Vaccine Information: FluMist Quadrivalent

FLUMIST QUADRIVALENT- influenza a virus a/switzerland/3330/2017 (h1n1) live (attenuated) antigen, influenza a virus a/kansas/14/2017 (h3n2) live (attenuated) antigen, influenza b virus b/phuket/3073/2013 live (attenuated) antigen and influenza b virus b/colorado/06/2017 live (attenuated) antigen spray
MedImmune, LLC

1 INDICATIONS AND USAGE

FluMist® Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine [see Description (11)].

FluMist Quadrivalent is approved for use in persons 2 through 49 years of age.

2 DOSAGE AND ADMINISTRATION

FOR INTRANASAL ADMINISTRATION BY A HEALTHCARE PROVIDER.

2.1 Dosing Information

Administer FluMist Quadrivalent according to the following schedule:

*
1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines.
Administer as 0.1 mL per nostril.

Age

Dose

Schedule

2 years through 8 years

1 or 2 doses *,0.2 mL each

If 2 doses, administer at least 1 month apart

9 years through 49 years

1 dose, 0.2 mL

-

“-” indicates information is not applicable.

2.2 Administration Instructions

Each sprayer contains a single dose (0.2 mL) of FluMist Quadrivalent; administer approximately one half of the contents of the single-dose intranasal sprayer into each nostril (each sprayer contains 0.2 mL of vaccine). Refer to Figure 1 for step-by-step administration instructions. Following administration, dispose of the sprayer according to the standard procedures for medical waste (e.g., sharps container or biohazard container).

Figure 1

Figure 1
(click image for full-size original)

3 DOSAGE FORMS AND STRENGTHS

Each 0.2 mL dose is a suspension supplied in a single-dose pre-filled intranasal sprayer.

4 CONTRAINDICATIONS

4.1 Severe Allergic Reactions

Do not administer FluMist Quadrivalent to persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine [see Description (11)] including egg protein, or after a previous dose of any influenza vaccine.

4.2 Concomitant Aspirin Therapy and Reye’s Syndrome in Children and Adolescents

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 infection [see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Risks of Hospitalization and Wheezing in Children Younger than 24 Months of Age

In clinical trials, risks of hospitalization and wheezing were increased in children younger than 2 years of age who received FluMist (trivalent Influenza Vaccine Live, Intranasal) [see Adverse Reactions (6.1)]. This observation with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see Description (11)].

5.2 Asthma, Recurrent Wheezing, and Active Wheezing

Children younger than 5 years of age with recurrent wheezing and persons of any age with asthma may be at increased risk of wheezing following administration of FluMist Quadrivalent. FluMist Quadrivalent has not been studied in persons with severe asthma or active wheezing.

5.3 Guillain-Barré Syndrome

The 1976 swine influenza vaccine (inactivated) was associated with an elevated risk of Guillain-Barré syndrome (GBS). Evidence for causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, based on data for inactivated influenza vaccines, it is probably slightly more than 1 additional case per 1 million persons vaccinated1. If GBS has occurred within 6 weeks of any prior influenza vaccination, the decision to give FluMist Quadrivalent should be based on careful consideration of the potential benefits and potential risks.

5.4 Altered Immunocompetence

FluMist Quadrivalent has not been studied in immunocompromised persons. The effectiveness of FluMist has not been studied in immunocompromised persons. Data on safety and shedding of vaccine virus after administration of FluMist in immunocompromised persons are limited to 173 persons with HIV infection and 10 mild to moderately immunocompromised children and adolescents with cancer [see Clinical Pharmacology (12.2)].

5.5 Medical Conditions Predisposing to Influenza Complications

The safety of FluMist Quadrivalent in individuals with underlying medical conditions that may predispose them to complications following wild-type influenza infection has not been established.

5.6 Management of Acute Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine [see Contraindications (4.1)].

5.7 Limitations of Vaccine Effectiveness

FluMist Quadrivalent may not protect all individuals receiving the vaccine.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

This safety experience with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see Description (11)]. A total of 9537 children and adolescents 1 through 17 years of age and 3041 adults 18 through 64 years of age received FluMist in randomized, placebo-controlled Studies D153-P501, AV006, D153-P526, AV019, and AV009 [3 used Allantoic Fluid containing Sucrose-Phosphate-Glutamate (AF-SPG) placebo, and 2 used saline placebo] described below. In addition, 4179 children 6 through 59 months of age received FluMist in Study MI-CP111, a randomized, active-controlled trial. Among pediatric FluMist recipients 6 months through 17 years of age, 50% were female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526, AV019, and AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black (6%), and Other (5%), while in D153-P501, 99% of subjects were Asian.

