HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FLULAVAL
safely and effectively. See full prescribing information for FLULAVAL.
FLULAVAL™ (Influenza Virus Vaccine)
Intramuscular Injection
2006-2007 Formula
Initial US Approval: 2006
-------------------------------------------INDICATIONS AND
USAGE----------------------------------
• FLULAVAL is an influenza virus vaccine indicated for active immunization of
adults 18 years of age and older against influenza disease caused by influenza
virus subtypes A and type B contained in the vaccine. (1)
• This indication is based on immune response elicited by FLULAVAL, and there
have been no controlled trials demonstrating a decrease in influenza disease
after vaccination with FLULAVAL. (14)
• FLULAVAL is not indicated for use in children. (8.4)
---------------------------------------DOSAGE AND
ADMINISTRATION-----------------------------
• A single 0.5-mL intramuscular injection. (2.2)
-------------------------------------DOSAGE FORMS AND
STRENGTHS---------------------------
• 5-mL multi-dose vial containing 10 doses (each dose is 0.5 mL). (3)
• Each 0.5-mL dose contains 15 micrograms (mcg) of influenza virus hemagglutinin
(HA) of each of the following 3 strains: A/New Caledonia/20/99 (H1N1),
A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. (3, 11)
• Thimerosal, a mercury derivative, is added as a preservative. Each 0.5 mL dose
contains 25 mcg mercury. (11)
----------------------------------------------CONTRAINDICATIONS-------------------------------------
• Known systemic hypersensitivity reactions to egg proteins, or any other
component of FLULAVAL. (4.1)
• Life threatening reaction to previous influenza vaccination. (4.1)
• Delay immunization in a patient with an acute evolving, neurologic disorder.
(4.2)
---------------------------------------WARNINGS AND
PRECAUTIONS------------------------------
• If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior
influenza vaccine, the decision to give FLULAVAL should be based on careful
consideration of the potential benefits and risks. (5.1) 1
• Individuals with bleeding disorders or receiving anticoagulants are at risk of
hematoma formation following intramuscular administration. Take steps to control
the risk of hematoma following the injection in these persons. (5.2)
• Immunocompromised persons may have a reduced immune response to FLULAVAL.
(5.3)
----------------------------------------------ADVERSE
REACTIONS------------------------------------
• Most common (≥10%) local adverse events were pain, redness, and/or swelling at
the injection site. (6.2)
• Most common (≥10%) systemic adverse events were headache, fatigue, myalgia,
low grade fever, and malaise. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249
or VAERS at 1-800-822-7967 and
www.vaers.hhs.gov.
----------------------------------------------DRUG
INTERACTIONS-------------------------------------
• Do not mix with any other vaccine in the same syringe or vial. (7.1)
• May increase blood levels of warfarin, theophylline, and phenytoin. (7.2)
• Immunosuppressive therapies may reduce immune responses to FLULAVAL. (7.3)
---------------------------------------USE IN SPECIFIC
POPULATIONS-----------------------------
• Safety and effectiveness of FLULAVAL have not been established in pregnant
women and children. (8.1, 8.4)
• Antibody responses were lower in geriatric subjects than in younger subjects.
(8.5)
See 17 for PATIENT COUNSELING INFORMATION.
______________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
2.2 Recommended Dose and Schedule
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Hypersensitivity
4.2 Acute Neurologic Disorder
5 WARNINGS AND PRECAUTIONS
5.1 Guillain-Barré Syndrome
5.2 Persons at Risk of Bleeding
5.3 Altered Immunocompetence
5.4 Preventing and Managing Allergic Vaccine Reactions
5.5 Limitations of Vaccine Effectiveness
6 ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
6.2 Clinical Trials Experience
6.3 Postmarketing Experience 2
6.4 Adverse Events Associated with Influenza Vaccines
7 DRUG INTERACTIONS
7.1 Concomitant Administration with Other Vaccines
7.2 Warfarin, Theophylline, and Phenytoin
7.3 Immunosuppressive Therapies
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
______________________________________________________________________
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
FLULAVAL is indicated for active immunization of adults (18 years of age and
older) against influenza disease caused by influenza virus subtypes A and type B
contained in the vaccine (see DOSAGE FORMS AND STRENGTHS [3]).
