PRODUCT MONOGRAPH

FLUAD®
(Influenza Vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1)

ATC: J07BB02

Sterile Suspension for Injection

Active Immunizing Agent for the Prevention of Influenza

2014/2015 Strains: an A/California/7/2009 (H1N1)pdm09-like virus

an A/Texas/50/2012 (H3N2)-like virus
a B/Massachusetts/2/2012-like virus

Sponsor:

Novartis Vaccines and Diagnostics, Inc. Date of Preparation:

350 Massachusetts Avenue April 11, 2014
Cambridge, MA 02139

Distributed by:

Novartis Pharmaceuticals Canada Inc.

385 Bouchard Blvd.
Dorval QC H9S 1A9
www.novartis.ca

Submission Control No:174156 Approved on: May 07, 2014

FLUAD is a registered Trademark

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 Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................ 3

SUMMARY PRODUCT INFORMATION ....................................................................... 3
DESCRIPTION................................................................................................................... 3
INDICATIONS AND CLINICAL USE ............................................................................. 4
CONTRAINDICATIONS .................................................................................................. 4
WARNINGS AND PRECAUTIONS ................................................................................. 5
ADVERSE REACTIONS................................................................................................... 6
DRUG INTERACTIONS ................................................................................................. 11
DOSAGE AND ADMINISTRATION ............................................................................. 12
OVERDOSAGE ............................................................................................................... 12
ACTION AND CLINICAL PHARMACOLOGY ........................................................... 13
STORAGE AND STABILITY ......................................................................................... 14
DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................ 14

PART II: SCIENTIFIC INFORMATION .............................................................................. 16

PHARMACEUTICAL INFORMATION ......................................................................... 16
CLINICAL TRIALS ......................................................................................................... 17
TOXICOLOGY ................................................................................................................ 23
REFERENCES ................................................................................................................. 24

PART III: CONSUMER INFORMATION............................................................................. 25

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 FLUAD®

(Influenza Virus Vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Clinically Relevant Nonmedicinal

Administration Strength Ingredients
Intramuscular Parenteral / Each 0.5 Polysorbate 80
injection mL prefilled syringe
contains 15 g of For a complete listing see Dosage Forms,
influenza virus Composition and Packaging Section.
haemagglutinin
surface antigens from
each of the three virus
strains, types A and B
(see DESCRIPTION)

DESCRIPTION

FLUAD® is a trivalent, surface antigen, inactivated influenza virus vaccine adjuvanted with
MF59C.1.

The influenza virus strains are individually grown in the allantoic cavity of embryonated hens’
eggs inoculated with a specific type of influenza virus suspension containing kanamycin and
neomycin sulphate. Each of the influenza virus strains is harvested and clarified separately by
centrifugation and filtration prior to inactivation with formaldehyde. The inactivated virus is
concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and
neuraminidase, are obtained from the influenza virus particle by further centrifugation in the
presence of cetyltrimethylammonium bromide (CTAB), a process which removes most of the
internal proteins. The CTAB is removed from the surface antigen preparation.

The MF59C.1 adjuvant contained in FLUAD® is an oil-in-water emulsion composed of squalene

as the oil phase, stabilised with the surfactants polysorbate 80 and sorbitan trioleate, in citrate
buffer.

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FLUAD® is presented as a sterile, milky-white suspension for intramuscular injection in a
prefilled syringe. It has been formulated to contain a total of at least 45 mcg hemagglutinin (HA)
per 0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following three
influenza strains recommended for the 2014/2015 influenza season: A/California/7/2009
(H1N1)pdm09-like virus; A/Texas/50/2012 (H3N2)-like virus; and B/Massachusetts/2/2012-like
virus, as recommended annually for immunization by the World Health Organisation (WHO)
and the National Advisory Committee on Immunization (NACI).

INDICATIONS AND CLINICAL USE

FLUAD® is an inactivated influenza virus vaccine indicated for active immunization against
influenza in the elderly (65 years of age and older) (see Part II CLINICAL TRIALS).

Consistently numerically higher immune responses to tested heterovariant and homologous

strains were observed for FLUAD® in the elderly population and the difference was statistically
significant for some strains and/or some endpoints, as compared to the comparator.

The National Advisory Committee on Immunization (NACI) encourages annual vaccination for
all Canadians who have no contraindication (CCDR 2009).

Vaccine should be offered to the elderly up to and even after influenza virus activity is
documented in a community.

CONTRAINDICATIONS

FLUAD® is contraindicated in persons with a known hypersensitivity to the active substances, to

any of the excipients and to eggs, chicken proteins, kanamycin and neomycin sulphate,
formaldehyde, and cetyltrimethylammonium bromide (CTAB), or to anyone who has had a life-
threatening reaction to previous influenza vaccination.

For a complete listing of ingredients in the formulation and components of the container, see the
Dosage Forms, Composition and Packaging section of the product monograph.

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WARNINGS AND PRECAUTIONS

General

FLUAD® should under no circumstances be administered by any other route than

intramuscularly.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be

insufficient.

Prior to administration of any dose of FLUAD®, the vaccine recipient should be asked about their
personal history, family history, and recent health status, including immunization history, current
health status, main allergies and any adverse event associated with previous immunizations.
Before the injection of any biological product, such as vaccines, the person responsible for
administration should take all precautions known for the prevention of allergic or any other
reactions. As with all injectable vaccines, appropriate medical treatment and supervision should
always be readily available in case of a rare anaphylactic event occurs following administration
of the vaccine.

Immunization with FLUAD® should be postponed in patients with febrile illness or acute
infections.

Hematologic

As with other intramuscular injections, administration of FLUAD® requires careful consideration

in patients with clinically significant bleeding disorders.

Immune

The immune response to FLUAD® in immunocompromised persons, including individuals

receiving immunosuppressive therapy, may be lower than in immunocompetent individuals.
Antibody response in patients with endogenous or iatrogenic immunosuppression may be
insufficient.

