Afluria

Name: Afluria

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) and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza vaccine have not been correlated with protection from influenza virus. In some human studies, antibody titers of 1:40 or greater 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 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 to one or more new strains in each year’s influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the HA of three strains (i.e., typically two type A and one type B) representing the influenza viruses likely to be circulating in the US during the upcoming winter. Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination and circulating strains of influenza virus change from year to year.1

Clinical Studies

Efficacy Against Laboratory-Confirmed Influenza

In Study 5, the efficacy of AFLURIA was demonstrated in a randomized, observer-blind, placebo-controlled study conducted in 15,044 subjects. Healthy subjects 18 through 64 years of age were randomized in a 2:1 ratio to receive a single dose of AFLURIA (enrolled subjects: 10,033; evaluable subjects: 9,889) or placebo (enrolled subjects: 5,011; evaluable subjects: 4,960). The mean age of all randomized subjects was 35.5 years. 54.4% were female and 90.2% were White. Laboratory-confirmed influenza was assessed by active and passive surveillance of influenza-like illness (ILI) beginning 2 weeks postvaccination until the end of the influenza season, approximately 6 months post-vaccination. ILI was defined as at least one respiratory symptom (e.g., cough, sore throat, nasal congestion) and at least one systemic symptom (e.g., oral temperature of 100.0°F or higher, feverishness, chills, body aches). Nasal and throat swabs were collected from subjects who presented with an ILI for laboratory confirmation by viral culture and real-time reverse transcription polymerase chain reaction. Influenza virus strain was further characterized using gene sequencing and pyrosequencing.

Attack rates and vaccine efficacy, defined as the relative reduction in the influenza infection rate for AFLURIA compared to placebo, were calculated using the per protocol population. Vaccine efficacy against laboratoryconfirmed influenza infection due to influenza A or B virus strains contained in the vaccine was 60% with a lower limit of the 95% CI of 41% (Table 6).

Table 6: Laboratory-Confirmed Influenza Infection Rate and Vaccine Efficacy in Adults 18 through 64 Years of Age (Study 5)

  Subjects a Laboratory- Confirmed Influenza Cases Influenza Infection Rate Vaccine Efficacy b
N N n/N % % Lower Limit of the 95% CI
Vaccine-matched Strains
  AFLURIA 9889 58 0.59 60 41
  Placebo 4960 73 1.47
Any Influenza Virus Strain
  AFLURIA 9889 222 2.24 42 28
  Placebo 4960 192 3.87
Abbreviations: CI, confidence interval
a The Per Protocol Population was identical to the Evaluable Population in this study.
b Vaccine efficacy = 1 minus the ratio of AFLURIA/placebo infection rates. The objective of the study was to demonstrate that the lower limit of the CI for vaccine efficacy was greater than 40%.

Immunogenicity In Children — Administration Via Needle And Syringe

Study 1 was a randomized, observer-blind, comparator-controlled study to evaluate the immunological non-inferiority of AFLURIA to a US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur, Inc.) in subjects 6 months through 17 years of age. Study vaccines were administered by needle and syringe. Results are presented for children 5 through 17 years of age (Table 7). A total of 832 subjects (aged 5 through 17 years) were enrolled. Subjects were randomized in a 1:1 ratio to receive AFLURIA (enrolled subjects: 417; evaluable subjects: 383) or the comparator vaccine (enrolled subjects: 415; evaluable subjects: 383).

Children 6 months through 8 years of age with no history of influenza vaccination received 2 doses approximately 28 days apart. Children 6 months through 8 years of age with a history of influenza vaccination and children 9 years of age and older received 1 dose. Children 6 months through 35 months of age received 0.25 mL of AFLURIA or comparator influenza vaccine, and children 3 years of age and older received 0.5 mL of AFLURIA or comparator influenza vaccine. Nearly equal proportions of subjects were male (49.9%) and female (50.1%), and the majority were White (85.0%) or Black (10.3%).

Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. The co-primary endpoints were HI Geometric Mean Titer (GMT) ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after the final vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 7, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For influenza type B, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects. Analysis of the 761 subjects aged 5 through 17 years reduced the power of the study and widened the confidence intervals. In the pre-specified analysis, AFLURIA was not inferior to the comparator vaccine for all three virus strains. Post-hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities.

