FluMist is indicated for the prophylaxis of influenza in individuals from 2 to less than 18 years of age.

Posology

0.2 ml (administered as 0.1 ml per nostril).

For children 2‑8 years of age who have not previously been vaccinated against seasonal influenza, a second dose should be given after an interval of at least 4 weeks.

Method of administration

Do not inject FluMist parenterally.

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.

FluMist is for nasal use, administered as a divided dose as described in Figure 1.

Figure 1:

Any unused product or waste material should be disposed of in accordance with local requirements for medical waste.

Risk in children < 24 months of age

Do not administer FluMist to children younger than 12 months. In a clinical study, an increase in hospitalisations was observed in children younger than 12 months after vaccination with FluMist. It is not recommended to administer FluMist to children 12‑23 months of age. In a clinical study, an increased rate of wheezing was observed in children 12‑23 months of age after vaccination with FluMist (see section 4.8).

Severe asthma or active wheezing

Individuals with severe asthma or active wheezing have not been adequately studied in clinical studies.

Management of acute allergic reactions

As with all vaccines, appropriate medical treatment and supervision should be readily available in case of an anaphylactic event following the administration of FluMist.

Concomitant aspirin therapy and Reye’s syndrome in children and adolescents

Those under 18 years of age receiving salicylate therapy should avoid vaccination with FluMist due to the association of Reye’s syndrome with salicylates and wild-type influenza infection.

Altered immunocompetence

FluMist has not been studied in immunocompromised individuals. Data on the safety and shedding of FluMist in immunocompromised individuals are limited (see section 5.1). FluMist administration to immunocompromised individuals should be based on careful consideration of potential benefits and risks.

Vaccination with a live vaccine

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, whenever possible, to avoid close association with severely immunocompromised individuals (e.g., bone marrow transplant recipients requiring isolation).

Those under 18 years of age receiving salicylate therapy should avoid vaccination with Flumist (see section 4.4). Do not use salicylates in children younger than 18 years of age for 4 weeks after vaccination with FluMist unless medically indicated.

FluMist may be given at the same time as other vaccines. Concurrent administration of FluMist with the Measles, Mumps and Rubella Vaccine (MMR) (1,233 children 11-23 months of age), the MMR and the Varicella Vaccine (1,245 children 12-15 months of age), and the orally administered Poliovirus Vaccine (2,503 children 6-35 months of age) has been studied (see section 5.1). Adverse events were similar to those seen in other clinical studies with FluMist. Studies did not show clinically meaningful changes in immune responses to measles, mumps, rubella, varicella, orally administered poliovirus or FluMist.

The concurrent use of FluMist with antiviral agents that are active against influenza A and/or B viruses has not been evaluated. However, based upon the potential for influenza antiviral agents to reduce the effectiveness of FluMist, it is recommended:

·        not to administer FluMist until 48 hours after the cessation of influenza antiviral therapy.

·        not to administer influenza antiviral agents until two weeks after administration of FluMist unless medically indicated.

If influenza antiviral agents and FluMist are administered concomitantly, revaccination should be considered when appropriate.

Pregnancy

There are limited data from the use of FluMist in pregnant women. There was no evidence of significant maternal adverse outcomes in 138 pregnant women who had a record of receiving FluMist in a US based health insurance claims database. In more than 300 case reports in the AstraZeneca safety database and over 150 case reports from the US Vaccine Adverse Event Reporting System of trivalent and quadrivalent version of FluMist administration to pregnant women, no unusual patterns of pregnancy complications or foetal outcomes were observed.

The effects of FluMist on embryo-foetal 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-foetal development were observed in either study and, in addition no adverse effects on pre-weaning development were observed in the rat study. There were no foetal malformations or other evidence of teratogenesis observed.

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

Breast-feeding

Available evidence suggests that FluMist is not excreted in human milk. However, because there are limited data to assess the effects of FluMist on the breast-fed infant, caution should be exercised when the vaccine is administered to a nursing woman: the developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for FluMist and any potential adverse effects on the breast-fed child from FluMist or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

The vaccine is not expected to have an effect on the ability to drive and use machines.

Overall summary of the safety profile

The safety of trivalent version of FluMist was analysed in a total of over 29,000 children and adolescents 2-17 years of age who received trivalent version of FluMist in clinical studies. Additional experience has occurred with marketed use of trivalent and quadrivalent version of FluMist.

Adverse drug reactions

Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Adverse reactions in clinical studies

Children and adolescents

Eight placebo-controlled studies (3,245 trivalent version and 868 quadrivalent version of FluMist recipients and 2,427 placebo recipients) and four active-controlled studies (4,108 trivalent version of FluMist recipients and 4,118 active-control recipients) were pooled to evaluate solicited events occurring in children and adolescents 2-17 years of age. Table 1 presents an analysis of solicited events post dose 1 occurring in trivalent and quadrivalent version of FluMist recipients with at least 2% higher rate compared to placebo and includes rates for these solicited events from active-controlled studies.