Neurologic

If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the
decision to give FLUAD® should be based on careful consideration of the potential benefits and
risks.

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Monitoring and Laboratory Tests

Following influenza vaccination, false positive results in serology tests using the ELISA method
to detect antibodies against HIV1, hepatitis C and, especially HTLV1 have been observed. The
Western Blot technique disproves the results. The transient false positive reactions could be due
to the IgM response by the vaccine.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Adverse event information is derived from both controlled and uncontrolled clinical trials and
worldwide post-marketing experience.

Vaccination with FLUAD® cannot cause influenza because the vaccine does not contain live
virus. Respiratory disease after vaccination represents coincidental illness unrelated to influenza
vaccination.

Allergic-type responses, such as urticarial rash, allergic bronchospasm, or systemic anaphylaxis

occur extremely rarely.

The most common FLUAD® local adverse drug reactions are pain at the injection site,
temperature at the injection site, and erythema. The incidence of subjects reporting any solicited
systemic reactions was generally slightly higher in the FLUAD® than in the comparator group
(17% vs. 12%). Reactions are generally mild or moderate and of limited duration. Prophylactic
acetaminophen may decrease the frequency of some side effects in adults.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse drug reaction information
from clinical trials is useful for identifying drug-related adverse events and for approximating
rates.

The safety profile of FLUAD® in adults 65 years and older is based on data from 39 studies.
Overall 12,889 subjects were exposed to at least one dose with FLUAD®. Of these 492 received
a second consecutive vaccination one year later, and 150 a third FLUAD® vaccine dose the
following year. In one study, two doses of FLUAD® were administered 4 weeks apart. In 38
studies solicited local (injection site) and systemic reactions were collected from subjects who
completed a symptom diary card for at least four days following vaccination.

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Adults 65 Years of Age and Older
Safety data after first vaccination for subjects 65 years of age and older were pooled from 31
trials, safety data after second consecutive vaccination were pooled from five studies and after
third consecutive vaccination from two studies.

Pooled Reactogenicity data are provided in Table 1, Table 2 and Table 3.

The most frequently reported solicited local adverse events within 4 days of vaccination were
injection site pain, followed by temperature at the injection site (“warm” or “hot”) and erythema.
Local injection-site reactions (pain and temperature on injection) were more frequent in subjects
who received the MF59C.1 adjuvanted vaccine than in those who received nonadjuvanted
vaccine. The frequency of pain was 26% in the FLUAD® group vs. 14% in the comparator
group. Temperature at the injection site was 18% in the FLUAD® group vs 11% in the
comparator group. Solicited local reactions were generally of mild or moderate intensity, and
generally resolved within 2-3 days with 3% or less of subjects reporting a severe local reaction.

The most frequently reported solicited systemic adverse events were headache, fatigue, malaise
and myalgia. Most reports of systemic reactions were mild to moderate in severity and generally
transient, with 1% or less of subjects reporting a severe systemic reaction across all studies.

In the subset of subjects who received second and third consecutive vaccinations, for both the
FLUAD® and the comparator vaccines groups, there was a trend for an increase in the percentage
of subjects reporting each local reaction during the 3 days after the second vaccination,
compared to the first vaccination, but no further increase after the third vaccination. Overall,
systemic reactions were reported by similar percentages of subjects after the first, second, and
third vaccinations in both the FLUAD® and comparator vaccines groups.

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Table 1 Any (Severea) Local and Systemic Reactions in Elderly Subjects 65 Years
(Days 0-3) After One Vaccination - Pooled Studies
Reaction Percentages of Subjects with Any (Severea) Solicited Reaction
FLUAD® Comparator
N = 3713 N = 1656
Subjects with Any Solicited Local 37% 30%
Reaction
Pain at injection site 26% (<1%) 14% (<1%)
N = 3712
Temperature at injection site 18% (1%) 11% (1%)
N = 2265 N = 1438
Ecchymosis 3% (<1%) 2% (0)
N = 1272 N = 44
Induration 11% (1%) 9% (1%)
N = 3712 N = 1655
Erythema 14% (1%) 14% (1%)
N = 3712 N = 1655
Swelling 5% (1%) 6% (1%)
N = 1447 N = 218
Subjects with Any Solicited 17% 12%
Systemic Reaction
Chills 3% (<1%) 2% (<1%)
N = 3712 N = 1655
Fatigue 6% (<1%) 7% (1%)
N = 1493 N = 264
Headache 6% (<1%) 5% (1%)
N = 3712 N = 1655
Malaise 6% (<1%) 5% (<1%)
N = 3712 N = 1655
Myalgia 7% (<1%) 3% (<1%)
N = 3712 N = 1655
Nausea 2% (<1%) 2% (<1%)
N = 2581 N = 1655
Rash <1% (<1%) <1% (<1%)
N = 2230 N = 1365
Sweating 3% (0) 3% (<1%)
N = 1447 N = 218
Arthralgia 4% (<1%) 2% (<1%)
N = 3666 N = 1609
Fever (38C/≥40°C) 1% (0) <1% (0)
N = 3675 N = 1652
a
Defined as ecchymosis, erythema, induration, and swelling >50mm; temperature at injection site “hot”; rash
“urticaria”

