Flumist Precautions

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- - - - - - - - - - - - - - - - - WARNINGS AND PRECAUTIONS - - - - - - - - - - - - - - - - - - - - - -• Do not administer FluMist to children <24 months of age because of increased risk ofhospitalization and wheezing observed in clinical trials. (5.1)• FluMist should not be administered to any individuals with asthma or children < 5 years of age withrecurrent wheezing because of the potential for increased risk of wheezing post vaccination. (5.2)• If Guillain-Barré syndrome has occurred with any prior influenza vaccination, the

decision to giveFluMist should be based on careful consideration of the potential benefits and risks. (5.3)• Administration of FluMist, a live virus vaccine, to immunocompromised persons should be basedon careful consideration of potential benefits and risks. (5.4)• Safety has not been established in individuals with underlying medical conditions predisposingthem to wild-type influenza infection complications. (5.5)- - - - - - - - - - - - - - - - - - - - - - - - - ADVERSE REACTIONS - - - - - - - - - - - -5 WARNINGS AND PRECAUTIONS5.1 Risks in Children <24 Months of AgeDo not administer FluMist to children <24 months of age. In clinical trials, an increased risk ofwheezing post-vaccination was observed in FluMist

recipients <24 months of age. An increasein hospitalizations was observed in children <24 months of age after vaccination with FluMist.[see Adverse Reactions (6.1).]5.2 Asthma/Recurrent WheezingFluMist should not be administered to any individuals with asthma or children <5 years of age withrecurrent wheezing because of the potential for increased risk of wheezing post vaccination unless thepotential benefit outweighs the potential risk.Do not administer FluMist to individuals with severe asthma or active wheezing because theseindividuals have not been studied in clinical trials.5.3 Guillain-Barré SyndromeIf Guillain-Barré syndrome has occurred within 6 weeks of any prior influenza vaccination, the decisionto give FluMist should be based on careful consideration of the potential benefits and potential

risks[see also Adverse Reactions (6.2)].5.4 Altered ImmunocompetenceAdministration of FluMist, a live virus vaccine, to immunocompromised persons should be based oncareful consideration of potential benefits and risks. Although FluMist was studied in 57 asymptomaticor mildly symptomatic adults with HIV infection [see Clinical Studies (14.3)], data supporting thesafety and effectiveness of FluMist administration in immunocompromised individuals are limited.5.5 Medical Conditions Predisposing to Influenza ComplicationsThe safety of FluMist in individuals with underlying medical conditions that may predispose them tocomplications following wild-type influenza infection has not been established.. FluMist should not beadministered unless the potential benefit outweighs

the potential risk.5.6 Management of Acute Allergic ReactionsAppropriate medical treatment and supervision must be available to manage possible anaphylacticreactions following administration of the vaccine [see Contraindications (4.1)].5.7 Limitations of Vaccine EffectivenessFluMist may not protect all individuals receiving the vaccine.6 ADVERSE REACTIONSFluMist is not indicated in children <24 months of age. In a clinical trial, among children 6-23 monthsof age, wheezing requiring bronchodilator therapy or with significant respiratory symptoms occurredin 5.9% of FluMist recipients compared to 3.8% of active control (injectable influenza vaccine made bySanofi Pasteur Inc.) recipients (Relative Risk 1.5, 95% CI: 1.2,

2.1). Wheezing was not increased inchildren ≥24 months of age.Hypersensitivity, including anaphylactic reaction, has been reported post-marketing.[see Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2).]6.1 Adverse Reactions in Clinical TrialsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.A total of 9537 children and adolescents 1-17 years of age and 3041 adults 18-64 years of age receivedFluMist in randomized, placebo-controlled Studies D153-P501, AV006, D153-P526, AV019 and AV009described below. In addition, 4179 children 6-59 months of age

received FluMist in Study MI-CP111,a randomized, active-controlled trial. Among pediatric FluMist recipients 6 months-17 years of age,50% were female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526, AV019and AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black (6%), and Other (5%),while in D153-P501, 99% of subjects were Asian.Adverse Reactions in Children and AdolescentsIn a placebo-controlled safety study (AV019) conducted in a large Health Maintenance Organization(HMO) in children 1-17 years of age (n = 9689), an increase in asthma events, captured by review ofdiagnostic codes, was observed in children <5 years of age (Relative Risk 3.53, 90% CI: 1.1, 15.7).This observation was prospectively evaluated in Study MI-CP111.InMI-CP111, an active-controlled study, increases in wheezing and hospitalization (for any cause)

wereobserved in children <24 months of age, as shown in Table 1.Table 1Percentages of Children with Hospitalizations and Wheezing from MI-CP111Adverse Reaction Age Group FluMist Active ControlaHospitalizationsb 6-23 months (n = 3967) 4.2 % 3.2 %24-59 months (n= 4385) 2.1 % 2.5 %Wheezingc 6-23 months (n = 3967) 5.9 % 3.8 %24-59 months (n = 4385) 2.1 % 2.5 %a Injectable influenza vaccine made by Sanofi Pasteur Inc.b From randomization through 180 days post last vaccination.c Wheezing requiring bronchodilator therapy or with significant respiratory symptoms evaluated

FluMist contains live attenuated influenza viruses that must infect and replicate in cells lining thenasopharynx of the recipient to induce immunity. Vaccine viruses capable of infection and replicationcan be cultured from nasal secretions obtained from vaccine recipients. The relationship of viralreplication in a vaccine recipient and transmission of vaccine viruses to other individuals has notbeen established.Using the frozen formulation, a prospective, randomized, double-blind, placebo-controlled trialwas performed in a daycare setting in children <3 years of age to assess the transmission of vaccineviruses from a vaccinated individual to a non-vaccinated individual. A total of 197 children 8-36 monthsof age were randomized to receive one dose of FluMist (n=98) or placebo (n=99). Virus shedding wasevaluated for 21 days by culture of

nasal swab specimens. Wild-type A (H3N2) influenza virus wasdocumented to have circulated in the community and in the study population during the trial, whereasType A (H1N1) and Type B strains did not.At least one vaccine strain was isolated from 80% of FluMist recipients; strains were recoveredfrom 1-21 days post vaccination (mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca) andtemperature-sensitive (ts) phenotypes were preserved in 135 tested of 250 strains isolated at the locallaboratory. Ten influenza isolates (9 influenza A, 1 influenza were cultured from a total of sevenplacebo subjects. One placebo subject had mild symptomatic Type B virus infection confirmed as atransmitted vaccine virus by a FluMist recipient in the

same playgroup. This Type B isolate retained theca, ts, and att phenotypes of the vaccine strain, and had the same genetic sequence when comparedto a Type B virus cultured from a vaccine recipient within the same playgroup. Four of the influenzaType A isolates were confirmed as wild-type A/Panama (H3N2). The remaining isolates could not befurther characterized.Assuming a single transmission event (isolation of the Type B vaccine strain), the probability of a youngchild acquiring vaccine virus following close contact with a single FluMist vaccinee in this daycaresetting was 0.58% (95% CI: 0, 1.7) based on the -Frost model. With documented transmissionof one Type B in one placebo subject and possible transmission of Type A viruses in four placebosubjects, the probability of acquiring a transmitted vaccine virus was estimated to be 2.4% (95%CI: 0.13, 4.6), using the -Frost

model.The duration of FluMist vaccine virus replication and shedding have not been established.