Flucelvax

Novartis Vaccines and Diagnostics GmbH
Novartis Vaccines and Diagnostics, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use FLUCELVAX safely and effectively. See full prescribing information for FLUCELVAX.FLUCELVAX (Influenza Virus Vaccine) Suspension for Intramuscular Injection2013-2014 FormulaInitial U.S. Approval: 2012 INDICATIONS AND USAGEFLUCELVAX® is an inactivated vaccine indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (1) FLUCELVAX is approved for use in persons 18 years of age and older. (1) DOSAGE AND ADMINISTRATIONA single 0.5 mL dose for intramuscular injection. (2.2) DOSAGE FORMS AND STRENGTHSSuspension for injection supplied in 0.5-mL single-dose pre-filled syringes. (3) CONTRAINDICATIONSHistory of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine. (4, 11) WARNINGS AND PRECAUTIONS If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLUCELVAX should be based on careful consideration of the potential benefits and risks. (5.1) The tip caps of the pre-filled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. (5.2) Side Effects The most common (≥10%) local and systemic reactions in adults 18-64 years of age were injection site pain (28%), injection site erythema (13%), headache (16%), fatigue (12%), myalgia (11%) and malaise (10%). (6) The most common (≥10%) local and systemic reactions in adults ≥65 years of age were injection site erythema (10%), fatigue (11%), headache (10%) and malaise (10%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Vaccines at 1-877-683-4732 or VAERS at 1-800-822-7967 and www.vaers.hhs.gov. USE IN SPECIFIC POPULATIONS Safety and effectiveness of FLUCELVAX have not been established in pregnant women or nursing mothers. (8.1) Geriatric Use: Antibody responses were lower in adults 65 years and older than in younger adults. (8.5)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 FLUCELVAX INDICATIONS AND USAGE
• 2 FLUCELVAX DOSAGE AND ADMINISTRATION
  • 2.1 Dosage and Schedule
  • 2.2 Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 FLUCELVAX CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Guillain-Barré Syndrome
  • 5.2 Latex
  • 5.3 Preventing and Managing Allergic Reactions
  • 5.4 Altered Immunocompetence
  • 5.5 Limitations of Vaccine Effectiveness
• 6 FLUCELVAX ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Concomitant use with Other Vaccines
  • 7.2 Concurrent use with Immunosuppressive Therapies
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 11 FLUCELVAX DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Efficacy against Culture-Confirmed Influenza
  • 14.2 Immunogenicity in Adults 18 through 64 Years of Age
  • 14.3 Immunogenicity in Adults 65 Years of Age and Older
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

FLUCELVAX^® is an inactivated vaccine indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine

FLUCELVAX is approved for use in persons 18 years of age and older.

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Dosage and Schedule

Administer FLUCELVAX as a single 0.5 mL intramuscular injection preferably in the region of the deltoid muscle of the upper arm. Do not inject the vaccine in the gluteal region or areas where there may be a major nerve trunk.

2.2 Administration

Shake the syringe vigorously before administering. FLUCELVAX should be inspected visually for particulate matter and discoloration prior to administration. [see Description (11)] If either condition exists, do not administer the vaccine. Do not use the vaccine if the contents have been frozen.

Attach a sterile needle to the pre-filled syringe and administer intramuscularly.

3 DOSAGE FORMS AND STRENGTHS

FLUCELVAX is a suspension for injection supplied in a 0.5 mL single-dose pre-filled Luer Lock syringe.

4 CONTRAINDICATIONS

Do not administer FLUCELVAX to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Guillain-Barré Syndrome

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

5.2 Latex

The tip caps of the pre-filled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. [see Description (11)]

5.3 Preventing and Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

5.4 Altered Immunocompetence

After vaccination with FLUCELVAX, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced immune response. [See Concurrent use with Immunosuppresive Therapies (7.2)]

5.5 Limitations of Vaccine Effectiveness

Vaccination with FLUCELVAX may not protect all vaccine recipients against influenza disease.

6 ADVERSE REACTIONS

Overall, the most common (≥10 %) solicited adverse reactions occurring in adults 18 to 64 years of age within 7 days of vaccination with FLUCELVAX were pain at the injection site (28%), erythema at the injection site (13%), headache (16%), fatigue (12%), myalgia (11%) and malaise (10%). The most common (≥10%) solicited adverse reactions occurring in adults 65 years of age and older within 7 days of vaccination were erythema at the injection site (10%), fatigue (11%), headache (10%) and malaise (10%).