Table 7: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a US-Licensed Comparator, Subjects 5 through 17 Years of Age (Study 1)

  Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both predefined non-inferiority criteria? c
Strain Comparator
N=381
AFLURIA
N=380
Comparator
over AFLURIA
(95% CI)
Comparator
N=381
AFLURIA
N=380
Comparator minus AFLURIA
(95% CI)
A (H1N1) 526.2 507.4 1.03
(0.88, 1.21)
62.7 62.6 0.1
(-6.8, 7.0)
Yes
A (H3N2 1060.0 961.3 1.07
(0.94, 1.23)
72.2 69.7 2.4
(-4.0, 8.9)
Yes
B 123.3 110.1 1.10
(0.94, 1.29)
75.1 70.0 5.1
(-1.3, 11.4)
No
Abbreviations: CI, confidence interval; GMT, geometric mean titer.
a GMT ratios are adjusted for baseline HI titers.
b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40.
c Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects.

Immunogenicity In Adults And Older Adults— Administration Via Needle And Syringe

Two randomized, controlled clinical studies of AFLURIA evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine in adults as compared to placebo (adults 18 through 64 years) or another USlicensed trivalent influenza vaccine (adults ≥ 65 years). In these studies, postvaccination immunogenicity was evaluated on sera obtained 21 days after administration of a single dose of AFLURIA.

Study 4 was a randomized, double-blinded, placebo-controlled, multi-center study in healthy subjects ages 18 through 64 years. A total of 1,357 subjects were vaccinated (1,089 subjects with AFLURIA and 268 with a placebo). Subjects who received AFLURIA were vaccinated using either the preservativefree or thimerosal-containing presentation. The evaluable population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group). The mean age of the entire evaluable population receiving AFLURIA was 38 years. 62.5% of subjects were female, 81.3% were White, 12.1% were Black, and 6.2% were Asian.

Serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 8). Similar responses were observed between genders. The study was not sufficiently diverse to assess immunogenicity by race or ethnicity.

Table 8: Serum Antibody Responses in Subjects 18 through 64 Years of Age Receiving AFLURIA (Study 4)

Strain Variable AFLURIA N=1077 value (95% CI) Placebo N=264 value (95% CI)
A(H1N1)
  HI Titer ≥ 1:40 a 97.8% (96.7, 98.6) 74.6% (68.9, 79.8)
  Seroconversion Rate (%) b 48.7% (45.6, 51.7) 2.3% (0.8, 4.9)
A(H3N2)
  HI Titer ≥ 1:40 a 99.9% (99.5, 100.0) 72.0% (66.1, 77.3)
  Seroconversion Rate (%) b 71.5% (68.7, 74.2) 0.0% (N/A)
B
  HI Titer ≥ 1:40 a 94.2% (92.7, 95.6) 47.0% (40.8, 53.2)
  Seroconversion Rate (%) b 69.7% (66.9, 72.5) 0.4% (< 0.1, 2.1)
a HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. Lower bound of 95% CI for HI antibody titer ≥ 1:40 should be > 70% for the study population.
b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40. Lower bound of 95% CI for seroconversion should be > 40% for the study population.

Study 6 was a randomized, observer-blind, comparator-controlled study that enrolled 1,268 subjects 65 years of age and older (Table 9). This study compared the immune response following administration of AFLURIA to that following a US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.). Subjects were randomized in a 1:1 ratio to receive a single vaccination of AFLURIA (enrolled subjects: 631; evaluable subjects: 605) or the comparator vaccine (enrolled subjects: 637; evaluable subjects: 610). Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. Most of the subjects in the per-protocol immunogenicity population were female (56.7%) and White (97.4%). 2.0% were Black and less than 1.0% were of other races or ethnicities.

The co-primary endpoints were HI GMT ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 9, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For the B strain, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Post-hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities.

Table 9: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a US-Licensed Comparator, Adults 65 Years of Age and Older (Study 6)

  Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined non-inferiority criteria?
Strain Comparator
N=610
AFLURIA
N=605
Comparator over AFLURIA
(95% CI)
Comparator
N=610
AFLURIA
N=605
Comparator minus AFLURIA
(95% CI)
A(H1N1) 59.2 59.4 1.04
(0.92, 1.18)
43.0 38.8 4.1
(-1.4, 9.6)
Yes
A(H3N2) 337.7 376.8 0.95
(0.83, 1.08)
68.7 69.4 -0.7
(-5.9, 4.5)
Yes
B 33.4 30.4 1.12
(1.01, 1.25)
34.4 29.3 5.2
(-0.1, 10.4)
No
Abbreviations: CI, confidence interval; GMT, geometric mean titer.
a Post-vaccination GMTs were adjusted for baseline HI titers.
b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40.

