FIRST NASAL VACCINE APPROVED FOR USE: On June 17, 2003,
the Food
and Drug Administration (FDA) approved the use of FluMist, an influenza
vaccine that is the first nasally administered vaccine to be marketed in the
United States. It is also the first live
virus influenza vaccine approved in the U.S.
FluMist is approved to prevent influenza illness due to influenza A and B
viruses in healthy children and adolescents, ages 5-17 years, and healthy
adults, ages 18-49. In clinical trials, FluMist was evaluated in 20,228
individuals, including over 10,000 healthy children 5-17 years old. The
efficacy of the vaccine in preventing influenza was approximately 87 percent
among children included in the trial. In healthy adults ages 18-49 years,
FluMist was effective in reducing severe illnesses with fever, and upper
respiratory problems which may be caused by influenza infection.
As with any live virus vaccines, FluMist should not be given for any reason
to people with immune suppression, including those with immune deficiency
diseases, such as AIDS or cancer, and people who are being treated with
drugs that cause immunosuppression. The safety of FluMist in people with
asthma or other reactive airway diseases has not been established; FluMist
should not be given to people with a history of these problems. In a large
safety study, children under five years of age were found to have increased
rate of asthma and wheezing within 42 days of vaccination compared to
placebo recipients, and thus FluMist is not recommended for young children.
For people age 50 years and over, the safe and effective use of FluMist has
also not been established.
The vaccine should also not be administered to those with therapies
including aspirin, a history of Guillain-Barre syndrome, chronic diseases,
allergies to eggs or those who are pregnant. The most common adverse events
associated with the vaccine were nasal congestion, runny nose, sore throat,
and cough. FluMist is produced by MedImmune Vaccines and will be distributed
by Wyeth. Both companies will market the product. For more information visit
www.fda.gov or www.cdc.gov/nip
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Questions and Answers on FluMist (Influenza Virus Vaccine Live, Intranasal)
What is FluMist approved for?
FluMist is approved to prevent influenza illness due to influenza A and B
viruses in healthy children and adolescents, ages 5-17 years, and healthy
adults, ages 18-49 years.
What is the difference between live attenuated influenza virus (LAIV) and
the flu shot that is made from inactivated viruses?
LAIV and inactivated influenza vaccine contain strains of influenza viruses
that are matched to protect against influenza strains that are likely to
circulate each year. Viruses for both vaccines are grown in eggs. Both
vaccines are administered annually to provide optimal protection against
influenza infection. Inactivated vaccines are produced by killing the flu
viruses. The killed viruses cannot cause influenza.
LAIV contains attenuated (or weakened) viruses. These weakened strains
usually do not cause illness because they have lost virulence
(disease-causing properties). There is, however, a possibility that they can
still reproduce and cause disease, especially in persons with weakened
immune systems.
FluMist (LAIV) is administered intranasally by sprayer, whereas inactivated
influenza vaccine is administered intramuscularly by injection. FluMist (LAIV)
is approved for use only among healthy persons aged 5-49 years; inactivated
influenza vaccine is approved for use among persons aged >6 months,
including those who are healthy and those with medical conditions.
Since the flu shot is recommended for many people over the age of 49, why
isn’t FluMist recommended for individuals 50 years of age and older?
Studies with FluMist did not include enough patients over the age of 49 to
determine if they respond differently than younger individuals. Therefore,
the safe and effective use of FluMist in persons 50 years and older has not
been established.
How many doses are recommended per season?
Children 5-8 years old need two doses at least 6 weeks apart in their first
year of vaccination with FluMist.
Individuals 9-49 years old need only one dose.
How well does this vaccine work?
The vaccine prevented influenza associated illness in approximately 87% of
the children included in the trial.
Adults (ages 18-49 years) who received FluMist experienced significantly
fewer episodes of severe febrile illness (SFI) when compared to those who
received placebo. Severe febrile illness was defined as having at least
three days of symptoms (runny nose, sore throat, cough, muscle aches,
tiredness/weakness) and one day of fever.
Adults who received FluMist did not experience a significant reduction in
any febrile illness (AFI). Adults were characterized as having AFI if they
had symptoms for at least two consecutive days, with fever on at least one
day.
As with any vaccine, FluMist may not protect 100% of individuals receiving
the vaccine.
What are the most common side affects of FluMist?
Nasal congestion, runny nose, sore throat, headache, irritability, decreased
activity, muscle ache and cough are the most common adverse events
associated with the vaccine.
However, a vaccine, like any medicine, is capable of causing serious
problems, such as severe allergic reactions. The risk of a vaccine causing
serious harm, or death, is extremely small, and serious problems from flu
vaccine are rare.
Are there certain people who should not receive FluMist?
As with any medication, individuals should check with their health care
provider before receiving any flu vaccines. According to the approved
package insert, the following people should not get the intranasal influenza
vaccine:
Adults 50 years of age or older, or children younger than 5 should not
receive FluMist.
FluMist should not be given for any reason to people with immune
suppression, including those with immune deficiency diseases, such as AIDS
or cancer, and people who are being treated with drugs that cause
immunosuppression.
The safety of FluMist in people with asthma or other reactive airway
diseases has not been established, and therefore, is not recommended for use
in patients with a history of reactive airway problems.
Additionally, FluMist should not be given to people with chronic underlying
medical conditions that may predispose them to severe flu infections. For
these people, the injected vaccine is indicated.
Individuals with egg allergies should not receive this or any other flu
vaccine.
People who have health problems associated with heart disease, kidney
disease, lung disease, or metabolic diseases such as diabetes, anemia and
other blood disorders should not receive FluMist.
Because Reye syndrome in children has been associated with administration of
aspirin during influenza virus infections, FluMist is not recommended in
children and adolescents 5-17 years of age if they are receiving aspirin or
aspirin-containing therapy.
Pregnant women (in their second or third trimesters during influenza season)
should not receive FluMist.
Anyone with a history of Guillain-Barré Syndrome (GBS) should not receive
FluMist.
Physicians, nurses, family members, or anyone else coming in close contact
with anyone with a weakened immune system should not receive FluMist.
If I receive FluMist, is it possible that I will get the flu from the
vaccine?
Yes, although strains of attenuated vaccines are weakened, there is a
possibility that they can still reproduce and cause disease, particularly in
people with weakened or compromised immune systems.
Can I get the flu from the inactivated vaccine?
No. Components in the inactivated influenza vaccine are made from killed
influenza viruses, and they cannot cause influenza infection.
What is the best time of year to receive the flu vaccine?
Flu vaccines should be administered prior to exposure to influenza. The peak
of influenza activity varies from year to year, but generally occurs in the
U.S. between late December and early March. Influenza vaccines usually
become available in early October, but contact your healthcare provider for
additional information.
Will I need to receive a vaccine every year?
Because yearly variation in the influenza strains is possible, annual
revaccination with FluMist, as well as with the inactivated vaccine, is
recommended.
If I would like to obtain additional information where can I find it?
We recommend that that you talk to your health care provider when you have
any questions related to the medication(s) you receive. He or she can also
suggest other sources of information.
Call your local or state health department.
Contact the Centers for Disease Control and Prevention (CDC):
Call 1-800-232-2522 (English)
Call 1-800-232-0233 (Español)
Visit CDC websites at www.cdc.gov/ncicod/diseases/flu/fluvirus.htm or
www.cdc.gov/nip
A copy of the vaccine package insert is available on CBER's web site at:
www.fda.gov/cber/lable/inflmed061703LB.pdf
Product approval information
Updated October 14, 2003
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FDA / Center for Biologics Evaluation and Research
Package Insert (Circular)
16 June 2003
Page 1 of 19
Influenza Virus Vaccine Live, Intranasal
FluMistTM
2003-2004 Formula
FOR NASAL ADMINISTRATION ONLY
Rx only
DESCRIPTION
Influenza Virus Vaccine Live, Intranasal (FluMist™) is a live trivalent
nasally administered vaccine
intended for active immunization for the prevention of influenza.
Each 0.5 mL dose is formulated to contain 106.5-7.5 TCID50 (median tissue
culture infectious dose)
of live attenuated influenza virus reassortants of the strains recommended
by the U.S. Public
Health Service (USPHS) for the 2003-2004 season: A/New Caledonia/20/99
(H1N1),
A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like), and B/Hong Kong/330/2001 [1].
These
strains are (a) antigenically representative of influenza viruses that may
circulate in humans
during the 2003-2004 influenza season; (b) cold-adapted (ca) (i.e., they
replicate efficiently at
25oC, a temperature that is restrictive for replication of many wild-type
viruses); (c) temperaturesensitive
(ts) (i.e., they are restricted in replication at 37oC (Type B strains) or
39oC (Type A
strains), temperatures at which many wild-type influenza viruses grow
efficiently); and (d)
attenuated (att) so as not to 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
phenotype is that the vaccine viruses replicate in the nasopharynx to
produce protective
immunity.