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Table 2 Any (Severea) Local and Systemic Reactions in Elderly Subjects 65 Years
(Days 0-3) Who Received Two Consecutive FLUAD® Vaccinations One Year
Apart, by Vaccination
Percentages of Subjects with Any (Severea) Solicited Reaction
1st Vaccination 2nd Vaccination
FLUAD® Comparator FLUAD® Comparator
N=487 N=329 N=487 N=329
Solicited Local Reactions
Pain at injection site 19% (1%) 7% (0) 27% (1%) 21% (<1%)
Temperature at injection site 6% (2%) 4% (1%) 15% (3%) 12% (2%)
Induration 9% (1%) 6% (1%) 13% (1%) 10% (<1%)
Erythema 9% (1%) 6% (0) 23% (2%) 20% (3%)
Solicited Systemic Reactions
Chills 4% (<1%) 4% (<1%) 3% (0) 2% (0)
Fatigue 15% (0) 0 0 3% (0)
N=39 N=35 N=39 N=35
Headache 5% (<1%) 5% (<1%) 8% (0) 5% (0)
Malaise 7% (<1%) 6% (0) 8% (0) 6% (<1%)
Myalgia 4% (<1%) 2% (<1%) 3% (0) 2% (0)
Nausea 3% (0) 2% (0) 2% (0) 3% (<1%)
Rash <1% (<1%) <1% (0) <1% (<1%) <1% (0)
N=306 N=222
Arthralgia 2% (<1%) 1% (<1%) 1% (0) 2% (0)
N=448 N=294
Fever (38C/≥40°C) 1% (0) 0 1% (0) 1% (0)
a
Severe defined as: induration, erythema and swelling >50mm; temperature at injection site “hot”; rash “urticaria”

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Table 3 Any (Severea) Solicited Local and Systemic Reaction in Elderly Subjects 65
Years (Days 0-3) Who Received Three Consecutive FLUAD® Vaccinations
One Year Apart, by Vaccination
Reaction Percentages of Subjects with Any (Severea) Solicited Reaction
st
1 Vaccination 2nd Vaccination 3rd Vaccination
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FLUAD Comp. FLUAD Comp. FLUAD® Comp.
N=149 N=87 N=150 N=87 N=150 N=87
Solicited Local Reactions
Pain at injection site 28% (1%) 5% (0) 29% (1%) 15% (0) 28% (1%) 16% (0)
Temperature at injection site 4% (1%) 5% (0) 7% (1%) 2% (1%) 12% (1%) 7% (0)
Induration 8% (0) 5% (0) 12% (1%) 6% (0) 13% (1%) 6% (0)
Erythema 9% (0) 6% (0) 14% (1%) 7% (1%) 22% (3%) 9% (0)
Solicited Systemic Reactions
Chills 4% (0) 6% (1%) 1% (0) 2% (0) 3% (0) 0
Fatigue 17% (0) 0 0 (N=35) 3%(N=32) - (N=0) - (N=0)
Headache 4% (0) 2% (0) 8% (0) 5% (0) 4% (1%) 3% (0)
Malaise 7% (0) 3% (0) 5% (0) 3% (0) 7% (0) 3% (0)
Myalgia 3% (0) 1% (1%) 5% (0) 2% (0) 1% (0) 2% (0)
Nausea 2% (0) 0 3% (0) 2% (0) 3% (0) 2% (0)
Rash - (N=0) - (N=0) 0 (N=115) 0 (N=55) 0 0
Arthralgia 2% (0) 2% (2%) 1% (0) 3% (0) 1% (0) 3% (0)
Fever (38C) 0 0 1% (0) 0 1% (0) 0
a
Severe defined as: induration, erythema and swelling >50mm; temperature at injection site “hot”; rash “urticaria”;
Comp.= comparator vaccine

Post-Market Adverse Drug Reactions

FLUAD® was first licensed in Italy in 1997. The authorization was extended to other European
Union countries through a Mutual Recognition Procedure that concluded in 2000 and currently
FLUAD® is registered for marketing authorization in many countries worldwide. The initial
formulation contained the preservative thimerosal, and thimerosal was also used in the
manufacturing process. Since 2003 FLUAD® has been thimerosal-free (see Pharmaceutical
Information section).

The post-marketing experience with FLUAD® is extensive. Because post-marketing reporting is

voluntary and from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to vaccine exposure.
The adverse events described below have been included because: a) they represent reactions that
are known to occur following immunizations generally or influenza immunizations specifically;
b) they are potentially serious; or c) of the frequency of reporting. The following additional
adverse reactions have been the subject of spontaneous reports during post-approval use of
FLUAD® since 2003.

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General disorders and administration site conditions:
Local injection site reactions including redness, swelling, pain at the injection site, ecchymosis,
induration. Injection-site cellulitis-like reaction (some cases of swelling, pain, and redness
extending more than 10 cm and lasting more than 1 week). Extensive swelling of injected limb
lasting more than one week.
Immune system disorders:
Allergic reactions in rare cases leading to shock, angioedema.
Vascular disorders:
Vasculitis (in rare cases associated with transient renal involvement), exudative erythema
multiforme.
Blood and lymphatic system disorders:
Thrombocytopenia (including very rare severe cases, <0.01%, with platelet counts less than
5,000 per mm3), lymphadenopathy.
Musculoskeletal and connective tissue disorders:
Muscular weakness
Nervous system disorders:
Neuralgia, paraesthesia, convulsion, myelitis (including encephalomyelitis and transverse
myelitis), neuritis and Guillain-Barré Syndrome.
Skin and subcutaneous tissue disorders:
Generalized skin reactions including pruritus, urticaria, and non-specific rash.

DRUG INTERACTIONS

Overview

No interaction between FLUAD® and other vaccines or medication are known.

Drug-Drug Interactions

FLUAD® may be given at the same time as other vaccines. FLUAD® should not be mixed with
any other vaccine in the same syringe. Immunization should be carried out on separate limbs. It
should be noted that any adverse reactions may be intensified.
Although a possible interaction has been suggested in the literature between influenza
vaccination and the use of warfarin and theophylline, clinical studies have not shown any
adverse effects attributable to these drugs in people receiving influenza vaccine. There were no
studies designed to evaluate the drug interactions with FLUAD®.

The immunological response may be diminished if the patient is undergoing immunosuppressant

treatment.

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DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Adults 65 years of age and older: a single dose of 0.5 mL should be administered
intramuscularly.

FLUAD® should under no circumstances be administered by any other route than

intramuscularly.

