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Flucelvax

Last reviewed on RxList: 10/15/2015
Drug Description

FLUCELVAX
(influenza vaccine) Intramuscular Injection

DESCRIPTION

FLUCELVAX (Influenza Vaccine), a vaccine for intramuscular injection, is a “subunit” influenza 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 -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 2015-2016 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 (wild type) (an A/California/7/2009 (H1N1)pdm09-like virus);

A/South Australia/55/2014 (wild type) (an A/Switzerland/9715293/2013 (H3N2)-like virus); B/Utah/9/2014 (a B/Phuket/3073/2013-like virus).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.

Indications & Dosage

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

For intramuscular injection only.

Dosage And Schedule

Administer FLUCELVAXas 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.

Administration

Shake the syringe vigorously before administering. FLUCELVAX should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. [see DESCRIPTION] 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.

HOW SUPPLIED

Dosage Forms And Strengths

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

Storage And Handling

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

  • Carton NDC number: 62577-614-01
  • Pre-filled syringe NDC number: 62577-614-11

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 (36°F to 46°F). Do not freeze. Protect from light. Do not use after the expiration date.

Manufactured by: Novartis Vaccines and Diagnostics, Inc. 350 Massachusetts Avenue, Cambridge, MA, USA. Revised: May 2015.

Side Effects & Drug Interactions

SIDE EFFECTS

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%).

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 administered Flucelvax.

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 (Study 1) was a randomized, double-blind, placebo-controlled study that evaluated three vaccines including: 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. Solicited adverse reactions for FLUCELVAX and placebo are summarized in Table 1.

Table 1: Solicited Adverse Reactions in the Safety Population1 Reported Within 7 Days of Vaccination in Study 1

  Adults 18 through 49 Years
Percentages (%)
FLUCELVAX
N=3813
Placebo2
N=3894
Local adverse reactions
  Injection site pain 30 10
  Erythema 13 10
  Induration 6 3
  Swelling 6 3
  Ecchymosis 4 4
Systemic adverse reactions
  Headache 15 15
  Fatigue 10 10
  Myalgia 12 7
  Malaise 8 6
  Chills 6 6
  Arthralgia 3 3
  Sweating 3 3
Fever ( ≥ 38°C) 1 < 1
1Safety population: all subjects in the exposed population who provided post vaccination safety data
2Placebo: 0.5 mL Phosphate Buffered Saline

Study 2 was a randomized, double-blind study comparing FLUCELVAX (N=1330) to a U.S. licensed inactivated influenza vaccine (N=1324) in adults 18 years of age or older. The mean age was 43.7 years of age for adults 18 through 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.

Table 2: Solicited Adverse Reactions in the Safety Population1 Reported Within 7 Days of Vaccination in Study 2

  Adults 18 through 64 Years Adults 65 Years of Age and Older
Percentages (%)
FLUCELVAX
N=821
Comparator2
N=841
FLUCELVAX
N=509
Comparator2
N=483
Local adverse reactions
  Injection site pain 20 15 8 4
  Erythema 14 15 10 11
  Induration 6 6 5 4
  Swelling 4 4 4 2
  Ecchymosis 3 3 4 4
Systemic adverse reactions
  Headache 12 11 10 11
  Fatigue 11 11 11 13
  Myalgia 7 8 6 8
  Malaise 11 11 10 11
  Chills 4 4 3 4
  Arthralgia 5 5 6 7
  Sweating 5 4 7 8
  Fever ( ≥ 38°C) 1 1 < 1 1
1Safety population: all subjects in the exposed population who provided post vaccination safety data
2AGRIFLU

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 inactivated influenza 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 fewer subjects.

In the seven controlled studies of FLUCELVAX, serious adverse events were collected for a duration of 21 days in two studies and for a duration of 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 influenza 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.

Postmarketing Experience

The following additional adverse events have been identified during post-approval use of FLUCELVAX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Nervous Systems Disorders

Syncope, Presyncope,

General Disorders and Administration Site Conditions

Extensive swelling of injected limb.

Immune System Disorders

Anaphylactic reaction, angioedema

Skin and Subcutaneous Tissue Disorders

Generalized skin reactions including pruritus, urticaria or non-specific rash.

DRUG INTERACTIONS

Concomitant Use With Other Vaccines

No data are available to assess the concomitant administration of FLUCELVAXwith 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.