Each of the three influenza virus strains contained in FluMist is a genetic
reassortant of a Master
Donor Virus (MDV) and a wild-type influenza virus. The MDVs (A/Ann
Arbor/6/60 and B/Ann
Arbor/1/66) were developed by serial passage at sequentially lower
temperatures in specific
pathogen-free (SPF) primary chick kidney cells [2]. During this process, the
MDVs acquired the
ca, ts and att phenotype and multiple mutations in the gene segments that
encode viral proteins
other than the surface glycoproteins. The individual contribution of the
genetic sequences of the
six non-glycoprotein MDV genes (“internal gene segments”) to the ca, ts, and
att phenotype is not
completely understood. However, at least five genetic loci in three
different internal gene
segments of the Type A MDV and at least three genetic loci in two different
internal gene
segments of the Type B MDV contribute to the ts property [3, 4]. For each of
the three strains in
FluMist, the six internal gene segments responsible for ca, ts, and att
phenotypes are derived
from the MDV, and the two segments that encode the two surface glycoproteins,
hemagglutinin
Package Insert (Circular)
16 June 2003
Page 2 of 19
(HA) and neuraminidase (NA), are derived from the corresponding
antigenically relevant wild-type
influenza viruses that have been recommended by the USPHS for inclusion in
the annual vaccine
formulation. Thus, the three viruses contained in FluMist maintain the
replication characteristics
and phenotypic properties of the MDV and express the HA and NA of wild-type
viruses that are
related to strains expected to circulate during the 2003-2004 influenza
season.
Viral harvests used in the production of FluMist are produced by inoculating
each of the three
reassortant viruses into specific pathogen-free (SPF) eggs that are
incubated to allow for vaccine
virus replication. The allantoic fluid of these eggs is harvested, clarified
by centrifugation, and
stabilized with buffer containing sucrose, potassium phosphate, and
monosodium glutamate (0.47 mg/dose). Viral harvests from the three strains (H1N1, H3N2, and B)
are subsequently
blended and diluted to desired potency with allantoic fluid derived from
uninfected SPF eggs to
produce trivalent bulk vaccine. Each lot of viral harvest is tested for ca,
ts, and att and is also
tested extensively by in vitro and in vivo methods to detect adventitious
agents. The bulk vaccine
is then filled directly into individual sprayers for nasal administration.
These sprayers are labeled
and stored at ≤-15oC.
Gentamicin sulfate is added early in the manufacturing process during
preparation of reassortant
viruses at a calculated concentration of approximately 1 µg/mL. Later steps
of the manufacturing
process do not use gentamicin, resulting in a diluted residual concentration
in the final product of
<0.015 µg/mL (limit of detection of the assay). FluMist does not contain any
preservatives.
Each pre-filled FluMist sprayer contains a single 0.5 mL dose. The teflon
tip attached to the
sprayer is equipped with a one-way valve that produces a fine mist that is
primarily deposited in
the nose and nasopharynx. When thawed for administration, FluMist is a
colorless to pale yellow
liquid and is clear to slightly cloudy (see DOSAGE AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Influenza is a highly infectious respiratory viral infection that causes
recurrent winter epidemics of
acute disease in persons of all ages. Highest rates of illness are generally
reported among
5-14 year-olds [5, 6]. Among healthy individuals 15-44 years of age, the
average rate of excess
hospitalizations attributable to influenza is 20-25 per 100,000 per year
[7], with an annual
influenza-associated mortality rate of 0.2-1.5 per 100,000 person-years [8].
Types A and B influenza viruses are the principal causes of influenza in
humans. Type A
influenza viruses are divided into subtypes on the basis of the two surface
antigens,
hemagglutinin (HA) and neuraminidase (NA), while influenza virus B is
classified as a single
subtype. Continuous mutation of the influenza virus genome leads to an
accumulation of genetic
and accompanying antigenic changes that result in the evolution of viruses
into recognizable
antigenic lineages or strains within a subtype. Protective immune responses
following natural
Package Insert (Circular)
16 June 2003
Page 3 of 19
infection result in population-based immunity to circulating strains.
However, this immune barrier
eventually results in the emergence of strains that have undergone antigenic
change, or “drift.”
Because these “drifted” strains can escape immunity to HA and NA antigens of
previously
circulating strains, experience with inactivated influenza vaccines suggests
that vaccines may
require annual updating to match the contemporary strains.
Vaccination is the principal means of prevention of influenza and
influenza-associated
complications [1].
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 and recovery from infection [9, 10].
Vaccination with FluMist has
been demonstrated to induce influenza strain-specific serum antibodies [11,
12].
Clinical Studies
FluMist was administered to 20,228 subjects in clinical studies. The
population evaluated
included 10,297 healthy children 5-17 years of age (14,058 doses of FluMist
received) and 3297
healthy adults 18-49 years of age (3335 doses of FluMist received) who
received at least one
dose of vaccine. Second and third annual doses have been given to 1766 and
128 children 5-17
years of age, respectively. In randomized, placebo-controlled trials, 4719
healthy children 5-17
years of age and 2864 healthy adults 18-49 years of age received FluMist.
The efficacy of FluMist against culture-confirmed influenza disease for
Types A/H3N2 and B was
assessed in a field trial in children. The effectiveness of FluMist against
Types A/H3N2 and B,
defined as a reduction in influenza-like illness and illness-associated
health care utilization, was
assessed in a field trial in adults. Type A/H1N1 did not circulate during
either trial, and no field
efficacy data against this strain are available.
Pediatric Study
The Pediatric Efficacy Study was a multi-center, randomized, double-blind,
placebo-controlled
trial performed in healthy U.S. children to evaluate the efficacy of FluMist
against cultureconfirmed
influenza over two successive seasons [13, 14]. The primary endpoint for the
first year
of the trial was the prevention of culture-confirmed influenza illness due
to antigenically matched
wild-type influenza in healthy children who received two doses of vaccine.
During the first year of
the study a subset of 312 children 60-71 months of age were randomized 2:1 (vaccine:placebo).
All children with culture-confirmed influenza experienced respiratory
symptoms (cough, runny
Package Insert (Circular)
16 June 2003
Page 4 of 19
nose, or sore throat) and most experienced fever (68%), health care provider
visits (68%), and
missed school days (74%).
As shown in Table 1, when compared with placebo recipients, FluMist
recipients 60-71 months of
age who received two doses of vaccine (n=238) experienced a significant
reduction in the
incidence of culture-confirmed influenza (efficacy 87.4%, 95% CI: 59.4,
97.9). In the 60-71 month
old age group, children who received one dose of FluMist when compared to
one dose of placebo
experienced a significant reduction in the incidence of culture-confirmed
influenza (0 of 54 FluMist
recipients vs 3 of 20 placebo recipients; efficacy 100%, 95% CI: 47.0, 100).
Approximately 85% of the participants in the first year returned for the
second year of the
Pediatric Efficacy Study, including a subset of 544 children 60-84 months of
age [4]. During the
second year of the trial, the H3N2 strain included in the vaccine was A/Wuhan/359/95.
However,
the H3N2 strain that primarily circulated was A/Sydney/05/97, which differed
antigenically from
A/Wuhan/359/95. Type A/Wuhan/359/95 (H3N2) also circulated as did Type B
strains. Children
remained in the same treatment group as in year one and received a single
dose of FluMist or
placebo. The primary endpoint of the trial was the prevention of
culture-confirmed influenza
illness due to antigenically matched wild-type influenza after a single
annual revaccination dose
of FluMist.
In the subset of 544 children 60-84 months of age, illness associated with
culture-confirmed illness
in the second year was similar in scope and severity to that in the first
year. The overall efficacy of
FluMist against culture-confirmed wild-type influenza, regardless of
antigenic match, was 86.9%
(95% CI: 70.8, 94.1).
Table 1
Efficacy of FluMist Against Culture-Confirmed
Influenza in Children ≥ 60 Months of Age
Endpoint Cases Efficacy (%) (95% CI)
FluMist Placebo
Year One (60 – 71 mo of age)
N=163
n (%)
N= 75
n (%)
Culture-confirmed influenzaa 3 (1.8) 11 (14.7) 87.4 (59.4, 97.9)*
Year Two (60 – 84 mo of age)
N=375
n (%)
N=169
n (%)
Culture-confirmed influenzaa,b 7 (1.9) 24 (14.2) 86.9 (70.8, 94.1)*
* Denotes statistically significant, p≤0.05.
a Overall efficacy against Type A (H3N2) and Type B wild-type viruses. Field
efficacy
against wild Type A (H1N1) viruses could not be determined because those
strains did not
circulate during the study period.
b Includes illness caused by A/Sydney/05/97 (H3N2), an antigenic variant not
included in
the vaccine.