Administration

Gently shake the contents of each syringe to aid inspection for the presence of particulate matter.
After shaking, the normal appearance of FLUAD® is a milky-white suspension.

If there are visible particles, allow the vaccine to come to room temperature and shake before use
(FLUAD® can be kept at room temperature (20º-25ºC) for up to 2 hours as a holding time before
injection).

Do not use the vaccine if particles remain, if it is discoloured, or if it has been frozen.

Before immunization, the skin over the site to be injected should be cleansed with a suitable
germicide.

FLUAD® should be administered as a single 0.5 mL intramuscular injection preferably in the

region of the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal
region or areas where there may be a major nerve trunk.

FLUAD® should under no circumstances be administered by any other route than

intramuscularly.

Administration with Other Vaccines

FLUAD® should not be mixed with other vaccines in the same syringe. Separate injection limbs
should be used if more than one vaccine is being administered during the same visit.

OVERDOSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
No data are available.

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ACTION AND CLINICAL PHARMACOLOGY

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 hemagglutination inhibition (HI) antibody titers induced by
vaccination with inactivated influenza virus vaccine have not been correlated with protection
from influenza illness. Some studies of influenza infection, including human challenge studies
following vaccination, have suggested that HI antibody titers ranging from 1:15 to 1:65 may be
associated with protection from illness in 50% of subjects and protection from illness is
increased with higher titers (CBER Guidance, May 2007).

Antibody against one influenza virus type or subtype may confer limited or no protection against
another. 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 virologic 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 hemagglutinin of influenza virus
strains (typically two type A and one type B), representing the influenza viruses likely to be
circulating in Canada during the upcoming flu season, on the basis of the recommendations from
the World Health Organization (WHO) and the National Advisory Committee on Immunization
(NACI).

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 (MMWR).

Pharmacodynamics

The antibody response to FLUAD® is increased when compared to the response to vaccines
without adjuvant, and is most pronounced for B and A/H3N2 influenza antigens.Seroprotection
is generally obtained within 2 to 3 weeks after vaccination.

This increased response is seen particularly in elderly subjects with low pre-immunization titre
and/or with underlying diseases (diabetes, cardiovascular and respiratory diseases) who are at
increased risk of complications of influenza infection. A similar immunogenicity profile has
been noted after a second and third immunization with FLUAD®.

Consistent numerically higher antibody titers after immunization with FLUAD® have also been
observed against homologous and heterovariant strains, antigenically different from those
included in the vaccine and the difference was statistically significant for some strains and/or

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some endpoints, as compared to the comparator.

Duration of Effect

The duration of post-vaccination immunity to homologous strains or to strains closely related to

the vaccine strains varies, but it is usually 6-12 months.

STORAGE AND STABILITY

Store FLUAD® between 2C and 8C. Do not freeze. Do not use if vaccine has been frozen.
Protect from light. Do not use vaccine after expiration date.

FLUAD® can be administered following a 2 hour exposure at temperatures between 8° and 25°C.
This is not, however, a recommendation for storage.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

FLUAD® is a sterile milky-white suspension for intramuscular injection in 1 mL prefilled

syringes containing a 0.5 mL dose.

Composition

Each 0.5 mL dose contains

 Active Ingredients:

- influenza virus haemagglutinin (HA) and neuraminidase (NA) from each of the following 3
strains:

A/California/7/2009 (H1N1)pdm09-like virus; 15 µg (HA)

A/Texas/50/2012 (H3N2)-like virus; 15 µg (HA)
and B/Massachusetts/2/2012-like virus; 15 µg (HA)

- adjuvant: MF59C.1 which is an proprietary adjuvant:

squalene 9.75 mg
polysorbate 80 1.175 mg

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sorbitan trioleate 1.175 mg
sodium citrate 0.66 mg
citric acid 0.04 mg
water for injection

 Other Ingredients:

Excipients:

sodium chloride 4.00 mg

potassium chloride 0.10 mg
potassium dihydrogen phosphate 0.10 mg
disodium phosphate dihydrate 0.67 mg
magnesium chloride hexahydrate 0.05 mg
calcium chloride dihydrate 0.06 mg
water for injection to volume

Manufacturing Process Residuals:

The vaccine may contain trace amounts of the following:

neomycin (trace)
kanamycin (trace)
ovalbumin (egg protein, residual)
formaldehyde (residual)
cetyltrimethylammonium bromide (CTAB) (residual)
barium (residual)

The syringe plunger does not contain latex and FLUAD® is considered safe for use in persons
with latex allergies.

Packaging

FLUAD® is supplied in packages containing one or ten single dose prefilled glass syringes (Type
I), without needles.

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 PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Purified haemagglutinin (HA) and neuraminidase (NA) surface

antigens from each of the three influenza virus strains, types A and
B, recommended annually for immunization by the World Health
Organisation (WHO) and the National Advisory Committee on
Immunization (NACI).

Chemical name: As above

Product Characteristics

FLUAD® is a trivalent, surface antigen, inactivated influenza vaccine adjuvanted with MF59C.1.

The influenza virus strains are individually grown in the allantoic cavity of embryonated hens’
eggs inoculated with a specific type of influenza virus suspension containing kanamycin and
neomycin sulphate. Each of the influenza virus strains is harvested and clarified separately by
centrifugation and filtration prior to inactivation with formaldehyde. The inactivated virus is
concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and
neuraminidase, are obtained from the influenza virus particle by further centrifugation in the
presence of cetyltrimethylammonium bromide (CTAB), a process which removes most of the
internal proteins. The CTAB is removed from the surface antigen preparation.

The MF59C.1 adjuvant contained in FLUAD® is an oil-in-water emulsion composed of squalene

as the oil phase, stabilised with the surfactants polysorbate 80 and sorbitan trioleate, in citrate
buffer.