Table 1: Summary of solicited events observed within 10 days after dose 1 for the trivalent and quadrivalent version of FluMist for either placebo or active-control recipients; children and adolescents 2-17 years of age

NOTE: The adverse reaction terms that are common to both the paediatric and adult populations are highlighted in grey.

^a Includes Studies D153-P002, D153-P501 (Year 1), D153-P502 (Year 1), D153-P504 (Year 1), D153-P511, D153-P513, D153-P526 and D2560C00006. 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 MedDRA v 22.0.

^d Number of subjects evaluated for the specific solicited event.

^e Pyrexia collected as a solicited event did not occur at a 2% higher rate compared with placebo. Pyrexia did occur at a 2% higher rate compared with placebo based on a pooled analysis of adverse events of the same placebo-controlled studies (9.6% trivalent version of FluMist versus 7.5% placebo).

In an active-controlled clinical study (MI-CP111), an increased rate of hospitalisations (for any cause) through 180 days after final vaccination dose was observed in children 6‑11 months of age [6.1% (42/684) trivalent version of FluMist versus 2.6% (18/683) injectable influenza vaccine]. The rate of hospitalisations was not increased in trivalent version of FluMist recipients 12 months and older. In the same study, an increased rate of wheezing through 42 days was observed in children 6‑23 months of age [5.9% (117/1992) trivalent version of FluMist versus 3.8% (75/1975) injectable influenza vaccine]. The rate of wheezing was not increased in FluMist recipients 24 months and older. FluMist is not indicated for use in children younger than 24 months (see section 4.4).

Post-marketing experience

The following adverse reactions have been identified during post-approval use of trivalent version 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.

To report any side effect (s)

Saudi Arabia

Other GCC States:

There have been occasional reports of administration of twice the recommended dose of FluMist in the post-marketing setting. The adverse reactions reported were similar to those seen with the recommended single dose of FluMist.

Therapeutic classification

Influenza vaccines, influenza live attenuated; ATC Code: J07BB03

Mechanism of action

Immune mechanisms conferring protection against influenza following receipt of FluMist vaccine 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 of infection and in recovery from infection.

Clinical efficacy

Efficacy data in the paediatric population for FluMist consists of 9 controlled studies comprising over 20,000 children, conducted during 7 influenza seasons. Four placebo-controlled studies included second season revaccination. FluMist has demonstrated superiority in 3 active-controlled studies with injectable influenza vaccine. See Table 2 and Table 4 for a summary of FluMist efficacy results in children.

Study D153-P501

A randomised, double-blind, placebo-controlled trial (D153-P501) was performed to evaluate the efficacy of FluMist in children 12-35 months of age without high-risk medical conditions against culture-confirmed influenza illness. The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza. A total of 3,174 children were randomised 3:2 (vaccine: placebo) to receive 2 doses of study vaccine or placebo at least 28 days apart in Year 1. See Table 3 for a description of the results.

During the second year of Study D153-P501, for children who received two doses in Year 1 and one dose in Year 2, FluMist demonstrated 84.3% (95% CI: 70.1, 92.4) efficacy against culture-confirmed influenza illness due to antigenically matched wild-type influenza.

Study AV006

AV006 was a multi-centre, randomised, double-blind, placebo-controlled trial performed in U.S. children without high-risk medical conditions to evaluate the efficacy of FluMist against culture-confirmed influenza over two successive seasons. The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza in children who received two doses of vaccine in the first year and a single revaccination dose in the second year. During the first year of the study, 1,602 children 15‑71 months of age were randomised 2:1 (vaccine: placebo). In Year 2, children remained in the same treatment group as in year one and received a single dose of FluMist or placebo. See Table 3 for a description of the results.

Table 3: Efficacy^a of FluMist vs. placebo against culture-confirmed influenza illness due to antigenically matched wild-type strains (D153-P501 & AV006, Year 1)

^a D153-P501 and AV006 data are for subjects who received two doses of study vaccine.

^b Number and percent of subjects in per-protocol efficacy analysis population with culture-confirmed influenza illness.

^c Number of subjects in per-protocol efficacy analysis population of each treatment group of each study for the “any strain” analysis.

^d For D153-P501, influenza circulated through 12 months following vaccination.

^e Estimate includes A/H1N1 and A/H1N2 strains. Both were considered antigenically similar to the vaccine.

During the second year of Study AV006, the primary circulating strain was the A/Sydney/05/97 H3N2 strain, which was antigenically dissimilar from the H3N2 strain represented in the vaccine, A/Wuhan/359/95; FluMist demonstrated 87.0% (95% CI: 77.0, 92.6) efficacy against culture-confirmed influenza illness.

Table 4: FluMist relative efficacy in active-controlled paediatric studies with injectable influenza vaccine

^a M = months. Y = years.  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 illness relative to injectable influenza vaccine.

^d FluMist demonstrated 55.7% (39.9, 67.6) fewer cases than injectable influenza vaccine in 3,686 children 6‑23 months of age and 54.4% (41.8hospitali in 4,166 children 24‑59 months of age.

^e FluMist demonstrated 64.4% (1.4, 88.8) fewer cases than injectable influenza vaccine in 476 children 6‑23 months of age and 48.2% (12.7, 70.0) fewer cases in 1,609 children 24‑71 months of age.