Package Insert (Circular)
16 June 2003
Page 5 of 19
Studies in Adults
The Adult Effectiveness Study was a multi-center, randomized, double-blind,
placebo-controlled
trial in which healthy adults were enrolled, including 3920 adults 18-49
years of age (2150 women
and 1770 men). Participants were randomized 2:1, vaccine:placebo. The trial
was designed to
evaluate the effectiveness of FluMist in the reduction of influenza-like
illness during the peak
influenza outbreak period at each site, based on community surveillance
[15]. Cultures for
influenza virus were not obtained from subjects in the trial, so that the
efficacy against cultureconfirmed
influenza was not assessed. The predominant circulating strain of influenza
virus
during the trial period was A/Sydney/05/97 (H3N2), a strain that differed
antigenically from the
A/Wuhan/359/95 (H3N2) strain contained in FluMist. Type A/Wuhan (H3N2) and
Type B strains
also circulated in the U.S. during the study period. The primary endpoint of
the trial was the
reduction in the proportion of participants with one or more episodes of any
febrile illness (AFI).
Two other, more specific febrile influenza-like illness definitions were
also prospectively
assessed: severe febrile illness (SFI), and febrile upper respiratory
illness (FURI). Adults were
characterized as having AFI if they had symptoms for at least two
consecutive days with fever on
at least one day and if they had two or more symptoms (fever, chills,
headache, runny nose, sore
throat, cough, muscle aches, tiredness/weakness) on at least one day. SFI
was defined as
having at least three consecutive days of symptoms, at least one day of
fever, and two or more
symptoms on at least three days. FURI was defined as at least two
consecutive days of upper
respiratory infection (URI) symptoms (runny nose, sore throat, or cough),
fever on at least one
day, and at least two URI symptoms on at least one day. Adults meeting the
three illness
definitions often had associated health care provider visits (25-31%), used
antibiotics (28-32%),
and missed at least one day of work (51-58%).
During the seven-week site-specific outbreak period, in the subset of
subjects age 18-49 years,
FluMist recipients did not experience a significant reduction in AFI;
significant reductions were
observed for SFI and FURI (Table 2). An additional measure of the severity
of disease was illness associated
days of health care provider visits; FluMist recipients experienced
significant
reductions in days of health care provider visits associated with SFI
(17.8%, 95% CI: 2.0, 31.0),
and FURI (36.9%, 95% CI: 24.4, 47.3) when compared to placebo recipients.
However, no
significant reduction in days of health care provider visits associated with
AFI was observed
among FluMist recipients when compared to placebo recipients.
Package Insert (Circular)
16 June 2003
Page 6 of 19
Table 2
Effectiveness of FluMist in Adults 18–49 Years of Age
During the 7-week Site-Specific Outbreak Period
Endpoint
FluMist
N=2411a
n (%)
Placebo
N=1226a
n (%)
Percent
Reduction (95% CI)
Participants with one or
more events of:b
Any febrile illness 331 (13.73) 189 (15.42) 10.9 (-5.1, 24.4)
Severe febrile illness 250 (10.37) 158 (12.89) 19.5 (3.0, 33.2)*
Febrile upper respiratory
illness 213 ( 8.83) 142 (11.58) 23.7 (6.7, 37.5)*
* Denotes p-value ≤0.05.
Note: The proportion of participants with any febrile illness (AFI) was the
primary study endpoint;
effectiveness was not demonstrated for this endpoint (p-value >0.05).
a Number of evaluable subjects (92.7% and 93.0% of FluMist and placebo
recipients, respectively).
b The predominantly circulating virus during the trial period was A/Syndey/05/97
(H3N2), an
antigenic variant not included in the vaccine.
Challenge Study
The ability of FluMist to protect adults from influenza illness after
challenge with wild-type
influenza was assessed in a multi-center, randomized, double-blind,
placebo-controlled trial in
healthy adults 18-41 years of age who were serosusceptible to at least one
strain included in the
vaccine [12]. Adults were randomized to receive FluMist (n=29) or placebo
(n=31). Each subject
was challenged intranasally with only a single strain of wild-type virus
(Type A/H3N2, Type
A/H1N1 or Type B) to which he/she was serosusceptible, and the results were
pooled for all three
strains combined within each treatment group. Laboratory-documented
influenza illness due to
all three strains combined was reduced compared to placebo by 85% (95% CI:
28, 100) in
FluMist recipients.
Transmission
FluMist contains live attenuated influenza viruses that replicate in the
nasopharynx of the
recipient and are shed in respiratory secretions. Assessing the probability
that these shed
vaccine viruses will be transmitted from a vaccinated individual to a
non-vaccinated individual
was the primary objective of a prospective, randomized, double-blind,
placebo-controlled trial in a
daycare setting in Finland [16]. Children enrolled in the study attended
daycare at least three
days per week for four hours per day, and were in a playroom with at least
four children, at least
one of whom was vaccinated with FluMist. A total of 197 children 8-36 months
of age were
randomized to receive one dose of FluMist (n=98) or placebo (n=99). Virus
shedding was
evaluated for 21 days by culture of nasal swabs obtained from each subject
approximately three
times per week. Wild-type A (H3N2) influenza virus was documented to have
circulated in the
Package Insert (Circular)
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16 June 2003
Page 7 of 19
community and in the study population during the trial, whereas Type A
(H1N1) and Type B
strains did not.
Eighty percent of FluMist recipients shed at least one vaccine strain, with
a mean duration of
shedding of 7.6 days (range 1-21 days). The cold-adapted (ca) and
temperature-sensitive (ts) phenotypes were preserved in all shed viruses tested (n=135 tested of 250
strains isolated at the
local laboratory). A total of seven placebo subjects shed 10 influenza
isolates. One placebo
subject shed a Type B virus confirmed to be a vaccine strain. 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 shed by a vaccine recipient within the same playgroup. Six
placebo subjects
shed nine isolates identified as Type A, two of these subjects had two
cultures that grew Type A
strains (four isolates) confirmed as wild-type A/Panama (H3N2). The
remaining four placebo
subjects shed Type A isolates that could not be further characterized, and
thus vaccine strains
could not be excluded.
Assuming that a single transmission event occurred (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 [17].
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.
The frequency and duration of shedding FluMist viral strains by individuals
5-49 years of age has
not been established.
INDICATIONS AND USAGE
FOR NASAL ADMINISTRATION ONLY
FluMist is indicated for active immunization for the prevention of disease
caused by influenza A
and B viruses in healthy children and adolescents, 5-17 years of age, and
healthy adults, 18-49
years of age.
FluMist is not indicated for immunization of individuals less than 5 years
of age, or 50 years of
age and older, or for therapy of influenza, nor will it protect against
infections and illness caused
by infectious agents other than influenza A or B viruses.
CONTRAINDICATIONS
Under no circumstances should FluMist be administered parenterally.
Individuals with a history of hypersensitivity, especially anaphylactic
reactions, to any component
of FluMist, including eggs or egg products, should not receive FluMist (see
DESCRIPTION).
Package Insert (Circular)
16 June 2003
Page 8 of 19
FluMist is contraindicated in children and adolescents (5-17 years of age)
receiving aspirin
therapy or aspirin-containing therapy, because of the association of Reye
syndrome with aspirin
and wild-type influenza infection.
FluMist should not be administered to individuals who have a history of
Guillain-Barré syndrome.
As with other live virus vaccines, FluMist should not be administered to
individuals with known or
suspected immune deficiency diseases such as combined immunodeficiency,
agammaglobulinemia, and thymic abnormalities and conditions such as human
immunodeficiency
virus infection, malignancy, leukemia, or lymphoma. FluMist is also
contraindicated in patients
who may be immunosuppressed or have altered or compromised immune status as
a
consequence of treatment with systemic corticosteroids, alkylating drugs,
antimetabolites,
radiation, or other immunosuppressive therapies.
WARNINGS
The safety of FluMist in individuals with asthma or reactive airways disease
has not been
established. In a large safety study in children 1-17 years of age, children
<5 years of age who
received FluMist were found to have an increased rate of asthma within 42
days of vaccination
when compared to placebo recipients (see ADVERSE REACTIONS). FluMist should
not be
administered to individuals with a history of asthma or reactive airways
disease.
The safety of FluMist in individuals with underlying medical conditions that
may predispose them
to severe disease following wild-type influenza infection has not been
established. FluMist is not
indicated for these individuals. According to the Advisory Committee on
Immunization Practices
(ACIP), such individuals include, but are not limited to, adults and
children with chronic disorders
of the cardiovascular and pulmonary systems, including asthma; pregnant
women who will be in
their second or third trimesters during influenza season; adults and
children who required regular
medical follow-up or hospitalization during the preceding year because of
chronic metabolic
diseases (including diabetes), renal dysfunction, or hemoglobinopathies; and
adults and children
with congenital or acquired immunosuppression caused by underlying disease
or
immunosuppressive therapy (see CONTRAINDICATIONS). Intramuscularly
administered
inactivated influenza vaccines are available to immunize high-risk
individuals [1].
