Vaccine Information: FLUZONE High-Dose Quadrivalent Northern Hemisphere (Page 2 of 4)

6.2 Postmarketing Experience

The following additional adverse events have been spontaneously reported during the postmarketing use of Fluzone High-Dose, Fluzone, or Fluzone Quadrivalent and may occur in people receiving Fluzone High-Dose Quadrivalent. 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 vaccine exposure. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Fluzone High-Dose, Fluzone, or Fluzone Quadrivalent.

  • Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy
  • Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema)
  • Eye Disorders: Ocular hyperemia
  • Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paresthesia
  • Vascular Disorders: Vasculitis, vasodilatation
  • Respiratory, Thoracic and Mediastinal Disorder s: Dyspnea, cough, wheezing, throat tightness, oropharyngeal pain, and rhinorrhea
  • Gastrointestinal Disorders: Vomiting
  • Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
  • General Disorders and Administration Site Conditions: pruritus, asthenia/fatigue, chest pain, chills

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Fluzone High-Dose Quadrivalent is not approved for use in persons <65 years of age. There are limited human data on Fluzone High-Dose and no animal data available on Fluzone High-Dose Quadrivalent to establish whether there is a vaccine-associated risk with use of Fluzone High-Dose Quadrivalent in pregnancy.

8.2 Lactation

Fluzone High-Dose Quadrivalent is not approved for use in persons <65 years of age. No human or animal data are available to assess the effects of Fluzone High-Dose Quadrivalent on the breastfed infant or on milk production/excretion.

8.4 Pediatric Use

Safety and effectiveness of Fluzone High-Dose Quadrivalent in children younger than 18 years of age have not been established.

8.5 Geriatric Use

Safety, immunogenicity, and efficacy of Fluzone High-Dose Quadrivalent have been evaluated in adults 65 years of age and older [see Adverse Reactions (6.1) and Clinical Studies (14)].

11 DESCRIPTION

Fluzone High-Dose Quadrivalent for intramuscular injection is an inactivated influenza vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, octylphenol ethoxylate (Triton® X-100), producing a “split virus.” The split virus is further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone High-Dose Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration.

Fluzone High-Dose Quadrivalent suspension for injection is clear and slightly opalescent in color.

Neither antibiotics nor preservative are used in the manufacture of Fluzone High-Dose Quadrivalent.

The Fluzone High-Dose Quadrivalent prefilled syringe presentation is not made with natural rubber latex.

Fluzone High-Dose Quadrivalent is standardized according to United States Public Health Service requirements and is formulated to contain HA of each of the following four influenza strains recommended for the 2021-2022 influenza season: A/Victoria/2570/2019 IVR-215 (H1N1), A/Tasmania/503/2020 IVR-221 (an A/Cambodia/e0826360/2020-like virus) (H3N2), B/Phuket/3073/2013 (B Yamagata lineage), and B/Washington/02/2019 (B Victoria lineage). The amounts of HA and other ingredients per dose of vaccine are listed in Table 2.

Table 2: Fluzone High-Dose Quadrivalent Ingredients
Ingredient Quantity(per dose)
Fluzone High-Dose Quadrivalent 0.7 mL Dose
*
per United States Public Health Service (USPHS) requirement
Quantity sufficient
Active Substance: Split influenza virus, inactivated strains *: 240 mcg HA total
A (H1N1) 60 mcg HA
A (H3N2) 60 mcg HA
B (Victoria Lineage) 60 mcg HA
B (Yamagata Lineage) 60 mcg HA
Other:
Sodium phosphate-buffered isotonic sodium chloride solution QS to appropriate volume
Formaldehyde ≤140 mcg
Octylphenol ethoxylate ≤350 mcg
Gelatin None
Preservative None

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Influenza illness and its complications may follow influenza infection. Global surveillance of influenza viruses identifies 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 titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of participants. (See references 3 and 4.)

Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies 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, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating in the U.S. during the influenza season.

Fluzone High-Dose Quadrivalent stimulates the immune system to produce antibodies that help prevent influenza disease.

13 NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluzone High-Dose Quadrivalent has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.

14 CLINICAL STUDIES

14.1 Immunogenicity of Fluzone High-Dose Quadrivalent in Adults 65 Years of Age and Older

Study 1 (NCT03282240, see http://clinicaltrials.gov) was a randomized, active-controlled, modified double-blind trial in adults 65 years of age and older conducted in the US. The study compared the safety and immunogenicity of Fluzone High-Dose Quadrivalent to those of Fluzone High-Dose. The objective was to demonstrate immunologic non-inferiority of Fluzone High-Dose Quadrivalent to Fluzone High-Dose, as assessed by HAI geometric mean antibody titers (GMTs) at Day 28 and seroconversion rates, to strains common to formulations of both vaccines, based on pre-specified criteria.