This indication is based on immune response elicited by FLULAVAL, and there have
been no controlled trials demonstrating a decrease in influenza disease after
vaccination with FLULAVAL (see CLINICAL STUDIES [14]).
FLULAVAL is not indicated for use in children.
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
Inspect FLULAVAL visually for particulate matter and/or discoloration prior to
administration whenever solution and container permit. If either of these
conditions exists, the vaccine should not be administered.
Shake the multi-dose vial vigorously each time before withdrawing a dose of
vaccine.
Between uses, return the multi-dose vial to the recommended storage conditions,
between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has
been frozen. Once entered, a multi-dose vial, and any residual contents, should
be discarded after 28 days.
A separate sterile syringe and needle or a sterile disposable unit should be
used for each injection to prevent transmission of infectious agents from one
person to another. Needles should be disposed of properly and should not be
recapped.
3
2.2 Recommended Dose and Schedule
FLULAVAL should be administered as a single 0.5-mL injection by the
intramuscular route preferably in the region of the deltoid muscle of the upper
arm.
The vaccine should not be injected in the gluteal area or areas where there may
be a major nerve trunk. A needle length of ≥1 inch is preferred because needles
<1 inch might be of insufficient length to penetrate muscle tissue in certain
adults. Before injection, the skin over the site to be injected should be
cleansed with a suitable germicide. After insertion of the needle, aspirate to
ensure that the needle has not entered a blood vessel.
Do not inject intravenously or subcutaneously.
3 DOSAGE FORMS AND STRENGTHS
FLULAVAL is available as 5-mL multi-dose vials containing 10 doses. Each 0.5–mL
dose contains a total of 45 mcg hemagglutinin from the 3 influenza virus types
in the vaccine.
4 CONTRAINDICATIONS
4.1 Hypersensitivity
FLULAVAL should not be administered to anyone with known systemic
hypersensitivity reactions to egg proteins (eggs or egg products), to chicken
proteins, or to any component of FLULAVAL, or who has had a life threatening
reaction to previous influenza vaccination.
4.2 Acute Neurologic Disorder
Immunization should be delayed in a patient with an acute evolving neurologic
disorder but should be considered when the disease process has been stabilized.
5 WARNINGS AND PRECAUTIONS
5.1 Guillain-Barré Syndrome
If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior
influenza vaccine, the decision to give FLULAVAL should be based on careful
consideration of the potential benefits and risks.
5.2 Persons at Risk of Bleeding
FLULAVAL should not be given to individuals with bleeding disorders such as
hemophilia or thrombocytopenia, or to persons on anticoagulant therapy unless
the potential benefit clearly outweighs the risk of administration. If the
decision is made to administer FLULAVAL to such persons, steps should be
considered to control the risk of hematoma following the injection.
5.3 Altered Immunocompetence
If FLULAVAL is administered to immunocompromised persons, including individuals
receiving immunosuppressive therapy, the expected immune response may not be
obtained.
5.4 Preventing and Managing Allergic Vaccine Reactions
Prior to administration, the healthcare provider should review the patient’s
immunization history for possible vaccine sensitivity, previous
vaccination-related adverse reactions and occurrence of any adverse
event-related symptoms and/or signs, in order to determine the
4
existence of any contraindication to immunization with FLULAVAL and to allow an
assessment of benefits and risks. Epinephrine injection (1:1,000) and other
appropriate agents used for the control of immediate allergic reactions must be
immediately available should an acute anaphylactic reaction occur.
5.5 Limitations of Vaccine Effectiveness
Vaccination with FLULAVAL may not protect 100% of susceptible individuals.
6 ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
Adverse event information from clinical trials provides a basis for identifying
adverse events that appear to be related to vaccine use and for approximating
rates. However, because clinical trials are conducted under widely varying
conditions, adverse event 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.