6.1 Clinical Trials Experience

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

The safety of FLUCELVAX was evaluated in seven randomized, controlled studies conducted in the US, Europe and New Zealand. The safety population includes 5709 adults 18 through 64 years of age and 572 adults 65 years of age and older.

In all studies, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination.

One of the 7 clinical trials was a randomized, double-blind, placebo-controlled study that evaluated a total of 11376 subjects: FLUCELVAX (N=3813), placebo (N=3894) and another influenza vaccine. The population was 18 through 49 years of age (mean 32.8 years), 55% were female and 84% were Caucasian. The safety data observed for FLUCELVAX and placebo are summarized in Table 1.

Study 2 was a randomized, double-blind study comparing FLUCELVAX (N=1330) to a U.S. licensed comparator (N=1324) in adults 18 years of age or older. The mean age was 43.7 years of age for adults 18 to 64 years of age and 71.3 years of age for adults 65 years of age and older; 57% of subjects were female and 100% were Caucasian. The safety data observed are summarized in Table 2.

Unsolicited adverse events, including serious adverse events (SAEs), were collected for 21 days after vaccination in five studies. In adults 18 through 64 years of age (N=4038), 13% (284 out of 2266) of subjects who received FLUCELVAX and 13% (224 out of 1772) of subjects who received a U.S. licensed comparator vaccine reported at least one unsolicited adverse event within 21 days after vaccination. The most commonly reported unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%), headache (2%) and oropharyngeal pain (2%). In adults 65 years of age and older (N=2013), 11% (110 out of 997) of subjects who received FLUCELVAX and 9% ( 95 out of 1016) of subjects who received a U.S. licensed comparator vaccine reported at least one unsolicited adverse event within 21 days after vaccination. Within this age group, the most commonly reported unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%) and cough (2%). In both age groups, all other unsolicited adverse events were reported in 1% or less of subjects.

In the seven controlled studies of FLUCELVAX, the rates of serious adverse events were collected for 21 days in two studies and for 6 to 9 months in five studies. The rates (in all seven controlled studies) of serious adverse events among adults 18 through 64 years of age were 1% (84 out of 6388) in groups that received FLUCELVAX, 1% (55 out of 5745) in groups that received US licensed comparator vaccines and 1% (37 out of 3894) in groups that received placebo. The rates of serious adverse events among adults 65 years of age and older were 4% (36 out of 997) in groups that received FLUCELVAX and 4% (44 out of 1016) in groups that received a US licensed comparator vaccine.

6.2 Postmarketing Experience

There are no available postmarketing safety data with FLUCELVAX.

7 DRUG INTERACTIONS

7.1 Concomitant use with Other Vaccines

No data are available to assess the concomitant administration of FLUCELVAX with other vaccines.

If FLUCELVAX is to be given at the same time as another injectable vaccine(s), the vaccine(s) should always be administered at different injection sites. Do not mix FLUCELVAX with any other vaccine in the same syringe or vial.

7.2 Concurrent use with 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 FLUCELVAX. [See Altered Immunocompetence (5.4)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B: A reproductive and developmental toxicity study has been performed in rabbits with a dose level that was approximately 15 times the human dose based on body weight. The study revealed no evidence of impaired female fertility or harm to the fetus due to FLUCELVAX. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this vaccine should be used during pregnancy only if clearly needed.

In a reproductive and developmental toxicity study, the effect of FLUCELVAX on embryo-fetal and post-natal development was evaluated in pregnant rabbits. Animals were administered FLUCELVAX by intramuscular injection 3 times prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (approximately 15-fold excess relative to the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, embryo-fetal development, or post-natal development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.

8.3 Nursing Mothers

FLUCELVAX has not been evaluated in nursing mothers. It is not known whether FLUCELVAX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUCELVAX is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness have not been established in children less than 18 years of age.

8.5 Geriatric Use

Of the total number of subjects who received one dose of FLUCELVAX in clinical studies (6711), 9% (572) were 65 years of age and older and 2% (140) were 75 years or older.