Study MI-CP111: Paediatric comparative study

A multinational, randomised, double-blind, active-controlled trial (MI-CP111) was performed to assess the efficacy and safety of FluMist compared to an injectable influenza vaccine made by Sanofi Pasteur Inc. (active control) in children < 5 years of age. During the 2004‑2005 influenza season, a total number of 3,916 children < 5 years of age and without severe asthma, without use of bronchodilator or steroids and without wheezing within the prior 6 weeks were randomised to FluMist and 3,936 were randomised to active control. Participants were then followed through the influenza season to identify illness caused by influenza virus. As the primary endpoint, culture-confirmed modified CDC-ILI (CDC-defined influenza-like illness) was defined as a positive culture for a wild-type influenza virus associated within ±7 days of modified CDC-ILI. Modified CDC-ILI was defined as fever (temperature ³100°F oral or equivalent) plus cough, sore throat or runny nose/nasal congestion on the same or consecutive days.

In the primary efficacy analysis, FluMist demonstrated a 44.5% (95% CI: 22.4, 60.6) reduction in influenza rate compared to active control as measured by culture-confirmed modified CDC-ILI caused by wild-type strains antigenically similar to those contained in the vaccine. See Table 5 for a description of the results by strain and antigenic similarity.

Table 5: Comparative efficacy against culture-confirmed modified CDC-ILI^a caused by wild-type strains in children < 5 years of age

ATP Population.

^a Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) plus cough, sore throat, or runny nose/nasal congestion on the same or consecutive days.

^b Injectable influenza vaccine made by Sanofi Pasteur Inc.

^c Reduction in rate was adjusted for country, age, prior influenza vaccination status and wheezing history status.

Studies in immunocompromised individuals

Safety and shedding of vaccine virus following FluMist administration were evaluated in children in a randomised (1:1), cross-over, double-blind, placebo-controlled trial in 24 HIV-infected children [median CD4 cell count of 1013 cells/mm3] and 25 HIV-negative children 1-7 years of age, and in a randomised (1:1), open-label, inactivated influenza vaccine-controlled trial in 243 HIV-infected children and adolescents 5-17 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 5-17 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 in preventing influenza illness in HIV-infected individuals has not been evaluated.

Twenty mild to moderately immunocompromised children and adolescents 5-17 years of age (receiving chemotherapy and/or radiation therapy or who had received chemotherapy in the 12 weeks prior to enrolment) were randomised 1:1 to receive FluMist or 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 in preventing influenza illness in immunocompromised individuals has not been evaluated.

Study with concomitant live vaccines

In Study AV018, concomitant administration of FluMist, MMR (manufactured by Merck & Co., Inc) and Varicella Virus Vaccine Live (manufactured by Merck & Co.,) was studied in 1,245 subjects 12-15 months of age. Subjects were randomised in a 1:1:1 ratio to MMR, Varicella vaccine and placebo (group 1); MMR, Varicella vaccine and FluMist (group 2); or FluMist alone (group 3).  Immune responses to MMR and Varicella vaccines were evaluated 6 weeks post-vaccination while the immune responses to FluMist were evaluated 4 weeks after the second dose.  Adverse reactions were similar to those seen in other clinical trials with FluMist (see section 4.8). No evidence of interference with immune response to measles, mumps, rubella, varicella and FluMist vaccines was observed.

Immune response studies with quadrivalent version of FluMist

Children and adolescents

A multicentre, randomised, double-blind, active-controlled, non-inferiority study (MI-CP208) was performed to assess the immunogenicity of FluMist compared to trivalent version of FluMist (active control) in children and adolescents 2 through 17 years of age. A total of 2,312 subjects were randomised at a 3:1:1 ratio to receive either FluMist or one of two formulations of comparator vaccine trivalent version of FluMist, each containing a B strain that corresponded to one of the two B strains in FluMist.

Immunogenicity was evaluated by comparing the 4 strain-specific serum haemagglutination inhibition (HAI) antibody geometric mean titres (GMTs) post dosing. FluMist demonstrated immunologic non-inferiority to the two formulations of trivalent version of FluMist, as the upper bound for each of the four 95% CIs for the post dose strain specific GMT HAI antibody ratios was less than the pre-specified non-inferiority criterion of 1.5.  These data provide evidence that the addition of the second B strain did not result in immune interference to other strains included in the vaccine.

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional non-clinical studies of repeated dose toxicity, reproduction and developmental toxicity, local tolerance and neurovirulence.

Sucrose

Dibasic potassium phosphate

Monobasic potassium phosphate

Gelatin hydrolysate (porcine Type A)

Arginine hydrochloride

Monosodium glutamate

Residual(s):

Gentamicin sulfate

Ovalbumin

Not applicable.

Store in a refrigerator (2°C - 8°C). 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.

FluMist is supplied as a 0.2 mL pre-filled, single‑use sprayer in a package of 10 and package of 1.

Any unused product or waste material should be disposed of in accordance with local requirements for medical waste.