Immunogenicity In Adults – Administration Via Pharmajet Stratis Needle-Free Injection System

Study 8 was a randomized, comparator-controlled non-inferiority study that enrolled 1,250 subjects 18 through 64 years of age. This study compared the immune response following administration of AFLURIA when delivered IM using either the PharmaJet Stratis Needle-Free Injection System or needle and syringe. Immunogenicity assessments were performed prior to vaccination and at 28 days after vaccination in the immunogenicity population (1,130 subjects, 562 PharmaJet Stratis Needle-Free Injection System group, 568 needle and syringe group). The co-primary endpoints were HI GMT ratios for each vaccine strain and the absolute difference in seroconversion rates for each vaccine strain 28 days after vaccination. As shown in Table 10, noninferiority of administration of AFLURIA by the PharmaJet Stratis Needle-Free Injection System compared to administration of AFLURIA by needle and syringe was demonstrated in the immunogenicity population for all strains. Post-hoc analyses of immunogenicity by age showed that younger subjects (18 through 49 years) elicited higher immunological responses than older subjects (50 through 64 years). Post-hoc analyses of immunogenicity according to gender and body mass index did not reveal significant influences of these variables on immune responses. The study population was not sufficiently diverse to assess immunogenicity by race or ethnicity.

Table 10: Baseline and Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA Administered by PharmaJet Stratis Needle-Free Injection System or Needle and Syringe, Adults 18 through 64 Years of Age (Study 8)

  Baseline GMT Post-vaccination GMT GMT Ratio a Seroconversion % b Difference Met both pre-defined non-inferiority criteria? c
Strain Needle and Syringe
N=568
PharmaJet Stratis Needle-Free Injection System
N=562
Needle and Syringe
N=568
PharmaJet Stratis Needle-Free Injection System
N=562
Needle and Syringe over PharmaJet Stratis Needle-Free Injection System
(95% CI)
Needle and Syringe
N=568
PharmaJet Stratis Needle-Free Injection System
N=562
Needle and Syringe minus PharmaJet Stratis Needle-Free Injection System
(95% CI)
A(H1N1) 79.5 83.7 280.6 282.9 0.99
(0.88, 1.12)
38.4 37.5 0.8
(-4.8, 6.5)
Yes
A(H3N2) 75.4 68.1 265.9 247.3 1.08
(0.96, 1.21)
45.1 43.8 1.3
(-4.5, 7.1)
Yes
B 12.6 13.5 39.7 42.5 0.94
(0.83, 1.06)
35.2 34.9 0.3
(-5.2, 5.9)
Yes
Abbreviations: CI, confidence interval; GMT, geometric mean titer
a GMT ratio is defined as post-vaccination GMT for Needle and Syringe/PharmaJet Stratis Needle-Free Injection System
b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40.
c Non-inferiority (NI) criteria for the GMT ratio: upper bound of 2-sided 95% CI on the ratio of Needle and Syringe/PharmaJet Stratis Needle-Free Injection System. GMT should not exceed 1.5. NI criteria for the seroconversion rate (SCR) difference: upper bound of 2-sided 95% CI on the difference between SCR Needle and Syringe – SCR PharmaJet Stratis Needle-Free Injection System should not exceed 10%.

REFERENCES

1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59 (RR-8):1-62.

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 AS, et al. The Role of Serum Hemagglutination-Inhibiting Antibody in Protection against Challenge Infection with Influenza A2 and B Viruses. J Hyg Camb 1972;70:767-777.

Patient information

  • Inform the vaccine recipient or guardian of the potential benefits and risks of immunization with AFLURIA.
  • Inform the vaccine recipient or guardian that AFLURIA is an inactivated vaccine that cannot cause influenza but stimulates the immune system to produce antibodies that protect against influenza, and that the full effect of the vaccine is generally achieved approximately 3 weeks after vaccination.
  • Instruct the vaccine recipient or guardian to report any severe or unusual adverse reactions to their healthcare provider.
  • Encourage women who receive AFLURIA while pregnant to participate in the exposure and surveillance study. Pregnant women can contact the pregnancy study center by calling 1-877-311-8972 or visiting the website http://www.pregnancystudies.org.
  • Provide the vaccine recipient or guardian with Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).
  • Instruct the vaccine recipient or guardian that annual revaccination is recommended.

Uses of Afluria

Afluria is a vaccine used to prevent influenza. It is approved for use in persons 5 years of age and older.

Afluria Dosage

The dose your doctor recommends will be based on age:

A single dose of Afluria is 0.5ml. The dose and schedule for Afluria is as follows:

  • 5 years through 8 years old: one dose or two doses at least 1 month apart
  • 9 years and older: one dose

The preferred site for intramuscular injection is the deltoid muscle of the upper arm.