Safety information for FLULAVAL was collected in 2 clinical trials and is
discussed in the following section (6.2). There is the possibility that broad
use of FLULAVAL could reveal adverse events not observed in clinical trials.
6.2 Clinical Trials Experience
Safety information for FLULAVAL was collected in 2 randomized, controlled
clinical trials, one in the United States (IDB707-105) and the second in Canada
(SPD707-104). The safety population from these trials includes 1,049 adults 18
years of age and older vaccinated with products representative of the current
formulation of FLULAVAL. The US study included subjects 18 to 64 years of age
who were randomized to receive FLULAVAL (n = 721) or a US-licensed trivalent,
inactivated influenza virus vaccine (FLUZONE) (n = 279). The Canadian study
compared 4 vaccine groups: FLULAVAL, a similar investigational formulation of
FLULAVAL with reduced thimerosal, and 2 Canadian-licensed trivalent influenza
vaccines.
Among recipients of FLULAVAL, 56.6% were women; 92.4% of subjects were White,
6.5% Black, 2.7% Native American, and 1.0% Asian. In the US study, 74.8% of the
recipients of FLULAVAL were Hispanic/Latino. The mean age of subjects in the US
study was 38 years (range 18-64 years) and 19% of subjects were 50 to 64 years
of age. In the Canadian study, the mean age was 63 years (range 50-92 years),
and 46.6% were 65 years of age and older.
A series of symptoms and/or findings were specifically solicited by a
diary/memory aid used by subjects for at least the day of vaccination and 3 days
post-treatment (see Table 1). Subjects were actively queried about changes in
their health status through 42 days post-vaccination in the US trial, and six
months post-vaccination in the Canadian study. In addition, spontaneous reports
of adverse events were also collected (see Table 2).
5
Table 1. Solicited Adverse Events in the First 4 Days After Administration of
FLULAVAL or Comparator Influenza Vaccine
US Trial
Adults 18 to 64 years of age
(80% <50 years of age)
Canadian Trial
Adults 50 years of age and older
FLULAVAL
Comparator Influenza Vaccine*
FLULAVAL†
N = 721
N = 279
N = 328
Local Adverse Events
Pain
174 (24%)
85 (31%)
70 (21%)
Redness
76 (11%)
28 (10%)
48 (14%)
Swelling
71 (10%)
29 (10%)
21 (6%)
Systemic Adverse Events
Headache
127 (18%)
48 (17%)
34 (10%)
Fatigue
123 (17%)
43 (15%)
33 (10%)
Myalgia
93 (13%)
44 (16%)
35 (11%)
Fever‡
79 (11%)
28 (10%)
1 (1%)
Malaise
73 (10%)
28 (10%)
13 (4%)
Sore throat
64 (9%)
26 (9%)
17 (5%)
Reddened eyes
44 (6%)
15 (5%)
10 (3%)
Cough
44 (6%)
19 (7%)
11 (3%)
Chills
38 (5%)
6 (2%)
10 (3%)
Chest tightness
24 (3%)
4 (1%)
6 (2%)
Facial swelling
7 (1%)
1 (1%)
1 (1%)
Results >1% reported to nearest whole percent; results >0 but ≤1 reported as 1%.
* US-licensed trivalent, inactivated influenza virus vaccine (FLUZONE).
† Includes subjects who received FLULAVAL and a similar investigational
formulation of FLULAVAL with reduced thimerosal.
‡ Fever defined as ≥37.5°C in the US study, and ≥38.0°C in the Canadian study.
Local adverse events occurred with similar frequency in the 2 trials. In the US
study, the only significant difference between FLULAVAL and a US-licensed
trivalent, inactivated influenza virus vaccine was an increased frequency of
chills in subjects receiving FLULAVAL.