FLUAD® appears as a sterile, milky-white suspension for intramuscular injection in a prefilled

syringe. It has been formulated to contain a total of at least 45 mcg hemagglutinin (HA) per
0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following three influenza
strains recommended for the 2014/2015 influenza season: A/California/7/2009 (H1N1)pdm09-
like virus; A/Texas/50/2012 (H3N2)-like virus; and B/Massachusetts/2/2012-like virus, as
recommended annually for immunization by the World Health Organisation (WHO) and the
National Advisory Committee on Immunization (NACI).

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CLINICAL TRIALS

Study Demographics and Trial Design

Five randomized, comparator controlled, observer blind clinical studies, were selected as pivotal
studies to support the immunogenicity of FLUAD®, compared with conventional non adjuvanted
influenza vaccines. Additionally, immunogenicity results of one study have been presented to
support the cross reactivity to heterovariant influenza strains conferred by FLUAD®. Immune
responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in
sera obtained 28 days after administration of the single dose of FLUAD®.

In the five pivotal studies and the one study investigating heterologous immune response, 212,
204, 154, 150, 448, and 46 subjects 65 years and older were enrolled to receive FLUAD®.
The demographic and baseline characteristics were well balanced both between vaccine groups
in each study as well as across studies. In these studies the mean age ranged from 72 to 79.1
years, sex ratio was mostly balanced except for a prevalence (72%-75%) of females in one study,
and Caucasians were the most represented ethnic group across studies. As expected in a
population with a high percentage of subjects with previous influenza vaccinations (63% to 97%
across studies and vaccine groups), the percentage of subjects with seroprotection at baseline was
relatively high.

Study Results

Evaluation of vaccine immunogenicity was originally based on the CHMP criteria defined in the
CPMP/BWP/214/96 guideline. Generally all 3 CHMP criteria were met with FLUAD® for each
strain (see Table 4 below). When not all 3 criteria were met, the GMR and
seroconversion/significant increase CHMP criteria were more frequently achieved with
FLUAD® than with the comparator vaccine.

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Table 4 CHMP Criteria Fulfilled Against Homologous Influenza Strains After One
Vaccination a - HI assay (PP-Population)
V7P5 V7P8 V7P17 V7P24 V7P34
® ® ® ®
FLUAD ®
FLUAD ®
FLUAD ®
FLUAD FLUAD® ®
AGRIFLU AGRIFLU AGRIFLU Flushield AGRIFLU
(w) (w) (w) (c) (c)
N=94 N=97 N=100 N=99 N=147 N=150 N=140 N=140 N=211 N=106
H3N2 3/3 3/3 3/3 2/3 3/3 3/3 3/3 3/3 1/3 1/3
H1N1 3/3 2/3 1/3 1/3 3/3 2/3 2/3 2/3 3/3 2/3
B 3/3 2/3 3/3 2/3 3/3 3/3 3/3 2/3 3/3 2/3
® ® ®
Source: FLUAD (w) = ‘water’ formulation (FLUAD /MF59W.1); FLUAD (c) = ‘citrate’ formulation
(FLUAD®/MF59C.1); Note: for all studies only results with FLUAD® (single syringe) are presented; ai.e., on
day 28.

In all five pivotal clinical trials consistent numerically higher HI antibody titers (i.e., day 28
GMT FLUAD®/comparator ratio >1) and greater percentages of subjects achieving
seroconversion or significant increase in HI titres (i.e., vaccine group difference for the
seroconversion rate of FLUAD®/comparator >0) for homologous strains were observed for
FLUAD®. The differences were statistically significant for some strains and/or some endpoints
(see Table 5 and Table 6). However, clinical relevance of the difference is unknown.

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Table 5: Postvaccination GMTs and Vaccine Group Ratios - HI assay (PP-Population)
Study Antigen FLUAD® Comparator
Vaccine Group Ratio
N GMT (95% CI) N GMT (95% CI)
(99.17% CI)#
§
V7P5 H3N2 94 331 (271-406) 97 161 (132-196) 2.06 (1.4-3.03)
§
H1N1 94 252 (214-297) 97 179 (152-211) 1.41 (1.03-1.92)
§
B 94 137 (115-162) 97 85 (71-100) 1.62 (1.17-2.24)
§
V7P8 H3N2 100 121 (69-210) 99 62 (37-104) 1.94 (1.25-3.01)
H1N1 100 179 (121-265) 99 153 (106-220) 1.17 (0.86-1.6)
B 100 77 (52-115) 99 60 (41-86) 1.3 (0.95-1.78)
§
V7P17 H3N2 147 276 (228-335) 150 153 (127-185) 1.81 (1.25-2.61)
§
H1N1 147 367 (314-429) 150 266 (228-311) 1.38 (1.03-1.85)
§
B 147 289 (250-335) 150 206 (178-238) 1.41 (1.07-1.86)
V7P24 H3N2 140 251 (213-295) 140 204 (173-240) 1.23 (0.9-1.68)
H1N1 140 223 (183-272) 140 217 (178-266) 1.03 (0.7-1.5)
B 140 182 (149-222) 140 133 (109-162) 1.37 (0.94-2.0)
V7P34 H3N2 211 243 (220-267) 106 203 (177-233) 1.19 (0.95-1.5)
H1N1 211 203 (175-235) 106 155 (126-190) 1.31 (0.93-1.85)
B 211 168 (147-191) 106 140 (116-168) 1.2 (0.89-1.63)

#
2-sided 99.17% Bonferroni adjusted CI within each study for 6 comparisons (3 strains by 2 endpoints).
§
indicate that if CI does not contain 1, i.e. statistically significant difference.