Afluria is an inactivated vaccine that cannot cause influenza but stimulates the immune system to produce antibodies that protect against influenza. The full effect of the vaccine is generally achieved approximately 2 weeks after vaccination, and protection lasts through the flu season.

Uses of Afluria

  • It is used to prevent the flu.

Afluria Dosage and Administration

Prior to Administration

Afluria should be inspected visually for particulate matter and discoloration prior to administration (see Description [11]), whenever suspension and container permit. If either of these conditions exists, the vaccine should not be administered. Any vaccine that has been frozen or is suspected of being frozen must not be used.

Administration

When using a preservative-free, single-dose syringe, shake the syringe thoroughly and administer the dose immediately.

When using the multi-dose vial, shake the vial thoroughly before withdrawing each dose, and administer the dose immediately. Between uses, store the vial at 2–8°C (36–46°F) (see How Supplied/Storage and Handling [16]). Once the stopper has been pierced, the vial must be discarded within 28 days.

Children

Children 6 months through 35 months of age not previously vaccinated with an influenza vaccine, or vaccinated for the first time last season with only one dose, should receive two 0.25 mL doses: one on day 1 followed by another approximately 4 weeks later. Children 6 months through 35 months of age given two doses of any influenza vaccine last season, or at least one dose two or more years ago, should receive only one 0.25 mL dose.1

Children 36 months through 8 years of age not previously vaccinated with an influenza vaccine, or vaccinated for the first time last season with only one dose, should receive two 0.5 mL doses: one on day 1 followed by another approximately 4 weeks later. Children 36 months through 8 years of age given two doses last season, or at least one dose two or more years ago, should receive only one 0.5 mL dose.1

Children 9 years of age and older should receive a single 0.5 mL intramuscular dose.1

The preferred sites for intramuscular injections are the anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in toddlers and young children.

Adults

Afluria should be administered as a single 0.5 mL intramuscular injection, preferably in the deltoid muscle of the upper arm.

Contraindications

Afluria is contraindicated in individuals with known hypersensitivity to eggs, neomycin, or polymyxin, or in anyone who has had a life-threatening reaction to previous influenza vaccination (see Description [11]).

References

  1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009;58 (RR-8):1-46.
  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 AS, et al. The Role of Serum Hemagglutination-Inhibiting Antibody in Protection Against Challenge Infection with Influenza A2 and B Viruses. J Hyg Camb 1972;70:767-777.

How Supplied/Storage and Handling

How Supplied NDC Number
Package of ten 0.5 mL single-dose, prefilled syringes without needles 33332-010-01
Package of one 5 mL multi-dose vial, which contains ten 0.5 mL doses 33332-110-10

Store refrigerated at 2–8°C (36–46°F). Do not freeze. Protect from light. Do not use Afluria beyond the expiration date printed on the label.

What is the most important information i should know about this vaccine?

The injectable influenza virus vaccine (flu shot) is a "killed virus" vaccine. Influenza virus vaccine is also available in a nasal spray form, which is a "live virus" vaccine. This medication guide addresses only the injectable form of this vaccine.

You can still receive a vaccine if you have a minor cold. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

Keep track of any and all side effects you have after receiving this vaccine. If you ever need to receive influenza virus vaccine in the future, you will need to tell your doctor if the previous shot caused any side effects.

Like any vaccine, influenza virus vaccine may not provide protection from disease in every person. This vaccine will not prevent illness caused by avian flu ("bird flu").

Influenza virus injectable (killed virus) vaccine will not cause you to become ill with the flu virus that it contains. However, you may have flu-like symptoms at any time during flu season that may be caused by other strains of influenza virus.

Becoming infected with influenza is much more dangerous to your health than receiving this vaccine. However, like any medicine, this vaccine can cause side effects but the risk of serious side effects is extremely low.

For the Consumer

Applies to influenza virus vaccine, inactivated: intramuscular solution

Other dosage forms:

  • solution, suspension

Along with its needed effects, influenza virus vaccine, inactivated (the active ingredient contained in Afluria) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking influenza virus vaccine, inactivated:

Incidence not known
  • Cough
  • difficulty with swallowing
  • dizziness
  • fast heartbeat
  • hives, itching, or skin rash
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • tightness in the chest
  • unusual tiredness or weakness

Some side effects of influenza virus vaccine, inactivated may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Difficulty with moving
  • headache
  • joint pain
  • muscle aching or cramping
  • muscle pains or stiffness
  • nausea
  • pain at the injection site
  • swollen joints
Less common
  • Chills
  • redness, bruising, or swelling at the injection site

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