Table 2 summarizes the most common adverse events in the 2 clinical trials;
adverse events were reported, either spontaneously or in response to queries
about changes in health status. The most common events were headache and cough
in both studies. These, as well as throat pain, were the only adverse events
reported by >1% of subjects in the US trial. The Canadian trial featured a
longer safety follow-up (6 months vs. 42 days) and enrolled a population
exclusively 50 years of age and older. Therefore, spontaneous adverse event
reports were more frequent in this trial. As indicated in Table 2, upper
respiratory infection, arthralgia,
6
myalgia, nasopharyngitis, back pain, injection site erythema, diarrhea, fatigue,
nausea, and nasal congestion were each reported by ≥5% of the recipients of
FLULAVAL in the Canadian study.
Table 2. Adverse Events Reported Spontaneously* by ≥5% of Subjects in Either
Clinical Trial of FLULAVAL
US Trial
(safety follow-up 42 days)
Adults 18 to 64 years of age
(80% <50 years of age)
Canadian Trial
(safety follow-up 6 months)
Adults 50 years of age and older
FLULAVAL
Comparator Influenza Vaccine†
FLULAVAL‡
N = 721
N = 279
N = 328
Adverse Events
Headache
49 (7%)
18 (7%)
63 (19%)
Cough
16 (2%)
5 (2%)
48 (15%)
Pharyngolaryngeal pain
17 (2%)
9 (3%)
38 (12%)
Upper respiratory infection
3 (1%)
2 (1%)
30 (9%)
Arthralgia
5 (1%)
3 (1%)
27 (8%)
Myalgia
4 (1%)
2 (1%)
23 (7%)
Nasopharyngitis
1 (1%)
1 (1%)
23 (7%)
Back pain
5 (1%)
3 (1%)
19 (6%)
Injection site erythema
2 (1%)
1 (1%)
18 (5%)
Diarrhea
5 (1%)
0
18 (5%)
Fatigue
6 (1%)
2 (1%)
17 (5%)
Nausea
5 (1%)
1 (1%)
17 (5%)
Nasal congestion
7 (1%)
2 (1%)
16 (5%)
Results >1% reported to nearest whole percent; results >0 but ≤1 reported as 1%.
* Adverse events in this table were reported spontaneously or in response to
queries about changes in health status.
† US-licensed trivalent, inactivated influenza virus vaccine (FLUZONE).
‡ Includes subjects who received FLULAVAL and a similar investigational
formulation of FLULAVAL with reduced thimerosal.
6.3 Postmarketing Experience
The following additional adverse events have been identified during postapproval
use of FLULAVAL in Canada since 2001. Because these events are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their incidence rate or establish a causal relationship to
vaccine exposure. Adverse events described here are included
7
because: a) they represent reactions which are known to occur following
immunizations generally or influenza immunizations specifically; b) they are
potentially serious; or c) the frequency of reporting.
Blood and lymphatic system disorders: Lymphadenopathy.
Eye disorders: Conjunctivitis, eye pain, photophobia.
Gastrointestinal disorders: Dysphagia, vomiting.
General disorders and administration site conditions: Chest pain, injection site
inflammation, rigors, asthenia, injection site rash, influenza-like symptoms,
abnormal gait, injection site bruising, injection site sterile abscess.
Immune system disorders: Allergic edema of the face, allergic edema of the
mouth, anaphylaxis, allergic edema of the throat.
Infections and infestations: Pharyngitis, rhinitis, laryngitis, cellulitis.
Musculoskeletal and connective tissue disorders: Muscle weakness, back pain,
arthritis.
Nervous system disorders: Dizziness, paresthesia, hypoesthesia, hypokinesia,
tremor, somnolence, syncope, Guillain-Barré syndrome, convulsions/seizures,
facial or cranial nerve paralysis, encephalopathy, limb paralysis.
Psychiatric disorders: Insomnia.
Respiratory, thoracic, and mediastinal disorders: Dyspnea, dysphonia,
bronchospasm, throat tightness.
Skin and subcutaneous tissue disorders: Urticaria, localized or generalized
rash, pruritus, periorbital edema, sweating.
Vascular disorders: Flushing, pallor.