The majority of local and general adverse events were reported less frequently in adults 65 years of age and older as compared to adults <65 years of age. [See Adverse Reactions (6.1)]

Antibody responses to FLUCELVAX were lower in the geriatric (adults 65 years and older) population than in younger subjects. [see Clinical Studies (14.3)]

11 DESCRIPTION

FLUCELVAX (Influenza Virus Vaccine), a vaccine for intramuscular injection, is a “subunit” influenza virus vaccine prepared from virus propagated in Madin Darby Canine Kidney (MDCK) cells, a continuous cell line. These cells were adapted to grow freely in suspension in culture medium. The virus is inactivated with ß-propiolactone, disrupted by the detergent cetyltrimethylammonium bromide and purified through several process steps. Each of the 3 virus strains is produced and purified separately then pooled to formulate the trivalent vaccine.

FLUCELVAX is a sterile, slightly opalescent suspension in phosphate buffered saline. FLUCELVAX is standardized according to United States Public Health Service requirements for the 2013-2014 influenza season and is formulated to contain a total of 45 micrograms (mcg) hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following three influenza strains: A/Brisbane/10/2010 (H1N1) (an A/California/7/2009-like virus); A/Texas/50/2012, NYMC X-223A (H3N2) (an A/Victoria/361/2011-like virus); and B/Massachusetts/2/2012. Each dose of FLUCELVAX may contain residual amounts of MDCK cell protein (≤8.4 mcg), protein other than HA (≤ 120 mcg), MDCK cell DNA (≤ 10 ng), polysorbate 80 (≤ 1125 mcg), cetyltrimethlyammonium bromide (≤ 13.5 mcg), and β-propiolactone (≤ 0.5 mcg), which are used in the manufacturing process.

FLUCELVAX contains no preservative or antibiotics.

The tip caps of the pre-filled syringes may contain natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance and analysis of influenza virus isolates permits identification of yearly antigenic variants. 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. In some studies, HI antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.^4,5

Antibody against one influenza virus type or subtype confers little 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 strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains representing the influenza viruses likely to circulate in the United States in the upcoming winter.

Annual influenza vaccination is recommended by the Advisory Committee on Immunization Practices because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.⁶

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

FLUCELVAX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals.

FLUCELVAX did not affect female fertility in a rabbit reproductive and developmental toxicity study.

14 CLINICAL STUDIES

14.1 Efficacy against Culture-Confirmed Influenza

A multinational (US, Finland, and Poland), randomized, observer-blinded, placebo-controlled trial (study 1) was performed to assess clinical efficacy and safety of FLUCELVAX during the 2007-2008 influenza season in adults aged 18 through 49 years. A total of 11,404 subjects were enrolled to receive FLUCELVAX (N=3828), AGRIFLU (N=3676) or placebo (N=3900) in a 1:1:1 ratio. Among the overall study population enrolled, the mean age was 33 years, 55% were female, 84% were Caucasian, 7% were Black, 7% were Hispanic, and 2% were of other ethnic origin.

FLUCELVAX efficacy was assessed by the prevention of culture-confirmed symptomatic influenza illness caused by viruses antigenically matched to those in the vaccine and prevention of influenza illness caused by all influenza viruses compared to placebo. Influenza cases were identified by active and passive surveillance of influenza-like illness (ILI). ILI was defined as a fever (oral temperature ≥100.0°F / 38°C) and cough or sore throat. Nose and throat swab samples were collected for analysis within 120 hours of onset of an influenza-like illness. Efficacy against individual influenza viral subtypes was calculated (Tables 3 and 4).

14.2 Immunogenicity in Adults 18 through 64 Years of Age

Data evaluating immunogenicity in adults 18 through 64 years of age were derived from 3 clinical studies, including 1353 subjects that received FLUCELVAX. Immune responses measured by hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine were evaluated in sera obtained 21 days after administration of FLUCELVAX.

These studies included clinical study 1 performed in 2007-2008 in the US, Finland and Poland, in which immunogenicity was evaluated in a subset of 978 subjects enrolled at US sites. Among the overall study population enrolled, 58% were female; 67% were Caucasian, 20% Hispanic, 11% Black, 1% Asian and 1% of other ethnic origin; and the mean age was 33 years.

In clinical study 2 conducted in Poland in 2004-2005, immunogenicity data were obtained for 1655 subjects (818 and 837 for FLUCELVAX and AGRIFLU, respectively). Among the overall study population enrolled, 59% were female, 100% of subjects were Caucasian, and the mean age was 43.6 years.