As with any vaccine, FluMist may not protect 100% of individuals receiving
the vaccine.
PRECAUTIONS
General
CARE IS TO BE TAKEN BY THE HEALTH CARE PROVIDER FOR THE SAFE AND
EFFECTIVE USE OF THIS PRODUCT.
Package Insert (Circular)
16 June 2003
Page 9 of 19
Prior to administration of FluMist, individuals or their parent/guardian
should be asked about their
current health status, their personal medical history and the medical
history of household and
close contacts, including immune status, to determine the existence of any
contraindications (see
CONTRAINDICATIONS and WARNINGS) to immunization with FluMist. FluMist
recipients
should avoid close contact (e.g., within the same household) with
immunocompromised
individuals for at least 21 days.
EPINEPHRINE INJECTION (1:1000) OR COMPARABLE TREATMENT MUST BE READILY
AVAILABLE IN THE EVENT OF AN ACUTE ANAPHYLACTIC REACTION FOLLOWING
VACCINATION. The health care provider should ensure prevention of any
allergic or other
adverse reactions by reviewing the individual's history for possible
sensitivity to influenza vaccine
components, including eggs and egg products.
Administration of FluMist should be postponed until after the acute phase
(at least 72 hours) of
febrile and/or respiratory illnesses.
Information for Vaccine Recipients or Parents/Guardians
Vaccine recipients or their parents/guardians should be informed by the
health care provider of
the potential benefits and risks of FluMist, and the need for two doses for
the first use of FluMist
in 5-8 year olds. Due to the possible transmission of vaccine virus, vaccine
recipients or their
parents/guardians should be advised to avoid close contact (e.g., within the
same household)
with immunocompromised individuals for at least 21 days. The vaccine
recipient or the
parent/guardian accompanying the vaccine recipient should be told to report
any suspected
adverse events to the physician or clinic where the vaccine was administered
(see ADVERSE
EVENT REPORTING).
Drug Interactions
Children or adolescents who are receiving aspirin therapy or
aspirin-containing therapy should
not receive FluMist (see CONTRAINDICATIONS). FluMist should not be
administered to persons
on immunosuppressive therapy.
The concurrent use of FluMist with antiviral compounds that are active
against influenza A and/or
B viruses has not been evaluated. However, based upon the potential for
interference between
such compounds and FluMist, it is advisable not to administer FluMist until
48 hours after the
cessation of antiviral therapy and that antiviral agents not be administered
until two weeks after
administration of FluMist unless medically indicated.
There are no data regarding co-administration of FluMist with other
intranasal preparations,
including steroids.
Package Insert (Circular)
16 June 2003
Page 10 of 19
Concurrent Administration with Other Vaccines
The safety and immunogenicity of FluMist when administered concurrently with
other vaccines
have not been determined. Therefore, FluMist should not be administered
concurrently with other
vaccines. Studies of FluMist in healthy individuals excluded subjects who
received any live virus
vaccine within one month of enrollment and any inactivated or subunit
vaccine within two weeks
of enrollment; therefore, health care providers should adhere to these
intervals when
administering FluMist.
Laboratory Interactions
Data related to shedding of FluMist in children and adults are limited.
Nasopharyngeal secretions
or swabs collected from vaccinees may test positive for influenza virus for
up to three weeks.
Carcinogenesis, Mutagenesis, Impairment of Fertility
FluMist has not been evaluated for its carcinogenic or mutagenic potential
or its potential to
impair fertility.
Pregnancy (Category C)
Animal reproduction studies have not been conducted with FluMist. It is also
not known whether
FluMist can cause fetal harm when administered to a pregnant woman or affect
reproduction
capacity. Therefore, FluMist should not be administered to pregnant women.
Nursing Mothers
It is not known whether FluMist is excreted in human milk. Therefore, as
some viruses are
excreted in human milk and additionally, because of the possibility of
shedding of vaccine virus
and the close proximity of a nursing infant and mother, caution should be
exercised if FluMist is
administered to nursing mothers.
Pediatric Use
The safety of FluMist in infants and children <60 months of age has not been
established (see
CLINICAL STUDIES, INDICATIONS AND USAGE, and ADVERSE REACTIONS).
Geriatric Use
Clinical studies with FluMist did not include sufficient numbers of adults
age 65 years and older to
determine if they respond differently from younger individuals. The safe use
of FluMist in persons
65 years and older has not been established (see CLINICAL PHARMACOLOGY and
DOSAGE
AND ADMINISTRATION).
Package Insert (Circular)
16 June 2003
Page 11 of 19
ADVERSE REACTIONS
See CLINICAL STUDIES for a description of the number of participants in
clinical trials.
Serious Adverse Events
Across all clinical trials, serious adverse events (SAEs) were monitored
after vaccination for 42
days in children and for 28 days in adults. SAEs occurred at a similar rate
(<1%) in FluMist and
placebo recipients for both healthy children and healthy adults.
Overall, across the placebo-controlled trials in adults and children, the
incidence of selected
adverse reactions that may be complications of influenza (such as pneumonia,
bronchitis,
bronchiolitis, or central nervous system events) was similar in FluMist and
placebo groups.
Adverse Events in Placebo-Controlled Trials
In all placebo-controlled studies, allantoic fluid from uninfected eggs was
used as the placebo. In
randomized, placebo-controlled trials, 4719 healthy children 5-17 years of
age and 2864 healthy
adults 18-49 years of age received FluMist and 2327 healthy children and
1454 healthy adults
received the placebo. In placebo-controlled clinical trials conducted in
healthy populations,
solicited adverse events and daily temperatures were collected on diary
cards. These solicited
events included runny nose/nasal congestion, sore throat, cough,
irritability, headache, chills,
vomiting, muscle aches, and decreased activity and a feeling of
tiredness/weakness.
Solicited Adverse Events in Children
Table 3 shows an analysis of solicited events for the Pediatric Efficacy
Study in the subset of
healthy children 60-71 months of age. The largest absolute differences
between FluMist and
placebo after Dose One were observed in the incidences of headache and runny
nose/nasal
congestion. No differences were observed for fever (>100°F oral). Following
Dose Two, the
largest absolute differences between FluMist and placebo were runny
nose/nasal congestion and
cough.
Package Insert (Circular)
16 June 2003
Page 12 of 19
Table 3
Summary of Solicited Events Observed within 10 Days after Each Dose for
Vaccine and Placebo Recipients; Healthy Children 60–71 Months of Age
Post-Dose One Post-Dose Two
FluMist Placebo FluMist Placebo
214a 95a 161a 75a
Event % % % %
Any event 65.4 61.4 66.5 53.3
Cough 26.8 32.7 38.5 30.7
Runny Nose/
Nasal Congestion 48.1 44.2 46.0 32.0
Sore Throat 12.6 19.8 9.3 16.0
Irritability 19.5 16.8 9.9 9.3
Headache 17.8 11.6 6.8 16.0
Chills 6.1 5.3 2.5 4.0
Vomiting 4.7 3.2 5.6 12.0
Muscle Aches 6.1 4.2 5.0 4.0
Decreased Activity 14.0 12.6 10.6 13.3
Feverb
Temp 1 9.5 9.9 4.3 4.0
Temp 2 2.2 2.0 0.6 1.3
Temp 3 0.0 0.0 0.0 0.0
Note: There were no statistically significant differences in any of these
events (p-value >0.05); Fisher’s
Exact method.
a Number of evaluable subjects (those who returned diary cards) for each
event.
b Fever
Temp 1: Oral >100°F, rectal or aural >100.6°F, or axillary >99.6°F.
Temp 2: Oral >102°F, rectal or aural >102.6°F, or axillary >101.6°F.
Temp 3: Oral >104°F, rectal or aural >104.6°F, or axillary >103.6°F.
For the cohort of 128 children who received FluMist across three consecutive
years, rates of
solicited adverse events were not significantly increased when compared to
placebo recipients
[4].
Other Adverse Events in Children
In addition to the solicited events, parents also reported other adverse
events that occurred
during the course of the clinical trials.
Among healthy children age 60-71 months in the Pediatric Efficacy Study, the
events that
occurred in at least 1% of FluMist recipients and at a higher rate compared
to placebo were:
abdominal pain (3.7% FluMist vs 0% placebo), otitis media (1.4% FluMist vs
0% placebo),
Package Insert (Circular)
16 June 2003
Page 13 of 19
accidental injury (2.3% FluMist vs 2.1% placebo), diarrhea (3.7% FluMist vs
1.1% placebo),following Dose One and otitis media (3.1% FluMist vs 1.3% placebo) following
Dose Two. None
of these differences were statistically significant.