6.4 Adverse Events Associated with Influenza Vaccines
Anaphylaxis has been reported after administration of FLULAVAL. Although
FLULAVAL contains only a limited quantity of egg protein, this protein can
induce immediate hypersensitivity reactions among persons who have severe egg
allergy. Allergic reactions include hives, angioedema, allergic asthma, and
systemic anaphylaxis (see CONTRAINDICATIONS [4]).
The 1976 swine influenza vaccine was associated with an increased frequency of
Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with
subsequent vaccines prepared from other influenza viruses is unclear. If
influenza vaccine does pose a risk, it is probably slightly more than 1
additional case/1 million persons vaccinated.
Neurological disorders temporally associated with influenza vaccination such as
encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and
brachial plexus neuropathy have been reported.
Microscopic polyangitis (vasculitis) has been reported temporally associated
with influenza vaccination.
8
7 DRUG INTERACTIONS
7.1 Concomitant Administration with Other Vaccines
There are no data to assess the concomitant administration of FLULAVAL with
other vaccines. If FLULAVAL is to be given at the same time as another
injectable vaccine(s), the vaccines should always be administered at different
injection sites. FLULAVAL should not be mixed with any other vaccine in the same
syringe or vial.
7.2 Warfarin, Theophylline, and Phenytoin
Although it has been reported that influenza vaccination may inhibit the
clearance of warfarin, theophylline, and phenytoin, controlled studies have
yielded inconsistent results regarding pharmacokinetic interactions between
influenza vaccine and these medications. Nevertheless, clinicians should
consider the potential for an interaction when FLULAVAL is administered to
persons receiving these drugs.
7.3 Immunosuppressive Therapies
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating
agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic
doses), may reduce the immune response to FLULAVAL.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with
FLULAVAL. It is also not known whether FLULAVAL can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. FLULAVAL
should be given to a pregnant woman only if clearly needed.
8.3 Nursing Mothers
It is not known whether FLULAVAL is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when FLULAVAL is
administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of FLULAVAL in pediatric patients have not been
established.
8.5 Geriatric Use
In the 2 clinical trials, there were 157 subjects who were ≥65 years of age and
received FLULAVAL; 21 of these subjects were ≥75 years of age. Hemagglutination-inhibiting
(HI) antibody responses were lower in geriatric subjects than younger subjects
after administration of FLULAVAL. Solicited adverse events were similar in
frequency to those reported in younger subjects (see ADVERSE REACTIONS [6]).
11 DESCRIPTION
FLULAVAL is a trivalent, split-virion influenza virus vaccine prepared from
virus propagated in the allantoic cavity of embryonated hens’ eggs. Each of the
influenza virus strains is produced and purified separately. The virus is
inactivated with ultraviolet light treatment
9
followed by formaldehyde treatment, purified by centrifugation, and disrupted
with sodium deoxycholate.
FLULAVAL is a homogenized, sterile, colorless to slightly opalescent suspension
in a phosphate-buffered saline solution. FLULAVAL has been standardized
according to USPHS requirements for the 2006–2007 influenza season and is
formulated to contain 45 micrograms (mcg) hemagglutinin per 0.5-mL dose in the
recommended ratio of 15 mcg HA of each of the following 3 strains: A/New
Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004.
Thimerosal, a mercury derivative, is added as a preservative. Each dose contains
25 mcg mercury. Each dose may also contain residual amounts of egg proteins (≤1
mcg ovalbumin), formaldehyde (≤25 mcg), and sodium deoxycholate (≤50 mcg).
Antibiotics are not used in the manufacture of this vaccine.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Influenza illness and its complications follow infection with influenza viruses.
Global surveillance of influenza identifies yearly antigenic variants. For
example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses
and influenza B viruses have been in global circulation. Specific levels of HI
antibody titer post-vaccination with inactivated influenza virus vaccines have
not been correlated with protection from influenza illness but the antibody
titers have been used as a measure of vaccine activity. In some human challenge
studies, antibody titers of ≥1:40 have been associated with protection from
influenza illness in up to 50% of subjects.1,2 Antibody against one influenza
virus type or subtype confers little or no protection against another virus.
