The following events have been spontaneously reported during the post-approval use of Fluzone (trivalent) or Fluzone 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 (trivalent) 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/flushing
- Respiratory, Thoracic and Mediastinal Disorder s: Dyspnea, cough, wheezing, throat tightness, oropharyngeal pain, rhinorrhea
- Skin and Subcutaneous Tissue Disorders: Rash, pruritus, and Stevens-Johnson syndrome
- General Disorders and Administration Site Conditions: Asthenia/fatigue, pain in extremities, chest pain
- Gastrointestinal Disorders: Vomiting
Pregnancy Exposure Registry
Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes following vaccination with Fluzone Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive Fluzone Quadrivalent during pregnancy in Sanofi Pasteur Inc.’s vaccination pregnancy registry by calling 1-800-822-2463.
All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Available data with Fluzone Quadrivalent use in pregnant women are insufficient to inform vaccine-associated risk of adverse developmental outcomes.
A developmental and reproductive toxicity study was performed in female rabbits given a 0.5 mL/dose of Fluzone Quadrivalent prior to mating and during gestation (a single human dose is 0.5 mL). This study revealed no adverse effects to the fetus or pre-weaning development due to Fluzone Quadrivalent [see Animal Data (8.1)].
Animal Data: In a developmental and reproductive toxicity study female rabbits were administered a 0.5 mL/dose of Fluzone Quadrivalent by intramuscular injection 24 and 10 days before insemination, and on Days 6, 12, and 27 of gestation (a single human dose is 0.5 mL). There were no adverse effects on pre-weaning development or vaccine-related fetal malformations noted in this study.
Disease-associated Maternal and/or Embryo/Fetal Risk
Pregnant women are at increased risk of complications associated with influenza infection compared to non-pregnant women. Pregnant women who contract influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.
It is not known whether Fluzone Quadrivalent is excreted in human milk. Data are not available to assess the effects of Fluzone Quadrivalent on the breastfed infant or on milk production/excretion.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fluzone Quadrivalent and any potential adverse effects on the breastfed child from Fluzone Quadrivalent or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to the disease prevented by the vaccine.
Safety and effectiveness of Fluzone Quadrivalent in children below the age of 6 months have not been established.
Safety and immunogenicity of Fluzone Quadrivalent were evaluated in adults 65 years of age and older. [See Clinical Studies (14.6).] Antibody responses to Fluzone Quadrivalent are lower in persons ≥65 years of age than in younger adults.
Fluzone Quadrivalent (Influenza Vaccine) 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 Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. Antigens from the four strains included in the vaccine are produced separately and then combined to make the quadrivalent formulation.
Fluzone Quadrivalent suspension for injection is clear and slightly opalescent in color.
Antibiotics are not used in the manufacture of Fluzone Quadrivalent.
The Fluzone Quadrivalent prefilled syringe and vial presentations are not made with natural rubber latex.
Fluzone 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 7. The single-dose, pre-filled syringe (0.25 mL and 0.5 mL) and the single-dose vial (0.5 mL) are manufactured and formulated without thimerosal or any other preservative. The 5 mL multi-dose vial presentation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury. Each 0.25 mL dose from the multi-dose vial contains 12.5 mcg mercury.
|Ingredient||Quantity (per dose)|
|Fluzone Quadrivalent0.25 mL Dose||Fluzone Quadrivalent0.5 mL Dose|
|“-” Indicates information is not applicable|
|Active Substance: Split influenza virus, inactivated strains *:||30 mcg HA total||60 mcg HA total|
|A (H1N1)||7.5 mcg HA||15 mcg HA|
|A (H3N2)||7.5 mcg HA||15 mcg HA|
|B/(Victoria lineage)||7.5 mcg HA||15 mcg HA|
|B/(Yamagata lineage)||7.5 mcg HA||15 mcg HA|
|Sodium phosphate-buffered isotonic sodium chloride solution||QS † to appropriate volume||QS † to appropriate volume|
|Formaldehyde||≤50 mcg||≤100 mcg|
|Octylphenol ethoxylate||≤125 mcg||≤250 mcg|
|Multi-dose presentation (thimerosal)||12.5 mcg mercury||25 mcg mercury|
Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have co-circulated worldwide. Protection from influenza virus infection has not been correlated with a specific level of hemagglutination inhibition (HI) antibody titer post-vaccination. However, in some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects. (See ref. 2) (See ref. 3)
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 US during the influenza season.
Annual vaccination with the influenza vaccine is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year.
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