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Table 6: Postvaccination SC and Vaccine Group Differences - HI assay (PP-
Population)
Study Antigen FLUAD® Comparator
Vaccine Group
N SC (95% CI) N SC (95% CI) Difference
(99.17% CI)#
§
V7P5 H3N2 94 83 (74-90) 97 61 (50-71) 22 (5-38)
H1N1 94 32 (23-42) 97 23 (15-32) 9 (-8-26)
§
B 94 52 (42-63) 97 30 (21-40) 22 (4-40)
§
V7P8 H3N2 100 54 (44-64) 99 28 (20-38) 26 (7-42)
H1N1 100 23 (15-32) 99 11 (6-19) 12 (-2-26)
B 100 35 (26-45) 99 27 (19-37) 8 (-10-25)
55 (47-63) 36 (28-44) §
V7P17 H3N2 147 150 19 (4-33)
H1N1 147 35 (27-43) 150 23 (17-31) 11 (-3-25)
48 (40-57) 33 (25-41) §
B 147 150 16 (1-30)
56 (48-65) 35 (27-44) §
V7P24 H3N2 140 140 21 (6-36)
H1N1 140 26 (19-35) 140 24 (17-32) 2 (-12-16)
B 140 41 (32-49) 140 27 (20-35) 14 (-1-28)
V7P34 H3N2 211 23(18-30) 106 18(11-27) 5 (-8-17)
H1N1 211 40 (33-47) 106 30 (22-40) 10 (-6-24)
41 (34-48) 25 (17-34) §
B 211 106 16 (1-30)
SC = seroconversion or significant increase.
#
2-sided 99.17% Bonferroni adjusted CI within each study, for 6 comparisons (3 strains by 2 endpoints).
§
indicate that if CI does not contain 0, i.e. statistically significant difference.

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Postvaccination GMTs and seroconversion rates for heterovariant strains were observed to be
consistently higher for FLUAD® than for AGRIFLU®. The difference was statistically significant
for some strains and/or some endpoints (see Table 7).

Table 7 GMT and Seroconversion Response to Heterovariant Influenza Strains

After One Vaccination a – Study V7P3 - HI assay (PP-Population)

FLUAD® AGRIFLU® Vaccine Group

Comparisons
(99.17% CI)#
N=39 N=35
GMT (95% CI) 173 (117-256) 99 (65-150) 1.75 (0.81-3.8)
H3N2 §
% SC (95% CI) 79 (64-91) 46 (29-63) 34 (4-58)
§
GMT (95% CI) 270 (200-365) 133 (97-183) 2.03 (1.12-3.67)
H1N1 §
% SC (95% CI) 74 (58-87) 37 (21-55) 37 (7-61)
B §
GMT (95% CI) 200 (153-261) 105 (79-139) 1.9 (1.12-3.24)
% SC (95% CI) 92 (79-98) 69 (51-83) 24 (0-48)
SC= seroconversion or significant increase, i.e., ≥4-fold increase in HI titer from a pre-vaccination titer ≥1:10 or a
rise from <1:10 to ≥1:40 in those who were serum-negative at baseline;
a
i.e., on day 28.
#
2-sided 99.17% Bonferroni adjusted CI within each study, for 6 comparisons (3 strains by 2 endpoints).
§
indicate statistically significant difference/ratio.

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Seroprotection GMR and rates for heterovariant strains were observed to be consistently higher
for FLUAD® than for AGRIFLU® (see Table 8).

Table 8 Seroprotection and GMR Immune Response to Heterovariant Influenza

Strains After One Vaccination a – Study V7P3 - HI assay (PP-
Population)

FLUAD® AGRIFLU®
N=39 N=35
% SP (95% CI) 100 (91-100) 83 (66-93)
H3N2
GMR (95% CI) 7.86 (5.41-11) 4.08 (2.75-6.06)
% SP (95% CI) 100 (91-100) 94 (81-99)
H1N1
GMR (95% CI) 5.32 (3.84-7.36) 2.54 (1.8-3.57)
B % SP (95% CI) 100 (91-100) 97 (85-100)
GMR (95% CI) 9.06 (7.08-12) 3.84 (2.96-4.99)
SP= seroprotection, i.e., HI titer ≥1:40, GMR= day 28/day 0 geometric mean titer ratio.
a
i.e., on day 28.

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TOXICOLOGY

Nonclinical Toxicology Studies

Study type,
gender, and Route and regimena Results
species
Repeat dose There were no systemic adverse effects, and
Two or three 0.5 mL
toxicity - male FLUAD® was well tolerated locally.
intramuscular doses of
and female
FLUAD® two weeks apart
rabbits

Delayed contact Intradermal 0.1 mL and FLUAD® was not a skin sensitiser in Guinea
hypersensitivity topical 0.5 mL doses of pigs in this study.
- female Guinea FLUAD® during induction
pigs phase, and topical 0.5 mL
dose of FLUAD® during
challenge phase.
a
On a body weight basis, each dose administered to rabbits was approximately 15 times the human dose

FLUAD® has not been evaluated for reproductive and developmental toxicity, carcinogenic or
mutagenic potential.

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REFERENCES

1 Advisory Committee on Immunization Practices (ACIP) 2013. Prevention and Control of

Seasonal Influenza with Vaccines. MMWR 2013; 62 (RR07): 1-43.

2 Canada Communicable Disease Report (CCDR), November 15, 2001; V.27.

3 Colombo et al., Rev. Epidemiol. Santé Publique 2001 April; 49 (2): 157-16.

4 Glathe H., Lange W. Influenza Vaccination in Older Patients Drugs Aging 1995; 6 (5):
368-387.

5 Gross P.A., Hermogenes A.W., Sacks H.S., et.al. The Efficacy of Influenza Vaccine in
Elderly Persons - A Meta-analysis and Review of the Literature. Ann Intern Med .1995;
123 (7): 518-527.

6 FDA Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal
Inactivated Influenza Vaccines. CBER, May 2007.

7 Hamdy RC, Micklewright M, Beecham VF, Moore SW. Influenza vaccine may enhance
theophylline toxicity. A case report and review of the literature. Journal of the Tennessee
Medical Association 1995;88:463-4.