In clinical study 3 conducted in the US in 2005-2006, immunogenicity data were obtained for 610 subjects (307 and 303 for FLUCELVAX and FLUVIRIN, respectively). Among the overall study population enrolled, 64% were female, 96% were Caucasian, and the mean age was 33.9 years. Immunogenicity results are shown separately for the age cohorts 18 through 49 years of age (for which clinical endpoint efficacy data are available, Table 3 and Table 4) and 50 through 64 years of age in Tables 5 and 6.

For all studies, the following immunogenicity endpoints were assessed: 1) the lower bound of the two-sided 95% confidence intervals (CI) for the percentage of subjects with HI antibody titers ≥1:40 after vaccination, and 2) the lower bounds of the two-sided 95% CIs for percentages of subjects with seroconversion (defined as percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer > 1:40 or a pre-vaccination HI titer > 1:10 and at least a four-fold rise in post-vaccination HI antibody titer) (Table 5).

Non-inferiority in Adults 18 through 64 Years of Age

In study 2, non-inferiority of FLUCELVAX to AGRIFLU was demonstrated for HI antibody responses to all three strains for both post-vaccination geometric mean titer (GMT) ratios and seroconversion rates (i.e. the lower limit of the two-sided 95% CI for the ratio of the GMTs (FLUCELVAX / AGRIFLU) was >0.67; and the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX and AGRIFLU) was >-10%) (Table 6).

14.3 Immunogenicity in Adults 65 Years of Age and Older

In clinical study 2, an analysis of adults 65 years of age and older was performed by a post-hoc re-stratification of the age ranges. In this study, 985 subjects 65 years of age or older (504 and 481 for FLUCELVAX and AGRIFLU, respectively) were evaluated. Of these subjects, 56% were female, 100% were Causacian, and the mean age was 71.3 years (Table 7).

Non-inferiority in Adults 65 Years of Age and Older

In adults 65 years of age or older enrolled in study 2, non-inferiority of FLUCELVAX to AGRIFLU was demonstrated for HI antibody responses to all three strains for both post-vaccination GMT ratios and seroconversion rates (i.e. the lower limit of the two-sided 95% CI for the ratio of the GMTs (FLUCELVAX / AGRIFLU) was >0.67; and the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX and AGRIFLU) was >-10%) (Table 8).

15 REFERENCES

• Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998; 339(25):1797-1802.
• NCT00630331; see http://clinicaltrials.gov/
• NCT00492063; see http://clinicaltrials.gov/
• Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.
• Hobson D, Curry RL, Beare A, et.al. The role of serum hemagglutinin-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.
• Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(33): 1128-1132.
• NCT00264576; see http://clinicaltrials.gov/

16 HOW SUPPLIED/STORAGE AND HANDLING

FLUCELVAX is supplied in a carton containing ten 0.5 mL single-dose syringes without needles:

• Carton NDC number: 63851-612-01
• Pre-filled syringe NDC number: 63851-612-11

The tip caps of the pre-filled syringes may contain natural rubber latex. The syringe and syringe plunger stopper are manufactured without natural rubber latex.

Store this product refrigerated at 2°C to 8°C (36ºF to 46ºF). Do not freeze. Protect from light. Do not use after the expiration date.

17 PATIENT COUNSELING INFORMATION

Inform the vaccine recipients of the potential benefits and risks of immunization with FLUCELVAX.

Educate the vaccine recipients regarding the potential side effects; clinicians should emphasize that (1) FLUCELVAX contains non-infectious particles and cannot cause influenza and (2) FLUCELVAX is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against other respiratory illnesses.

Instruct vaccine recipients to report adverse reactions to their healthcare provider.

Provide vaccine recipients with the Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Inform vaccine recipients that annual vaccination is recommended.

FLUCELVAX^® is a registered trademark of Novartis Vaccines and Diagnostics, Inc.

Manufactured by: Novartis Vaccines and Diagnostics GmbH, D-35006 Marburg, Germany

An Affiliate of: Novartis Vaccines and Diagnostics, Inc.
350 Massachusetts Avenue
Cambridge, MA USA 02139
1-877-683-4732

Principal Display Panel - Vaccine Carton Label.

NDC 63851-612-01

For adults 18 years of age and older

For Intramuscular Injection only

Ten 0.5 mL, single-dose, pre-filled syringes

Rx Only

INFLUENZA VACCINE

FLUCELVAX®

2013/2014 SEASON