Medically Attended Events in Children and Adolescents
A large randomized, double-blind, placebo-controlled trial in healthy
children 1 through 17 years
of age was conducted at 31 clinics in the Northern California
Kaiser-Permanente Health
Maintenance Organization (HMO) to assess the rate of medically attended
events (MAEs) within
42 days of vaccination. Participants were randomized 2:1 (vaccine:placebo).
A total of 6657
evaluable children 5-17 years of age were enrolled, including 3244 boys and
3413 girls. Of these
6657 children, 2606 were 5-8 years of age and 4051 were 9-17 years of age.
Dose Two for
children less than nine years of age was to be administered 28 to 42 days
after Dose One.
Data regarding MAEs were obtained from the Kaiser-Permanente computerized
health care
utilization databases for hospitalizations, emergency department visits and
clinical visits. MAEs
were analyzed individually and within four pre-specified grouped diagnoses:
acute respiratory
tract events, systemic bacterial infections, acute gastrointestinal tract
events, and rare events
potentially related to influenza. For these four pre-specified grouped
diagnoses, no significant
increase in risk for FluMist recipients was seen in the combined analyses
across all utilization
settings, doses, and age groups. Selected respiratory tract illnesses of
special interest
(pneumonia, bronchitis, bronchiolitis, and croup) were included in acute
respiratory tract events
and were not associated with increased risk for FluMist recipients in any
protocol-specified
analysis. No systemic bacterial infection occurred. In FluMist recipients,
an increased risk was
not observed for rare events that have been reported with naturally
occurring influenza virus
infection, including seizures(s), febrile seizures, and epilepsy. No cases
of encephalitis, acute
idiopathic polyneuritis (Guillain-Barré syndrome), Reye syndrome, or
myocarditis (influenzaassociated
rare disorders) were reported in this study.
In this study, in individuals 5-17 years of age, four individual MAEs were
significantly increased
and 11 were significantly decreased. Of the four individual MAEs associated
with increased risk,
a biological association with FluMist is plausible for one: abdominal pain.
Of the 11 individual
MAEs associated with decreased risk, a biologically plausible association
with FluMist exists for
seven: asthma, bronchitis, conjunctivitis, cough, viral syndrome, otitis
media, and
wheezing/shortness of breath. However, in the same study, a statistically
significant increase in
asthma or reactive airways disease was observed for children 12-59 months of
age following
Dose One (Relative Risk 3.53, 90% CI: 1.1,15.7). As a result of this
finding, FluMist is not
indicated for children <60 months of age.
Package Insert (Circular)
16 June 2003
Page 14 of 19
Solicited Adverse Events in Adults
In the placebo-controlled Adult Effectiveness Study, the rate of solicited
adverse events in the
subset of healthy adults 18-49 years of age are shown in Table 4.
Statistically significant
differences were observed for any event, cough, runny nose, sore throat,
chills, and
tiredness/weakness. Fever >100° F was similar in FluMist and placebo
recipients after a single
dose.
Table 4
Summary of Solicited Events Observed within 7 Days after
Each Dose for Vaccine and Placebo Recipients;
Healthy Adults 18–49 Years of Age
FluMist Placebo
N=2548a N=1290a
Event (%) (%)
Any event 71.9* 62.6
Cough 13.9* 10.8
Runny Nose 44.5* 27.1
Sore Throat 27.8* 17.1
Headache 40.4 38.4
Chills 8.6* 6.0
Muscle Aches 16.7 14.6
Tiredness/Weakness 25.7* 21.6
Fever
Oral Temp >100°F 1.5 1.3
Oral Temp >101°F 0.5 0.7
Oral Temp >102°F 0.1 0.2
Oral Temp >103°F 0.0 0.0
* Denotes statistically significant p-value ≤0.05; no adjustments for
multiple comparisons;
Fisher’s Exact Method.
a Number of evaluable subjects (those who returned diary cards). [97.9% of
FluMist recipients and 97.9% of placebo recipients.]
Other Adverse Events in Adults
In addition to the solicited events, participants also reported other
adverse events that occurred
during the course of the clinical trials.
For adults 18-49 years of age in the Adult Effectiveness Study, nasal
congestion (9.2% FluMist vs
2.2% placebo), rhinitis (6.3% FluMist vs 3.1% placebo), and sinusitis (4.1%
FluMist vs 2.2%
placebo) were reported significantly more often by FluMist recipients
compared to placebo
recipients.
Package Insert (Circular)
16 June 2003
Page 15 of 19
ADVERSE EVENT REPORTING
Reporting by vaccine recipients or the parents/guardians of vaccinees and
health care providers
of all adverse events occurring after vaccine administration is encouraged.
The U.S. Department
of Health and Human Services (DHHS) has established a Vaccine Adverse Event
Reporting
System (VAERS) to accept all reports of suspected adverse events after the
administration of any
vaccine. The VAERS toll-free number is 1-800-822-7967. Reporting forms may
also be obtained
at the FDA web site at: http//www.vaers.org.
DOSAGE AND ADMINISTRATION
FOR NASAL USE ONLY. DO NOT ADMINISTER PARENTERALLY.
FluMist should be administered according to the following schedule:
Age Group Vaccination Status Dosage Schedule
Children age 5 years through 8
years
Not previously vaccinated
with FluMist
2 doses (0.5 mL each, 60
days apart ± 14 days) for
initial season
Children age 5 years through 8
years
Previously vaccinated with
FluMist 1 dose (0.5 mL) per season
Children and Adults age 9
through 49 years
Not applicable 1 dose (0.5 mL) per season
For healthy children age 5 years through 8 years who have not previously
received FluMist
vaccine, the recommended dosage schedule for nasal administration is one 0.5
mL dose followed
by a second 0.5 mL dose given at least 6 weeks later. Only limited data are
available on the
degree of protection in children who receive one dose (see CLINICAL
PHARMACOLOGY).
For all other healthy individuals, including children age 5-8 years who have
previously received at
least one dose of FluMist, the recommended schedule is one dose.
FluMist should be administered prior to exposure to influenza. The peak of
influenza activity is
variable from year to year, but generally occurs in the U.S. between late
December and early
March. Because the duration of protection induced by FluMist is not known
and yearly antigenic
variation in the influenza strains is possible, annual revaccination may
increase the likelihood of
protection.
FluMist must be thawed prior to administration. FluMist may be thawed by
holding the sprayer in
the palm of the hand and supporting the plunger rod with the thumb (see
ADMINISTRATION
INSTRUCTIONS); the vaccine should be administered immediately thereafter.
Alternatively,
FluMist may be thawed in a refrigerator and stored at 2-8oC (36-46oF) for no
more than 24 hours
prior to use. When thawed for administration, FluMist is a colorless to pale
yellow liquid and is
Package Insert (Circular)
16 June 2003
Page 16 of 19
clear to slightly cloudy; some proteinaceous particulates may be present but
do not affect the use
of the product.
Approximately 0.25 mL (i.e., half of the dose from a single FluMist sprayer)
is administered into
each nostril while the recipient is in an upright position. Insert the tip
of the sprayer just inside the
nose and depress the plunger to spray. The dose-divider clip is removed from
the sprayer to
administer the second half of the dose (approximately 0.25 mL) into the
other nostril. Once
FluMist has been administered, the used sprayer should be disposed of
according to the standard
procedures for biohazardous waste products.
ADD PDF PICTORIAL HERE (see pictorial, page 19).
HOW SUPPLIED
FluMist is supplied for intranasal delivery in a package of 10 pre-filled,
single-use sprayers
(NDC 66019-100-01).
STORAGE
STORE AT OR BELOW -15°C (5°F).
DO NOT REFREEZE AFTER THAWING.
UPON RECEIPT, FluMist SHOULD BE IMMEDIATELY STORED AT -15°C (5°F) OR BELOW.
FluMist may be stored in a non-frost-free freezer to be maintained
continuously at –15oC (5oF) or
below.
Storage of FluMist in a frost-free freezer should be avoided because the
temperature could cycle
above –15oC (5oF) and can therefore negatively impact the stability of the
product.
FluMist may be thawed in a refrigerator and stored at 2-8oC (36-46oF) for no
more than
24 hours prior to use.
For information regarding product storage and stability under conditions
other than those
recommended, call 1-800-411-0086.
REFERENCES
1. Centers for Disease Control and Prevention. Prevention and control of
Influenza:
recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR
2003; 52 (No.RR-8):1-34.
2. Murphy BR, Coelingh KC. Principles underlying the development and use of
live
attenuated cold-adapted influenza A and influenza B virus vaccines. Viral
Immunol.
2002;15:295-323.
Package Insert (Circular)
16 June 2003
Page 17 of 19
3. Jin H, et al. Multiple amino acid residues confer temperature sensitivity
to human
influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann
Arbor/6/60.