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]

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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]

Preventing And Managing Allergic Reactions

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

Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including Flucelvax. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope by maintaining a supine or Trendelenburg position.

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]

Limitations Of Vaccine Effectiveness

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

REFERENCES

1. 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.

Nonclinical Toxicology

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.

Use In Specific Populations

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.

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.

Pediatric Use

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

Geriatric Use

Of the total number of subjects who received one dose of FLUCELVAX in clinical studies and included in the safety population (6281), 9% (572) were 65 years of age and older and 2% (140) were 75 years of age or older.

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

Overdosage & Contraindications

OVERDOSE

No information provided.

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].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

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.2,3

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.4

Clinical Studies

Efficacy Against Culture-Confirmed Influenza

A multinational (US, Finland, and Poland), randomized, observer-blind, 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 in the period from 21 days to 6 months after vaccination. Overall vaccine efficacy against all influenza viral subtypes and vaccine efficacy against individual influenza viral subtypes were calculated (Tables 3 and 4, respectively).

Table 3: Vaccine Efficacy against Culture-Confirmed Influenza (Study 1)

  Number of subjects per protocol Number of subjects with influenza Attack Rate (%) Vaccine Efficacy1,2
% Lower Limit of OneSided 97.5% CI of VE2, 3
Antigenically Matched Strains
  FLUCELVAX 3776 7 0.19 83.8 61.0
  Placebo 3843 44 1.14 -- --
All Culture-Confirmed Influenza
  FLUCELVAX 3776 42 1.11 69.5 55.0
  Placebo 3843 140 3.64 -- --
1Efficacy against influenza was evaluated over a 9 month period in 2007/2008
2Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %
3VE success criterion: the lower limit of the one-sided 97.5% CI for the estimate of the VE relative to placebo is > 40%

Table 4: Efficacy of FLUCELVAX against Culture-Confirmed Influenza by Influenza Viral Subtype (Study 1)

  FLUCELVAX
(N=3776)
Placebo
(N=3843)
Vaccine Efficacy2
Attack Rate (%) Number of Subjects with Influenza Attack Rate (%) Number of Subjects with Influenza % Lower Limit of One-Sided 97.5% CI of VE1,2
Antigenically Matched Strains
A/H3N23 0. 05 2 0 0 -- --
A/H1N1 0.13 5 1.12 43 88.2 67.4
B3 0 0 0.03 1 -- --
All Culture-Confirmed Influenza
A/H3N2 0.16 6 0.65 25 75.6 35.1
A/H1N1 0.16 6 1.48 57 89.3 73.0
B 0.79 30 1.59 61 49.9 18.2
1No VE success criterion was prespecified in the protocol for each individual influenza virus subtype.
2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %;
3 There were too few cases of influenza due to vaccine-matched influenza A/H3N2 or B to adequately assess vaccine efficacy.

Immunogenicity In Adults 18 Through 64 Years Of Age

Immunogenicity data 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 or comparator vaccine.

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 (228, 695, and 55 for FLUCELVAX, AGRIFLU, and placebo, respectively). 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 outlined in Table 5, antibody responses after vaccination were evaluated according to percentages of subjects with HI antibody titers ≥ 1:40 and seroconversion. For subjects 18 through 64 years of age, success was defined as 1) the lower bound of the two-sided 95% CI for the percent of subjects achieving an HI antibody titer ≥ 1:40 should meet or exceed 70% and 2) the lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should meet or exceed 40% (Table 5).

Table 5: Percentage (%) of subjects with Post-Vaccination HI Titers ≥ 1:40 and Seroconversion in Adult FLUCELVAX Recipients 18 through 49 Years and 50 through 64 Years of Age

Study Vaccine strain 18 through 49 Years 50 through 64 Years
% HI Titer ≥ 1:40 (95% CI) % Seroconversion1 (95% CI) % HI Titer ≥ 1:40 (95% CI) % Seroconversion1 (95% CI)
    N=228 N=228    
Study 1 US, Finland, Poland 2007- 2008 N=228 A/H1N1 99 (97-100) 78 (72-83)    
A/H3N2 99 (98-100) 59 (53-66)    
B 78 (72-83) 51 (45-58)    
    N=478 N=478 N=340 N=340
Study 2 Poland 2004- A/H1N1 94 (91-96) 73 (69-77) 84 (79-88) 57 (52-63)
2005 N=818 A/H3N2 99 (98-100) 63 (59-68) 99 (97-100) 66 (61-71)
B 93 (90-95) 88 (84-90) 87 (83-90) 77 (70-79)
    N=307 N=307    
Study 3 US 2005- 2006 N=307 A/H1N1 96 (94-98) 62 (57-68)    
A/H3N2 91 (87-94) 85 (81-89)    
B 94 (91-96) 77 (72-81)    
1 Rates of seroconversion = 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