8 Monto S.A. Influenza: Quantifying Morbidity and Mortality. Am J Med Jun 1987; 82
(6A): 20-25.

9 National Advisory Committee on Immunization (NACI). Statement on seasonal trivalent

inactivated influenza vaccine (TIV) for 2013-2014. CCDR October 2013;39(ACS-4):1-
37.

10 Spila-Alegiani et al., Reactogenicity in the elderly of nine commercial influenza vaccines:

results from the Italian SVEVA study, Vaccine 17 (1999) 1898-1904.

11 Souto JC, Oliver A, Montserrat I, Mateo J, Sureda A, Fontcuberta J. Influenza

immunization is a safe procedure in patients undergoing long-term anticoagulation. Arch
Intern Med 1996;156:1589-92.

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FLUAD (Influenza Vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1) Page 24 of 27
 When it should not be used:
PART III: CONSUMER INFORMATION
FLUAD® should not be used where there is a history of
FLUAD ® hypersensitivity to egg proteins or other components of the
vaccine, any of the excipients or in people who have had a life-
(Influenza Virus Vaccine, surface antigen, inactivated, threatening reaction to previous influenza vaccination. (For a
Adjuvanted with MF59C.1) complete listing, see the Dosage Forms, Composition and
Packaging section of the Product Monograph).
This leaflet is part III of a three-part "Product Monograph"
published when FLUAD® was approved for sale in Canada and is What the medicinal ingredients are:
designed specifically for Consumers. This leaflet is a summary Influenza virus vaccine (surface antigen, inactivated) subtypes A
and will not tell you everything about FLUAD®. Contact your and B (2014/2015 season).
doctor or pharmacist if you have any questions about the drug.
Influenza virus surface antigens (haemagglutinin and
neuraminidase), of the following strains:
ABOUT THIS VACCINE
A/California/7/2009 (H1N1)pdm09-like virus;
What the vaccine is used for: 15 micrograms HA§

FLUAD® is an inactivated influenza virus vaccine against A/Texas/50/2012 (H3N2)-like virus;

influenza subtypes A and B contained in the vaccine, indicated in 15 micrograms HA§
adults 65 years of age and older.
B/Massachusetts/2/2012-like virus;
What it does: 15 micrograms HA§

FLUAD® provides active immunization of persons 65 years of Per 0.5 ml dose

age and older against influenza disease, used to prevent people
§
from developing influenza (the flu), or reduce flu symptoms. haemagglutinin

Like other influenza vaccines FLUAD® causes the body to This vaccine complies with the WHO recommendations (northern
produce antibodies against the virus. This means that when your hemisphere) for the 2014/2015 season.
body is exposed to the flu virus, your body is able to defend itself.
The antibodies stop the attacking virus. You cannot catch What the important nonmedicinal ingredients are:
influenza from the vaccine, since it only contains portions of the
virus, and not the whole live virus. Your body takes 2 to 3 weeks Sodium chloride, Potassium chloride, Potassium dihydrogen
to produce antibodies after vaccination. Therefore, if you are phosphate, Disodium phosphate dihydrate, Magnesium chloride
exposed to influenza immediately before or after your hexahydrate, Calcium chloride dihydrate, Squalene, Polysorbate
vaccination, you could still develop the illness. The vaccine will 80, Sorbitan trioleate, Sodium citrate, Citric acid and Water for
not protect you against the common cold, even though some of Injection.
the symptoms are similar to influenza. Influenza viruses change
all the time, so different vaccines are made every year. To stay May also contain trace amounts of:
protected against influenza, you need to be re-vaccinated every
year before the winter season. Neomycin, kanamycin, egg proteins, formaldehyde, or
cetyltrimethylammonium bromide (CTAB), barium (residual),
It is particularly important for some groups of people to be
vaccinated. These include people with certain medical conditions, For a full listing of nonmedicinal ingredients see Part 1 of the
elderly people, people who are likely to be exposed to the product monograph.
infection and people on certain medications. If you are in doubt
as to whether you should be vaccinated, talk to your local health What dosage forms it comes in:
professionals.
Each 0.5 mL dose contains 15 micrograms of influenza virus
FLUAD® follows the World Health Organisation (WHO) and haemagglutinin (HA) from each of the following 3 strains:
National Advisory Committee on Immunization (NACI) A/California/7/2009 (H1N1)pdm09-like virus,
recommendation for vaccination for the northern hemisphere for A/Texas/50/2012 (H3N2)-like virus, and
the 2014/2015 season. B/Massachusetts/2/2012-like virus.

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FLUAD (Influenza Vaccine, Surface Antigen, Inactivated, Adjuvanted with MF59C.1) Page 25 of 27
 Sterile suspension for intramuscular injection provided as one
or ten single dose prefilled glass syringes (Type I), without INTERACTIONS WITH THIS VACCINE
needles.
 FLUAD® does not contain thimerosal or any other preservative.
Overview
 The syringe plunger does not contain latex and FLUAD® is
considered safe for use in persons with latex allergies
No interaction between FLUAD® and other vaccines or
medication is known.
WARNINGS AND PRECAUTIONS
Drug-Drug Interactions
FLUAD® should not be administered to anyone with known
allergies to eggs or egg products, or any other constituent of the FLUAD® may be given at the same time as other vaccines.
vaccine or to anyone who has had a life-threatening reaction to FLUAD® should not be mixed with any other vaccine in the same
previous influenza vaccination. syringe. Immunization should be carried out on separate limbs. It
should be noted that the systemic adverse reactions may be
If Guillain-Barré Syndrome (GBS) has occurred within six weeks intensified.
of previous influenza vaccination, the decision to give FLUAD®
should be based on careful consideration of the potential benefits The immunological response may be diminished if the patient is
and risks. undergoing immunosuppressant treatment.