Furthermore, antibody to one antigenic variant of influenza virus might not
protect against a new antigenic variant of the same type or subtype. Frequent
development of antigenic variants through antigenic drift is the virological
basis for seasonal epidemics and the reason for the usual change of one or more
new strains in each year’s influenza vaccine. Therefore, inactivated influenza
vaccines are standardized to contain the hemagglutinins of strains (i.e.,
typically 2 type A and 1 type B), representing the influenza viruses likely to
circulate in the United States in the upcoming winter.
Annual revaccination with the current vaccine is recommended because immunity
declines during the year after vaccination, and because circulating strains of
influenza virus change from year to year.3
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
FLULAVAL has not been evaluated for carcinogenic or mutagenic potential, or for
impairment of fertility.
14 CLINICAL STUDIES
In 2 randomized, active-controlled trials of FLULAVAL, the immune responses,
specifically HI antibody titers to each virus strain in the vaccine, were
evaluated in sera obtained
10
21 days after administration of FLULAVAL. No controlled trials demonstrating a
decrease in influenza disease after vaccination with FLULAVAL have been
performed.
A 1,000-subject randomized, blinded, and controlled study was performed in the
United States in 18- to 64-year-old healthy adults. A total of 721 subjects
received FLULAVAL, and 279 received a US-licensed trivalent, inactivated
influenza virus vaccine (FLUZONE); 959 subjects had complete serological data
and no major protocol deviations. Among recipients of FLULAVAL, 57.4% were
women. The mean age of recipients of FLULAVAL was 37.9 years; 80.4% were 18 to
49 years of age and 19.6% were 50 to 64 years of age.
A second, randomized, blinded, and controlled study which enrolled 658 subjects
50 years of age and older (stratified by age <65 and ≥65 years) was conducted in
Canada. This study included elderly persons with medically controlled chronic
high-risk diagnoses who were clinically stable. This study compared 4 vaccine
groups: FLULAVAL, a similar investigational formulation of FLULAVAL with reduced
thimerosal, and 2 Canadian-licensed trivalent influenza vaccines. Results from
the 2 groups that received FLULAVAL were submitted in support of the US
licensure of FLULAVAL. Among these 2 groups, 54.9% of subjects were women. The
mean age of recipients of FLULAVAL was 63 years; 53.4% were 50 to 64 years of
age and 46.6% were 65 years of age and older.
For both studies, analysis of the following co-primary endpoints were performed
for each HA antigen contained in the vaccine: 1) assessment of the lower bounds
of 2-sided 95% confidence intervals for the proportion of subjects with HI
antibody titers of ≥1:40 after vaccination, and 2) assessment of the lower
bounds of 2-sided 95% confidence intervals for rates of seroconversion (defined
as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination
titer ≥1:10, or an increase in titer from <1:10 to ≥1:40). The pre-specified
targets for the 2 endpoints varied by study because of age of subjects enrolled.
The pre-specified target for endpoint 1) was 70% in the US study and 60% in the
Canadian study. For endpoint 2) the pre-specified target was 40% in the US study
and 30% in the Canadian study. For the Canadian study, the primary endpoints, as
originally designed, were descriptive comparisons of immune response; therefore,
a post-hoc analysis of the endpoints, as described above, was performed.