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. Success for non-inferiority of the GMT ratio was defined as the lower limit of the two-sided 95% CI for GMT ratio (FLUCELVAX / AGRIFLU) was > 0.67; and success for non-inferiority of seroconversion rate was defined as the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX – AGRIFLU) was > -10%) (Table 6).

Table 6: Non-inferiority Analysis of FLUCELVAX to a US licensed Comparator in Adults 18 through 49 Years and 50 through 64 Years of Age (Study 2)

  Vaccine Group Ratio/Difference (95% CI) FLUCELVAX Versus Comparator1
A/H1N1 A/H3N2 B
Subjects 18 through 49 Years: N Flucevax=478; N comparator=472
GMTs ratio (Flucelvax / Agriflu) 0.96 (0.81, 1.13) 0.98 (0.87, 1.11) 1.07 (0.93, 1.23)
Difference in Seroconversion Rates2 (Flucelvax - Agriflu) 2% (-4, 8) 2% (-5, 8) 5% (1, 10)
Subjects 50 through 64 Years: N Flucevax=340; N comparator=365
GMTs ratio (Flucelvax / Agriflu) 0.96 (0.79, 1.16) 0.87 (0.74, 1.02) 1.23 (1.02, 1.48)
Difference in Seroconversion Rates (Flucelvax - Agriflu) 1% (-6, 8) -2% (-9, 5) 3% (-4, 9)
1 AGRIFLU
2Rates of seroconversion = 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

Immunogenicity In Adults 65 Years Of Age And Older

In clinical study 2, a post-hoc analysis of immune response to Flucelvax among adults 65 years of age and older was performed. 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.

Antibody responses to Flucelvax in this older population were evaluated according to percentages of subjects with seroconversion and HI Titer ≥ 1:40 (Table 7) and were compared to antibody responses for non-inferiority to a licensed comparator vaccine (Agriflu, Table 8).

For subjects 65 years of age and older, success was defined as 1) the lower bound of the two-sided 95% CI for the percent of subjects achieving HI an antibody titer ≥ 1:40 should meet or exceed 60% and 2) the lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should meet or exceed 30%.

Table 7: Percentage (%) of subjects with Post-Vaccination HI Titers ≥ 1:40, Seroconversion Rate in Adult FLUCELVAX Recipients 65 Years of Age and Older (Study 2)

  Vaccine strain % of Subjects with HI Titer ≥ 1:40 (95% CI) % of Subjects with Seroconversion1 (95% CI)
Study 2 Poland 2004-2005 N=504 A/H1N1 86 (83-89) 55 (50-59)
A/H3N2 97 (95-98) 68 (64-72)
B 90 (87-93) 80 (76-84)
1Rates of seroconversion = 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.

Non-inferiority in Adults 65 Years of Age and Older

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. Success for non-inferiority of the GMT ratio was defined as the lower limit of the two-sided 95% CI for the GMT ratio (FLUCELVAX / AGRIFLU) > 0.67; and success for non-inferiority of seroconversion rate was defined as the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX – AGRIFLU) > -10%) (Table 8).

Table 8: Non-inferiority Analysis of FLUCELVAX to a US licensed Comparator in Adults 65 Years of Age and Older (Study 2)

  Vaccine Group Ratio/Difference (95% CI)
FLUCELVAX Versus Comparator1
(N FLUCELVAX=504; N comparator=481)
A/H1N1 A/H3N2 B
GMTs ratio (FLUCELVAX / Agriflu) 1.06 (0.92, 1.22) 0.97 (0.84, 1.12) 1.28 (1.1, 1.48)
Difference in Seroconversion Rates2 (FLUCELVAX -Agriflu) -1% (-7, 6) 3% (-2, 9) 7% (1, 12)
1AGRIFLU
2Rates of seroconversion = 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.

REFERENCES

2. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.

3. 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.

4. 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.

Medication Guide

PATIENT INFORMATION

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

Educate 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.

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