Virology. 2003;306:18-24.
4. MedImmune data on file.
5. Monto AS, Sullivan KM. Acute respiratory illness in the community.
Frequency of illness
and the agents involved. Epidemiol Infect. 1993;110:145-160.
6. Sullivan KM. Health impact of influenza in the United States.
Pharmacoeconomics.
1996;9 Suppl. 3:26-33.
7. Barker WH, Mullooly JP. Impact of epidemic Type A influenza in a defined
adult
population. Am J Epi. 1980; 112:798-811.
8. Thompson WW, et al. Mortality associated with influenza and respiratory
syncytial virus
in the United States. JAMA. 2003;289:179-186.
9. Murphy BR, Clements ML. The systemic and mucosal immune response of
humans to
influenza A virus. Curr Topics in Micro Immun. 1989;146:107-116.
10. McMichael AJ, et al. Cytotoxic T-cell immunity to influenza. N Engl J
Med. 1983;309:
13-17.
11. Belshe RB, et al. Correlates of immune protection induced by live,
attenuated, coldadapted,trivalent, intranasal influenza virus vaccine. J Infect Dis.
2000a;181:1133-1137.
12. Treanor JJ, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T)
and inactivated
(TIV) influenza vaccines in prevention of virus infection and illness
following challenge of
adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine.
2000;18:899-906.
13. Belshe RB, et al. The efficacy of live attenuated, cold-adapted,
trivalent, intranasal
influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412.
14. Belshe RB, et al. Efficacy of vaccination with live attenuated,
cold-adapted, trivalent,
intranasal influenza virus vaccine against a variant (A/Sydney) not
contained in the
vaccine. J Peds. 2000b;136:168-175.
15. Nichol KL, et al. Effectiveness of live, attenuated intranasal influenza
virus vaccine in
healthy, working adults. JAMA. 1999;282:137-144.
16. Vesikari T, et al. A randomized, double-blind, placebo-controlled trial
of the safety,
transmissibility and phenotypic stability of a live, attenuated,
cold-adapted influenza virus
vaccine (CAIV-T) in children attending day care. Presented at the 41st
Annual
Package Insert (Circular)
16 June 2003
Page 18 of 19
Interscience Conference on Antimicrobial Agents and Chemotherapy, (Chicago,
IL).
2001.
17. Longini IM, et al. Estimating household and community transmission
parameters for
influenza. Am J Epidemiol. 1982;115:736-751.
Manufactured by:
MedImmune Vaccines, Inc.
Gaithersburg, MD 20878
Marketed by:
MedImmune Vaccines, Inc.
Gaithersburg, MD 20878
and
Wyeth Vaccines
Philadelphia, PA 19101
Component No. Issue Date:
U.S. Government License No. 1652
Package Insert (Circular)
16 June 2003
Page 19 of 19
ADMINISTRATION INSTRUCTIONS
http://www.bouldernews.com/bdc/county_news/article/0,1713,BDC_2423_2363910,0
0.html
The Daily Camera
Nasal flu vaccine difficult to find Needle-free option carries more risks,
is more expensive
By Lisa Marshall, Camera Staff Writer
October 21, 2003
Needle-phobics wishing to fend off the flu have a new, injection-free option
this season. But they may have to look hard to find it and pay through the
nose for it. Five months after the Food and Drug Administration approved
FluMist, the nation's first nasal vaccine, few local clinics are offering
it, and despite a $25 million TV and print advertising blitz, few patients
are asking for it.
"When it first came out, people were like 'Oh wow. This is going to be a
great thing. But the practicality is, it is not that appealing financially
and there are more risks,'" said Louisville physician David Nuhfer, one of
the few Boulder County doctors offering the vaccine. While a traditional
influenza shot costs around $15 and is often covered by insurance, FluMist
costs $65 or more and must typically be paid for out-of-pocket. Because the
nasal vaccine is made from a weakened live
vaccine rather than a dead one, like the shot, there is some risk that a
person with a compromised immune system could get sick from it, or a healthy
person could get the shot and pass the virus on to a sick loved one.
The vaccine is only recommended for healthy people age 5 to 49.
"Potentially, you could pass it on to grandma who has cancer," said Nuhfer,
who plans to carefully screen anyone inquiring about the nasal vaccine. The
upside of the shot, doctors say, is that it may lure shot-averse adults and
kids who might otherwise skip their influenza vaccine altogether. "There are
a lot of people who don't get a flu shot at all because they are petrified
of needles," said Jennifer Freeman, of Boulder-based Passport Health, a
traveling clinic that is offering the shot.
There are, however, other problems with the vaccine.
On Friday, Wal-Mart Stores Inc. announced that the company was backing out
of plans to offer the vaccines at 1,000 of its stores because several state
pharmacy boards have been raising questions about whether it is legal or not
for pharmacists to administer it. The Colorado Board of Pharmacy is
currently considering the matter. The new vaccine must also be stored frozen
and shipped directly to the point of delivery, which can make it difficult
to offer at mass immunization clinics.
Despite the drug's seemingly rocky start, and the tumble its stock took —
from about $33.50 per share Wednesday to $28.64 per share Monday — at the
news of Wal Mart's change of heart, officials at Maryland-based MedImmune
Inc., which makes FluMist, say they are still optimistic. Recent television
ads and full-page ads in Newsweek and other publications are expected to
spike interest.
"It is still very early in the season," said MedImmune spokesperson Jamie
Lacey, noting that more than 14,000 outlets nationwide are offering the
vaccine. Ned Cologne, chief medical officer for the Colorado Department of
Public Health and Environment sees FluMist is an intriguing new breakthrough
that could someday change the way vaccines are administered. "It will be
interesting to watch," he says. If it will help more people get
immunized, that's great, he says.
"But my feeling as a patient is: The shot is quick. It's safe. It's
effective," Cologne said. "Why would I change?"
http://www.9news.com/storyfull.aspx?storyid=20041
9 NEWS, Denver, CO
Colorado flu clinics not stocking up on nasal flu vaccine
Written by: Dr. Stephanie Clements, Medical Reporter
10/22/2003 7:05:00 AM
DENVER - If you've got your mind set on the needle-less flu vaccine, you
might be disappointed at some flu clinics because the new nasal flu mist is
hard to come by in Colorado. It's expensive, needs to stay frozen and isn't
recommended for everyone. Unlike the conventional flu shot where the virus
is killed, the nasal flu mist contains live virus. The live virus has been
attenuated, meaning it's genetically altered so it won't make you sick, but
there have been some reports of what's called viral shedding.
In viral shedding, some of the virus can escape into the air if you sneeze
or blow your nose. And some people can have a reaction to it. The nasal
vaccine's greatest obstacle though is that it's recommended only for healthy
people ages 5 to 49. Pregnant women can't use it, and neither can people
with chronic diseases like asthma and diabetes. Plus, it has to be frozen
right up until you use it.
"That's why you're not going to be seeing it in mass immunization clinics
because the vaccine needs to be frozen and continuously frozen because it is
a live-virus vaccine," said Roberta Smith of Immunization Coalition. Cost is
also an issue. While a traditional flu shot costs around $15 and is
often covered by insurance, FluMist costs $65 or more and must typically be
paid for out-of-pocket.
There are other problems with the vaccine. Last week, Wal-Mart Stores Inc.
said the company was backing out of plans to offer the vaccines at 1,000 of
its stores because of questions about whether it is legal for pharmacists to
administer it. The Colorado Board of Pharmacy is currently considering the
matter.
The makers of the nasal spray FluMist say they are still optimistic. "It is
still very early in the season," said MedImmune Inc. spokesperson Jamie
Lacey, noting that more than 14,000 outlets nationwide are offering the
vaccine. Ned Cologne, chief medical officer for the Colorado Department of
Public Health and Environment, said FluMist could someday change the way
vaccines are administered. "It will be interesting to watch," he said. "But
my feeling as a patient is:
The shot is quick. It's safe. It's effective." The government approved the
nation's first nasal flu vaccine five months
ago.
FROM THE NEW YORK TIMES
http://www.nytimes.com/2003/11/19/business/media/19adco.html?ex=1070256844&e
i=1&en=81ae03bccd28d04a <<<end of address
Advertising: Nasal Spray Mishaps
November 19, 2003
By ANDREW POLLACK
Safety concerns were also an issue. FluMist is a live vaccine, made from
attenuated flu viruses. It can theoretically give people, especially
those with weakened immune systems, a mild case of the flu. MedImmune
executives said the chances of this were extremely low but that somehow
consumers and doctors had gotten misperceptions about the vaccine's
safety.