11
Table 3. Serum Hemagglutination-Inhibiting (HI) Antibody Responses to FLULAVAL
in 2 Clinical Trials* (Per Protocol cohort)†
US Trial in Adults 18 to 64 years of age
% of Subjects
(lower bound of 2-sided 95% confidence interval)‡
FLULAVAL
N = 692
Primary endpoint met
post-vaccination
HI titers ≥40 against:
Pre-vaccination
Post-vaccination
A/New Caledonia/20/99 (H1N1)
24.6
96.5 (94.9)
Yes
A/Wyoming/03/03 (H3N2)
58.7
98.7 (97.6)
Yes
B/Jiangsu/10/03
5.4
62.9 (59.1)
No
Seroconversion§ to:
A/New Caledonia/20/99 (H1N1)
85.6 (82.7)
Yes
A/Wyoming/03/03 (H3N2)
79.3 (76.1)
Yes
B/Jiangsu/10/03
58.4 (54.6)
Yes
Canadian Trial in Adults ≥50 years of age
% of Subjects
(lower bound of 2-sided 95% confidence interval)‡
FLULAVAL║
N = 324
Primary endpoint met
post-vaccination
HI titers ≥40 against:
Pre-vaccination
Post-vaccination
A/New Caledonia/20/99 (H1N1)
39.5
86.4 (82.2)
Yes
A/Wyoming/03/03 (H3N2)
67.9
99.1 (97.3)
Yes
B/Jiangsu/10/03
10.2
57.1 (51.5)
No
Seroconversion§ to:
A/New Caledonia/20/99 (H1N1)
44.8 (39.3)
Yes
A/Wyoming/03/03 (H3N2)
69.1 (63.
Yes
B/Jiangsu/10/03
49.1 (43.5)
Yes
* Results obtained following vaccination with FLULAVAL manufactured for the
2004–2005 season.
† Per Protocol cohort for immunogenicity included subjects with complete pre-
and post-dose HI titer data and no major protocol deviations.
‡ Lower bounds were calculated using Clopper-Pearson method.
§ Seroconversion = a 4-fold increase post-vaccination in HI antibody titer from
pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.
║ Includes subjects who received FLULAVAL and a similar investigational
formulation of FLULAVAL with reduced thimerosal.
Across both studies, serum HI antibody responses to FLULAVAL met the
pre-specified seroconversion criteria for all 3 virus strains, and also the
pre-specified criterion for the proportion of subjects with HI titers ≥1:40 for
both influenza A viruses. In both trials, both FLULAVAL and the comparator
vaccine did not meet the pre-specified criterion for the proportion of subjects
with HI titers ≥1:40 for the influenza B virus. The clinical relevance of this
12
finding on vaccine-induced protection against illness caused by influenza type B
strains is unknown.
15 REFERENCES
1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of
influenza vaccination. Virus Res 2004;103:133-138.
2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting
antibody in protection against challenge infection with influenza A2 and B
viruses. J Hyg Camb 1972;70:767-777.
3. Centers for Disease Control and Prevention. Prevention and control of
influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR 2006;55(RR-10):1-42.
16 HOW SUPPLIED/STORAGE AND HANDLING
FLULAVAL is supplied in a 5-mL multi-dose vial containing ten 0.5-mL doses. Once
entered, the multi-dose vial should be discarded after 28 days.
Store FLULAVAL refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze.
Discard if the vaccine has been frozen. Store in the original package to protect
from light.
Do not use after expiration date shown on the label.
The vial stopper does not contain latex.
NDC 19515-883-07 (package of 1 vial containing 10 doses)
17 PATIENT COUNSELING INFORMATION
Vaccine recipients and guardians should be informed by their healthcare provider
of the potential benefits and risks of immunization with FLULAVAL. When
educating vaccine recipients and guardians regarding potential side effects,
clinicians should emphasize that (1) FLULAVAL contains non-infectious killed
viruses and cannot cause influenza and (2) FLULAVAL is intended to provide
protection against illness due to influenza viruses only, and cannot provide
protection against all respiratory illness.
Vaccine recipients and guardians should be instructed to report any severe or
unusual adverse reactions to their healthcare provider.
The vaccine recipient or guardian should be given the Vaccine Information
Statements, which are required by the National Childhood Vaccine Injury Act of
1986 to be given prior to immunization. These materials are available free of
charge at the CDC website (www.cdc.gov/nip).
Vaccine recipients and guardians should be instructed that annual revaccination
is recommended.
Manufactured by ID Biomedical Corporation of Quebec, Quebec City, QC, Canada
US license 1739
Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709
13
FLULAVAL is a trademark of ID Biomedical Corporation of Quebec.
FLUZONE is a trademark of Sanofi Pasteur Inc.
©2006, GlaxoSmithKline. All rights reserved.
August 2006 FV:L1
14