A total of 2670 adults from 65 years of age were randomized (4:1:1) to receive one dose of either Fluzone High-Dose Quadrivalent or one of two formulations of Fluzone High-Dose (one formulation contained a B strain of the Victoria lineage [TIV-HD1] while the other contained a B strain of the Yamagata lineage [TIV-HD2]).

Females accounted for 58.2% of participants in the Fluzone High-Dose Quadrivalent group and 57.4% of participants in the Fluzone High-Dose group (TIV-HD1 and TIV-HD2, pooled). The mean age was 72.9 years (range: 65 through 100 years) in the Fluzone High-Dose Quadrivalent group and the mean age was 73.0 (range: 65 through 95 years) in the Fluzone High-Dose group. The percentage of subjects 75 years of age or older was 35.4% in the Fluzone High-Dose Quadrivalent group and 35.8% in the Fluzone High-Dose group. Most participants were White (91.2% and 89.7%), followed by Black (6.8% and 8.0%), and Hispanic (2.8% and 2.6%) in the Fluzone High-Dose Quadrivalent and Fluzone High-Dose groups, respectively.

The immunogenicity results of Study 1 are summarized in Table 3 and Table 4 below.

Table 3: Study 1*: Post-vaccination HAI Antibody GMTs and Analyses of Non-inferiority of Fluzone High-Dose Quadrivalent Relative to Fluzone High-Dose, Adults 65 Years of Age and Older, Per-Protocol Analysis Set
Influenza Strain GMT GMT Ratio Met Predefined Non-inferiority Criteria
QIV-HD TIV-HD1(B1 Victoria) TIV-HD2§(B2 Yamagata) QIV-HD over TIV-HD(95% CI)
N =1679-1680 N =423 N =430
*
NCT03282240
Predefined noninferiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (QIV-HD divided by TIV-HD) is >0.667
TIV-HD1 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008 (B1, Victoria lineage)
§
TIV-HD2 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Phuket/3073/2013 (B2, Yamagata lineage)
N is the number of vaccinated participants with available data for the immunologic endpoint listed
#
Pooled TIV-HD group includes subjects vaccinated with either TIV-HD1 or TIV-HD2 for the A strain comparison
A (H1N1)# 312 374 0.83(0.744; 0.932) Yes
A (H3N2)# 563 594 0.95(0.842; 1.066) Yes
B1 (Victoria) 516 476 1.08(0.958; 1.224) Yes
B2 (Yamagata) 578 580 1.00(0.881; 1.129) Yes
Table 4: Study 1*: Seroconversion Rates and Analyses of Non-inferiority of Fluzone High-Dose Quadrivalent Relative to Fluzone High-Dose, Adults 65 Years of Age and Older, Per-Protocol Analysis Set
Influenza Strain Seroconversion Rates (Percentage) Difference of Seroconversion Rates Met Predefined Non-inferiority Criteria
QIV-HD TIV-HD1§(B1 Victoria) TIV-HD2(B2 Yamagata) QIV-HD minus TIV-HD(95% CI)
N #=1668-1669 N #=420-421 N #=428
*
NCT03282240
Seroconversion Rates: For subjects with a pre-vaccination titer <10 (1/dil), proportion of subjects with a post-vaccination titer ≥40 (1/dil) and for subjects with a pre-vaccination titer ≥10 (1/dil), proportion of subjects with a ≥four-fold increase from pre-vaccination to post-vaccination titer
Predefined noninferiority criterion for seroconversion: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (QIV-HD minus TIV-HD) is >-10%
§
TIV-HD1 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008 (B1, Victoria lineage)
TIV-HD2 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Phuket/3073/2013 (B2, Yamagata lineage)
#
N is the number of vaccinated participants with available data for the immunologic endpoint listed
Þ
Pooled TIV-HD group includes subjects vaccinated with either TIV-HD1 or TIV-HD2 for the A strain comparison
A (H1N1)Þ 50.4 53.7 -3.27(-7.37; 0.86) Yes
A (H3N2)Þ 49.8 50.5 -0.71(-4.83; 3.42) Yes
B1 (Victoria) 36.5 39.0 -2.41(-7.66; 2.70) Yes
B2 (Yamagata) 46.6 48.4 -1.75(-7.04; 3.53) Yes

Fluzone High-Dose Quadrivalent was as immunogenic as Fluzone High-Dose for GMTs and seroconversion rates for the common influenza strains. Fluzone High-Dose Quadrivalent induced a superior immune response, based on a pre-specified superiority criterion, with respect to the additional B strain than the immune response induced by Fluzone High-Dose formulation that did not contain the additional B strain.

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