U.S. IMMUNIZATION NEWS
"MedImmune Seeks Help in Relaunching FluMist"
Washington Post (www.washingtonpost.com) (11/25/03) P. E5; Barbaro, Michael
Maryland biotechnology company MedImmune decreased its sales forecast for
its new, needle-free flu vaccine FluMist from up to $140 million to just $55
million. The company has hired a consultant to determine why the product
failed to generate sales this fall. Since FluMist involves a live vaccine
while injected flu vaccines involve a dead flu virus, some doctors are
advising against its use due to fears that it could cause the flu. MedImmune
will reintroduce FluMist next fall with a lower price and with an emphasis
on the product's safety and convenience. Another detrimental fact keeping
sales of FluMist below expectations is a lack of approval for the product to
treat children under the age of five years or adults over the age of 49
years; MedImmune expects approval for these segments of the market, who are
most vulnerable to the flu, by 2006.
I wanted to take some pictures to the one hour photo in Krogers today,
but remembered they are listed as giving the Flu Mist vax. So, I called them
and was transferred to the pharmacy.
I spoke with a pharmacist and asked her what precautions the store was
taking to protect the immunocompromised from the live flu vaccine being shed
by Flumist recipients. She says, (get this!), "The manufacturer has provided
us with a wall barrier to put up." Stifling my laugh I said, "What happens
when those people go out into the store and are sneezing on the groceries?"
She pauses and asks me to hold on. I'm on hold for several minutes when she
comes back and says "The manufacturer tells us that even when a person
sneezes after getting the flumist, it has already been absorbed and won't be
spread."
I say, "Then why does the package insert say under Precautions that 'Flumist
recipients should avoid close contact with immunocompromised individuals for
at least 21 days'?"
She again pauses and says, "Hold on, I'll check into that." I'm on hold for
at least 5 minutes then get disconnected. So I call back and get a different
pharmacist who won't let me speak to the original one. So I ask her the same
question. I told her I am concerned for myself (asthma) and those of us who
shouldn't be in contact with flumist recipients. She again spouts about the
wall barrier. I say, "But this is an airborne virus." (Double DUH!!) She
says the manufacturer has assured them that even if someone sneezes on them
when they give the vaccine, that it has already been absorbed (in
nanoseconds I assume!) and that they themselves shouldn't be concerned. HA!
They may be fools, but I'm not! : )
She tries to tell me that only those who live in close contact 24/7 need be
concerned (why though, if it isn't spread after it's given?) They're
contradicting themselves coming and going! I asked her what the difference
was with me being in a store where people are sneezing all over the produce
that I may be purchasing and living with someone who is doing the same??
She said it's no different than going into a doctor's office where it's been
given (excuse me, but even if I did go to one, I don't buy my groceries at
the doctor's office!)
She had no answers. All she had to offer was what the "manufacturer" had
assured them was ok and she said "Long term studies show it is safe to the
population." But in right before that she says they haven't even given any
flumist there at Krogers and she doesn't know anyplace that has actually
given it because it is so expensive and because it's brand new no one
expects it to be used anyway!!!!!
Idiots... they have no idea what they are doing and when questioned they
babble on and spout what the "manufacturer" has told them to say without
truly knowing the facts!
Kay
I forgot to add the kicker to my last post... After talking with the 2nd
pharmacist ad nauseum about the risks to the immunocompromised, she says,
"Well, the worst thing that could happen to you is you would get the flu."
It was then I realized I was up against a genius, thanked her for her time
and hung up!
Does This Smell Bad?
Health Sciences Institute e-Alert
December 10, 2003
Dear Reader,
You've probably heard the news by now: Doctors are running low on flu
vaccines and are expected to run out completely before the flu season winds
down. In one of the TV reports I saw, the commentator asked, "How could this
happen?" And I had to laugh. How could it happen?
Hmmm... let's put on our thinking caps and try real hard to figure it out.
Could it possibly be because nearly every TV news broadcast for the past
month has been saying that this will be the worst flu season in years and
everyone needs to drop what they're doing - RIGHT NOW! - and go get a flu
shot?
Making this news all the more dire is the fact that the final drop of flu
vaccine has already been shipped out, so once the vaccine supply is used up,
no more vaccine can be produced until next year. But before you barricade
yourself in your home, vowing to stay safe inside until the flu season has
passed, rest assured that there JUST HAPPENS to be an alternative to
the dwindling vaccine supplies.
--------------------------------------------------------------
Come and get it!
--------------------------------------------------------------
Remember FluMist? It's the nasal-spray flu vaccine I first told you about in
the e-Alert "Nose Candy" (7/8/03). Unlike the conventional flu shot, which
contains inactivated flu strains, FluMist contains three living flu strains.
The Centers for Disease Control (CDC) calls FluMist "live attenuated
influenza vaccine" or LAIV. In other words, the three strains are diluted.
They're alive as you or me, but watered down.
Now - a show of hands - how many would feel comfortable inhaling not one,
not two, but THREE LIVING flu strains? Not too many, is my guess. Which is
probably one of the main reasons why ABC News has described sales of FluMist
as "disappointing." Disappointing so far, anyway.
According to the Washington Post, the CDC gave FluMist a nice little boost
last week when a statement was released "reminding" the public that FluMist
is an appropriate alternative to the flu
shot for those who are both healthy and between the ages of 5 and 49. Then
on Monday, CDC director Dr. Julie Gerberding made appearances on several
national news broadcasts (including ABC and CNN) and mentioned that a large
supply of FluMist is still available.
Now is it just me and my cynical streak, or does it seem somehow to be a
very, let's say "interesting," coincidence that the country has been plunged
into this supposedly dire emergency of vaccine shortage in the same year
that a major new vaccine product is launched? No one I know has said they
haven't been able to get a flu shot. And I haven't read about any doctors
turning away patients who have requested a shot. But if the CDC says the
supply is low, then I suppose the supply is low. And if the CDC says that
the supply of FluMist is high, then I'm sure the supply is high.
What Dr. Gerberding didn't mention is that FluMist costs more than twice the
amount of the flu shot. And because of this much steeper cost, many
insurance companies won't offer coverage for
FluMist. But that's only part of the FluMist problem.
--------------------------------------------------------------
Pig in a poke
--------------------------------------------------------------
As I stated in the July e-Alert, there's a long list of potential problems
with FluMist, but one of the key problems is the fact that those who decide
to sniff living viruses into their heads instantly become infected by the
flu. The immune system then responds by creating more antibodies that, in
theory, will fight off any full-strength flu strains that might come along.
But in the meantime, there's a possibility that those who are recently
FluMisted could be (I'll bet you already guessed it) contagious!
Nice. Just what we need in the middle of a supposed flu epidemic: more
contagious people running around.
Of course, the makers of FluMist (MedImmune, a subsidiary of the drug giant
Wyeth) play down the possibility of their product spreading the flu, stating
that only a very small percentage of FluMist users will actually transmit a
virus. Nevertheless, according to a report in Knight-Ridder Newspapers, the
CDC cautions those who get a FluMist vaccine to stay away from people with
vulnerable immune systems, such as the elderly or those struggling with
diseases, for one week. But is one week long enough? Some hospitals are
telling their personnel to allow three full weeks between their
FluMist vaccine and contact with hospital patients.
Why the discrepancy? My guess is that this is such a new vaccine that no one
really knows the parameters yet. Nevertheless, the CDC seems to be going out
of their way to help MedImmune move their struggling product.
Add to that; the CDC web site states: "The optimal time to receive influenza
vaccine is usually in October or November." So if they're using the same
calendar I'm using, we're already 10 days past the optimal usage period.
And add to that; the people who supposedly need a flu vaccine the most - the
elderly, and those with immune system diseases - shouldn't be taking FluMist
at all. The FDA hasn't approved it for them. So the CDC is pressing those
who are least vulnerable to the flu to run out and get a snootful of this
expensive and relatively untested product, even though it's almost two weeks
past the optimal timing for the vaccine to even work!
Does any of this smell bad to you?
"The Vaccine
That Missed"
Washington Post (www.washingtonpost.com) (01/23/04) P. E1; Barbaro,
Michael
The true cost of the influenza vaccine nasal spray FluMist is becoming
clearer, as Wyeth has announced that it took a $20 million charge to
write off the FluMist doses it produced with MedImmune but was unable to
sell in 2003. Though the flu season was unusually early and relatively
severe, Wyeth and MedImmune were only able to sell one-fourth of the
FluMist they had originally expected to sell, resulting in 2003 sales of
just $15.3 million, which analysts say corresponds to fewer than 1
million doses sold. The poor sales underline the difficulty facing
vaccine makers in producing a big seller, even under positive conditions
for the product, especially as FluMist was much more expensive than the
injected version of the vaccine. Wyeth said on Thursday that it is
working with MedImmune to develop a new marketing and sales strategy for
FluMist in 2004, with analysts suggesting that they may agree to cut the
price for the nasal spray vaccine to a losing figure in order to build
demand for future flu seasons.
http://www.ajc.com/health/content/shared-auto/healthnews/flu-/517623.html
The Atlanta Journal-Constitution
Tough Times for Nasal Flu Vaccines
WEDNESDAY, Feb. 25 (HealthDayNews) -- When the U.S. Food and Drug
Administration gave approval last year to a new nasal spray flu vaccine
called FluMist, some analysts predicted it could become a blockbuster.