Immunocompromised patients may have a diminished immune Although a possible interaction has been suggested in the
response to FLUAD®. literature between influenza vaccination and the use of warfarin
and theophylline, clinical studies have not shown any adverse
BEFORE you use FLUAD®, talk to your doctor or pharmacist if: effects attributable to these drugs in people receiving influenza
vaccine. There were no studies designed to evaluate the drug
• You are allergic to eggs or egg-products interactions with FLUAD®.
• You are allergic to any of the following: kanamycin and
neomycin sulphate, formaldehyde,
cetyltrimethylammonium bromide, or polysorbate 80 PROPER USE OF THIS VACCINE
• You have a fever, or you think you may be getting a
fever
Usual dose: Adults aged 65 years and over: A single dose of 0.5
• You had a serious reaction to any flu vaccine in the past
• You have any known allergies mL should be administered intramuscularly.
• You have experienced any health problems
• You are pregnant: ask your doctor for advice Immunization should be carried out by intramuscular injection
• You are currently on any medication (i.e. only.
immunosuppressant, theophylline, anticoagulants such as
warfarin) As with all injectable vaccines, appropriate medical treatment and
supervision should always be readily available in case of a rare
FLUAD® may be given at the same time as other vaccines. anaphylactic event following the administration of the vaccine.
Do not mix with any other vaccine in the same syringe.
As with any vaccine, immunization with FLUAD® may not Overdose:
protect 100% of individuals against influenza disease. In case of drug overdose, contact a health care practitioner,
Immunosuppressive therapies may reduce immune response to hospital emergency department or regional Poison Control
FLUAD®. Centre immediately, even if there are no symptoms.

No data are available.

USE IN SPECIFIC POPULATIONS
 Safety and effectiveness of FLUAD® has not been
established in pregnant women and nursing mothers. Missed Dose: Not applicable
 Safety and effectiveness in children and adolescents has not
been established.
 Antibody responses were lower in the geriatric population
than in younger subjects.

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 SIDE EFFECTS AND WHAT TO DO ABOUT THEM MORE INFORMATION

Vaccination with FLUAD® (influenza vaccine, surface antigen, REPORTING SUSPECTED SIDE EFFECTS
inactivated) cannot cause influenza because the vaccine does not To monitor vaccine safety, the Public Health Agency of
contain live virus. Respiratory disease after vaccination represents Canada collects case reports on adverse events following
coincidental illness unrelated to influenza vaccination. immunization.
Occasionally people have side effects with influenza vaccines.
For health care professionals:
The most common of these are fever, feeling unwell, shivering,
If a patient experiences an adverse event following
tiredness, headache, sweating, muscle joint pain, and warmth.
immunization, please complete the appropriate Adverse Events
Skin reactions include redness, swelling, pain, ecchymosis
following Immunization (AEFI) Form and send it to your local
(blue/black staining of the skin) and a hardening of the skin at the
Health Unit in your province/territory.
injection site and itching. These reactions will normally disappear
without treatment in a day or two.
For the General Public:
Rarely, neuralgia (nerve pain), paresthesia (numbness and Should you experience an adverse event following
tingling), convulsions (seizures), thrombocytopenia (a blood immunization, please ask your doctor, nurse, or pharmacist to
disorder), lymphadenopathy (swelling of the glands in the neck, complete the Adverse Events following Immunization (AEFI)
armpit or groin), muscular weakness, and allergic reactions (this Form.
might include but is not limited to breathing or swallowing
difficulties, or swelling in the face or skin) have been reported If you have any questions or have difficulties contacting your
with influenza vaccination. In rare cases, allergic reactions may local health unit, please contact Vaccine Safety Section at
lead to shock. Public Health Agency of Canada :

Very rarely, vasculitis (inflammation of blood vessels) By toll-free telephone: 866-844-0018

temporarily affecting the kidneys, exudative erythema multiforme By toll-free fax: 866-844-5931
(severe skin rash), neurological disorders (affecting the nerves Email: caefi@phac-aspc.gc.ca
and brain), such as encephalomyelitis, and neuritis, injection-site Web: http://www.phac-aspc.gc.ca/im/vs-sv/index-eng.php
cellulitis-like reaction (some cases of swelling, pain, and redness
extending more than 10 cm and lasting more than 1 week) and Mail:
extensive swelling of injected limb lasting more than one week The Public Health Agency of Canada
have been reported. Vaccine Safety Section
130 Colonnade Road, A/L 6502A
The most common (≥ 10%) local (injection-site) adverse reactions Ottawa, ON K1A 0K9
observed in clinical studies were injection site pain, induration,
swelling, and erythema. NOTE: Should you require information related to the
management of the side effect, please contact your health care
The most common (≥ 10%) systemic adverse reactions observed provider before notifying the Public Health Agency of Canada.
in clinical studies were headache, myalgia, and malaise. The Public Health Agency of Canada does not provide medical
advice
This is not a complete list of side effects. For any unexpected
effects while taking FLUAD®, contact your doctor or pharmacist. This leaflet was prepared by Novartis Vaccines and Diagnostics,
S.r.l., Siena, Italy, an affiliate of: Novartis Vaccines and
HOW TO STORE IT Diagnostics, Inc., 350 Massachusetts Avenue, Cambridge, MA
USA 02139
This product should be stored at 2°C to 8°C (in a refrigerator), not This document plus the full product monograph, prepared for
frozen. The syringe should be kept in the outer carton, thus health professionals can be found at:
protecting it from light.
http://www.novartis.ca
FLUAD® can be administered following a 2 hour exposure at
temperatures between 8° and 25°C. This is not, however, a or by contacting the sponsor, Novartis Vaccines and Diagnostics
recommendation for storage. at 1-800-363-8883
Distributed by: Novartis Pharmaceuticals Canada Inc.
Do not use vaccine after the expiration date. 385 Bouchard Blvd.
Dorval, QC H9S 1A9
Last revised: April 11, 2014

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