A total of 1382 children and adolescents 2 through 17 years of age and 1198 adults 18 through 49 years of age received FluMist Quadrivalent in randomized, active-controlled Studies MI-CP208 and MI-CP185. Among pediatric FluMist Quadrivalent recipients 2 through 17 years of age, 51% were female; in the study of adults, 55% were female. In Studies MI-CP208 and MI-CP185, subjects were White (73%), Asian (1%), Black or African-American (19%), and Other (7%); overall, 22% were Hispanic or Latino.

FluMist in Children and Adolescents

The safety of FluMist was evaluated in an AF-SPG placebo-controlled Study (AV019) conducted in a Health Maintenance Organization (HMO) in children 1 through 17 years of age (FluMist = 6473, placebo = 3216). An increase in asthma events, captured by review of diagnostic codes, was observed in children younger than 5 years of age who received FluMist compared to those who received placebo (Relative Risk 3.53, 90% CI: 1.1, 15.7).

In Study MI-CP111, children 6 through 59 months of age were randomized to receive FluMist or inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia was prospectively monitored from randomization through 42 days post last vaccination. Hospitalization due to all causes was prospectively monitored from randomization through 180 days post last vaccination. Increases in wheezing and hospitalization (for any cause) were observed in children 6 months through 23 months of age who received FluMist compared to those who received inactivated Influenza Virus Vaccine, as shown in Table 1.

Table 1: Percentages of Children with Hospitalizations and Wheezing from Study MI-CP111*
*
NCT00128167; see www.clinicaltrials.gov
Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly.
Hospitalization due to any cause from randomization through 180 days post last vaccination.
§
Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia evaluated from randomization through 42 days post last vaccination.

Adverse Reaction

Age Group

FluMist (n/N)

Active Control (n/N)

Hospitalizations

6-23 months

4.2%(84/1992)

3.2%(63/1975)

24-59 months

2.1%(46/2187)

2.5%(56/2198)

Wheezing §

6-23 months

5.9%(117/1992)

3.8%(75/1975)

24-59 months

2.1%(47/2187)

2.5%(56/2198)

Most hospitalizations observed were due to gastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. In post-hoc analysis, rates of hospitalization in children 6 through 11 months of age were 6.1% (42/684) in FluMist recipients and 2.6% (18/683) in inactivated Influenza Virus Vaccine recipients.

Table 2 shows pooled solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo post Dose 1 for Studies D153-P501 and AV006, and solicited adverse reactions post Dose 1 for Study MI-CP111. Solicited adverse reactions were those about which parents/guardians were specifically queried after receipt of FluMist, placebo, or control vaccine. In these studies, solicited reactions were documented for 10 days post vaccination. Solicited reactions following the second dose of FluMist were similar to those following the first dose and were generally observed at a lower frequency.

Table 2: Summary of Solicited Adverse Reactions Observed Within 10 Days after Dose 1 for FluMist and Either Placebo or Active Control Recipients in Children 2 through 6 Years of Age
*
NCT00192244; see www.clinicaltrials.gov
NCT00128167; see www.clinicaltrials.gov
Study D153-P501 used saline placebo; Study AV006 used AF-SPG placebo.
§
Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly.
Number of evaluable subjects (those who returned diary cards) for each reaction. Range reflects differences in data collection between the 2 pooled studies.

