double-blind for vaccine versus placebo but open-label for nasal spray versus injection. In Years 1 and 2, the efficacy of FLUMIST and the injectable influenza vaccine were not statistically different. In Year 3 (2007-2008), 1,952 subjects were randomized and there was a 45% (95% CI: 3, 69) reduction in culture-confirmed cases of influenza among recipients of the injectable influenza vaccine as compared with recipients of FLUMIST.

Studies in HIV-Infected individuals: Safety and shedding of vaccine virus following FLUMIST administration were evaluated in 28 HIV-infected [median CD4 cell count of 604 cells/mm³] and 27 HIV-negative adults 18-58 years of age in a randomized, double-blind, placebo-controlled trial. In this study, there were no serious adverse events attributable to FLUMIST, and vaccine virus shedding in HIV-infected individuals was comparable to that seen in healthy populations. No adverse effects on HIV viral load or CD4 counts were identified following FLUMIST. The effectiveness of FLUMIST in preventing influenza illness in HIV-infected individuals has not been evaluated. A published study with 122 HIV-infected children 5-17 years of age receiving FLUMIST as well as stable antiretroviral therapy showed similar findings.

Study on self-administration and caregiver administration: A simulated-use assessment was conducted in 30 untrained healthy volunteers (15 adults and 15 caregivers) to evaluate the safety of self- or caregiver-administration of the vaccine. Following the instructions, all participants successfully completed the tasks and administered a full dose without errors.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology

Repeat-dose toxicity: In a single/repeat-dose toxicity study, no significant toxicity was observed in ferrets receiving intranasal inoculation of 10^6.5-7.5 FFU per strain FLUMIST, at weeks 0, 4, 14 and followed for 15 weeks total. No test-material related toxicity was observed except for increased incidence of inflammation of nasal turbinates and lymph node hyperplasia observed in the repeat dose toxicity study with FLUMIST at interim necropsy in both vaccine and saline placebo groups (likely due to intranasal inoculation three days prior to necropsy). This inflammatory response was transient; these observations were not noted during terminal necropsy.

Carcinogenicity

FLUMIST has not been evaluated for carcinogenic or mutagenic potential or potential to impair fertility.

Reproductive and developmental toxicology

In developmental toxicity studies with FLUMIST (rats and ferrets), the effect of the vaccine on embryo-fetal and pre-weaning development was evaluated in pregnant rats receiving FLUMIST. Groups of animals were administered the vaccine either once (during the period of organogenesis on gestation day 6) or twice (prior to gestation and during the period of organogenesis on gestation day 6), 250mcL/rat/occasion (approximately 110-140 human dose equivalents based on TCID50), by intranasal instillation. No adverse effects on pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. Ferrets were administered a single dose (200 mcL/ferret) of FLUMIST, either prior to implantation or during organogenesis. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in either study.

Special toxicology

Ocular Toxicity: Two ocular toxicity studies evaluated the effects of the inadvertent instillation of FLUMIST into the eyes in rabbits (Draize tests: 0.1 mL vaccine applied to eye and conjunctival sac). Both ocular toxicity studies showed that FLUMIST was well tolerated when administrated intraocular in rabbits.