Instead, sales sank like a stone. Appearing before a federal health panel
on Tuesday, officials from Maryland-based MedImmune Inc., the maker of
FluMist, said sales have been dismal. Only one million of five million
doses have been sold, despite a flu season marked by an usually early and
harsh start, The New York Times reports. "Our initial launch was very
disappointing," Dr. Peter A. Patriarca, of MedImmune, told the panel, the
Advisory Committee on Immunization Practices. The 15-person panel is
appointed by the U.S. Department of Health and Human Services to guide
the Centers for Disease Control and Prevention on recommendations for
influenza and a number of other immunizations, according to the Times.
Not even a shortage of traditional flu vaccines could boost sales of
FluMist, approved for healthy people ages 5 to 49. The drug companies
that make traditional vaccines produced 87 million flu doses for this
season. But because the season began in October, leading to high demand
for flu shots, the manufacturers said they had sold all their supplies to
distributors by December.
Patriarca attributed FluMist's sagging sales to a series of factors,
including price. Doctors charged their patients up to $150 for FluMist,
he said. Not even a rebate program offered by MedImmune could jumpstart
sales, the Times reports.
FluMist's woes aren't the only worrisome news about nasal flu vaccines.
A new study finds a possible link between a different nasal flu vaccine
and Bell's palsy, a temporary paralysis of the facial muscles.
Researchers who were looking into the cause of an unusual number of cases
of Bell's palsy in Switzerland began noticing a connection with people
who had used a nasal vaccine called Nasalflu. Bell's palsy is a
neurological paralysis of one side of the face that can
last from weeks to months, but doesn't normally have any permanent
effects. The study concludes that Nasalflu, which was used only in
Switzerland but was pulled from the market several years ago, could be a
possible cause of Bell's palsy.
"At this point these are hypothetical conclusions -- no cause has been
determined as to the reason why these people contracted Bell's palsy,"
says Dr. Robert Steffen, of the University of Zurich's Collaborating
Centre for Traveller's Health, and one of the study's authors. "What we
were able to do is prove a strong association between the flu vaccine and
Bell's palsy, but we cannot demonstrate why at this point."
The study appears in the Feb. 26 issue of the New England Journal of
Medicine. Health experts, however, don't see a link between the potential
problems associated with Nasalflu, and FluMist. "It would be hard to see
an association," says Ira M. Longini Jr., of Emory University. "I just
don't know where it would be. These are completely different vaccines:
one [FluMist] is a live attenuated and cold-adapted virus and one [Nasalflu]
is deactivated -- totally different." Nasalflu was manufactured by the
Swiss company Berna Biotech AG, and was used in Switzerland in the
2000-2001 flu season. It was pulled by the company when reports of
possible Bell's palsy cases began surfacing.
Wednesday, September 26, 2007
Moldy FluMist Holds Up Final FDA Approval
by Barbara Loe Fisher
Until June 2003, when the FDA approved the first live virus flu vaccine,
FluMist, the only flu vaccine that was used in the US was the killed or
inactivated flu vaccine injected into the arm. FluMist manufactured by
MedImmune was the first vaccine designed to be squirted up the nose and
given to healthy children and adults. Generally, Americans have not been
enthusiastic about squirting live virus flu vaccine up their noses. Call it
irrational. Call it the "yuck" factor. Call it instinct. FluMist has largely
remained a non-starter.
The fact that the FDA had to recently slap MedImmune on the hands after
inspectors reportedly found excessive amounts of mold and bacteria during
early stages of the production process of FluMist doesn't help. A September
10, 2007 Washington Post article said the company was cited for "significant
deviations for current good manufacturing practice."
http://www.washingtonpost.com/wp-dyn/content/article/2007/09/09/AR2007090901
612.html?nav=rss_business
In pre-licensure clinical trials of FluMist, there was an increased risk of
asthma, upper respiratory infections, musculoskeletal pain, otitis media and
croup for some children and an increased risk for upper respiratory symptoms
in adults after inhaling the live vaccine. FluMist contains attenuated live
flu viruses and poses a risk of transmission of live flu virus from the
recently vaccinated to close contacts. When I was sitting on the FDA
Vaccines and Related Biological Products Advisory Committee in 2002, I voted
"no" when asked if safety had been proven.
http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3912t1-03.pdf
Among other things, I said "The fact that live vaccine flu virus is shed in
80 percent of recipients poses an additional risk for our population at
large, particularly for immune compromised individuals across all age
groups. The outstanding questions about the true rate of transmission of
vaccine strain viruses among children needs to be clarified as does the
retention of the attenuation of shed viruses and the high frequency of
nucleotide changes. Because this live virus nasal vaccine is not indicated
for high risk health groups, which have historically been the targeted
populations to receive flu vaccine, it's a very serious step to move to the
use of a live virus vaccine for the majority of healthy individuals, and a
standard for proof of safety must be very high. I don't think that standard
has yet been met by the data which have been presented so far."
Initially, the FDA approved the vaccine for healthy children over 5 and
adults under 49. Both MedImmune and vaccine distributor, Wyeth, thought they
had a blockbuster on their hands. In the summer and fall of 2003, the
companies launched a $100 million ad campaign that featured Wal Marts
offering to squirt the vaccine up the noses of shoppers.(MedImmune,
Inc. [Investors] News Releases. September 10, 2003 "FluMist Available in
Pharmacies This Fall."). At a cost of between $46 and $150 a dose, the
companies were projecting between $120 million and $140 million in sales.
But by late October 2003, it became apparent that few of the four million
doses of FluMist that MedImmune had produced were being purchased. By
January 2004, the company was trying to give it away. MedImmune has been
trying to capture market share for FluMist ever since the disastrous FluMist
debut in the 2003-2004 flu season.
Now, the FDA has given MedImmune (recently acquired by British drug firm
Astra Zeneca) another chance by approving FluMist for healthy children over
two years. But still, the warning remains about not giving FluMist to anyone
with asthma or children under five with a history of wheezing.
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01705.html
What healthy adults and parents of healthy children need to ask themselves
is: why do healthy people need to deliberately inhale live flu viruses when
the majority of healthy people don't get that sick from the flu and recover
without any complications? Keep reading NVIC's E-News for further reports on
the Flu and You as the flu season approaches and the Flu Patrol gears up to
scare the living daylights out of you so you inhale deeply or roll up your
sleeve without giving it a second thought.
In the News:
"The FDA sent the Gaithersburg firm a lengthy warning letter in May, citing
"significant deviations from current good manufacturing practice." Agency
officials were concerned that MedImmune had not properly followed up after
excessive levels of mold and bacteria were found during early stages of the
production process. The FDA said the vaccine had not been contaminated. The
FDA's warning letter has held up shipments of FluMist. It also put on hold
MedImmune's efforts to win regulatory approval for use of the vaccine by
children under 5. Expanding the vaccine's use in that important market has
been a cornerstone of the firm's efforts to boost the prospects for FluMist,
which has not been a hit in the marketplace. It is now approved only for
people ages 5 to 49. FDA and MedImmune officials said the process to win
approval for use by younger children could now continue. Less than two weeks
before the warning letter was issued, an FDA advisory panel unanimously
agreed that FluMist worked in children under 5. The panel was mixed on
whether FluMist was safe enough for children younger than 2." - Michael
Rosenwald, Washington Post (September 10, 2007)
http://www.washingtonpost.com/wp-dyn/content/article/2007/09/09/AR2007090901612.html?nav=rss_business
"The U.S. Food and Drug Administration today approved expanding the
population for use of the nasal influenza vaccine FluMist to include
children between the ages of 2 and 5. Approval for the vaccine, which
contains a weakened form of the live virus and is sprayed in the nose, was
previously limited to healthy children 5 years of age and older and to
adults up to age 49.......Children under the age of 2 should not receive
FluMist because there was an increased risk of hospitalization and wheezing
for this age group during the clinical trials. Commonly observed adverse
events from the vaccine were generally mild and most often included runny
nose and/or nasal congestion, as well as a slight fever in children 2 to 6
years of age. FluMist should not be administered to anyone with asthma or to
children under the age of 5 years with recurrent wheezing because of the
potential for increased wheezing after receiving the vaccine. People who
are allergic to any of FluMist's components, including eggs or egg products,
should also not receive the vaccine....." - FDA Press Release
(September 19, 2007)
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01705.html
MedImmune Says FluMist Problems
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