Studies D153-P501 * & AV006

Study MI-CP111

FluMist

Placebo

FluMist

Active Control §

N = 876-1759

N = 424-1034

N = 2170

N = 2165

Event

%

%

%

%

Runny Nose/Nasal Congestion

58

50

51

42

Decreased Appetite

21

17

13

12

Irritability

21

19

12

11

Decreased Activity(Lethargy)

14

11

7

6

Sore Throat

11

9

5

6

Headache

9

7

3

3

Muscle Aches

6

3

2

2

Chills

4

3

2

2

Fever

> 100°F Oral > 100 — ≤ 101°F Oral > 101 — ≤ 102°F Oral

1694

1163

1364

1143

In clinical studies D153-P501 and AV006, unsolicited adverse reactions in children occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo were abdominal pain (2% FluMist vs. 0% placebo) and otitis media (3% FluMist vs. 1% placebo). An additional adverse reaction identified in the active-controlled trial MI-CP111 occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to active control was sneezing (2% FluMist vs.1% active control).

In a separate saline placebo-controlled trial (D153-P526) in a subset of older children and adolescents 9 through 17 years of age who received one dose of FluMist, the solicited adverse reactions as well as unsolicited adverse reactions reported were generally consistent with observations from the trials in Table 2.Abdominal pain was reported in 12% of FluMist recipients compared to 4% of placebo recipients and decreased activity was reported in 6% of FluMist recipients compared to 0% of placebo recipients.

In Study AV018, in which FluMist was concomitantly administered with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) to children 12 through 15 months of age, adverse reactions were similar to those seen in other clinical trials of FluMist.

FluMist Quadrivalent in Children and Adolescents

In the randomized, active-controlled Study MI-CP208 that compared FluMist Quadrivalent and FluMist in children and adolescents 2 through 17 years of age, the rates of solicited adverse reactions reported were similar between subjects who received FluMist Quadrivalent and FluMist. Table 3 includes solicited adverse reactions post Dose 1 from Study MI-CP208 that either occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in previous FluMist clinical studies (see Table 2). In this study, solicited adverse reactions were documented for 14 days post vaccination. Solicited adverse reactions post Dose 2 were observed at a lower frequency compared to those post Dose 1 for FluMist Quadrivalent and were similar between subjects who received FluMist Quadrivalent and FluMist.

Table 3: Summary of Solicited Adverse Reactions * Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP208 in Children and Adolescents 2 through 17 Years of Age
*
Solicited adverse reactions that occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in previous FluMist trials (see Table 2).
NCT01091246; see www.clinicaltrials.gov
Number of evaluable subjects for each event.
§
Represents pooled data from the two FluMist study arms [see Clinical Studies (14.2)].

FluMist Quadrivalent N = 1341-1377

FluMist § N = 901-920

Event

%

%

Runny Nose/Nasal CongestionHeadacheDecreased Activity (Lethargy)Sore ThroatDecreased AppetiteMuscle AchesFever> 100°F by any route> 100 — ≤ 101°F by any route> 101 — ≤ 102°F by any route

321310964732

3212101075522

In Study MI-CP208, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients.

FluMist in Adults

In adults 18 through 49 years of age in Study AV009, solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to AF-SPG placebo include runny nose (44% FluMist vs. 27% placebo), headache (40% FluMist vs. 38% placebo), sore throat (28% FluMist vs. 17% placebo), tiredness/weakness (26% FluMist vs. 22% placebo), muscle aches (17% FluMist vs. 15% placebo), cough (14% FluMist vs. 11% placebo), and chills (9% FluMist vs. 6% placebo).

In Study AV009, unsolicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo were nasal congestion (9% FluMist vs. 2% placebo) and sinusitis (4% FluMist vs. 2% placebo).

FluMist Quadrivalent in Adults

In the randomized, active-controlled Study MI-CP185 that compared FluMist Quadrivalent and FluMist in adults 18 through 49 years of age, the rates of solicited adverse reactions reported were generally similar between subjects who received FluMist Quadrivalent and FluMist. Table 4 presents solicited adverse reactions that either occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009.

Table 4: Summary of Solicited Adverse Reactions * Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP185 in Adults 18 through 49 Years of Age
*
Solicited adverse reactions that occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009.
NCT00860067; see www.clinicaltrials.gov
Number of evaluable subjects for each event.
§
Represents pooled data from the two FluMist study arms [see Clinical Studies (14.4)].

FluMist Quadrivalent N = 1197

FluMist § N = 597

Event

%

%

Runny Nose/Nasal CongestionHeadacheSore ThroatDecreased Activity (Lethargy)CoughMuscle AchesDecreased Appetite

4428191814106

4027201813105

In Study MI-CP185, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients.

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