FLUZONE TRIVALENT NORTHERN HEMISPHERE - Sanofi Vaccines US Inc.

The dose and schedule for Fluzone are presented in Table 1.

Fluzone is clear and slightly opalescent in color. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exist, the vaccine should not be administered.

Before administering a dose of vaccine, shake the prefilled syringe or multiple-dose vial. A maximum of ten doses can be withdrawn from the multiple-dose vial.

Administer each dose intramuscularly.

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of Fluzone.

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks following previous influenza vaccination, the decision to give Fluzone should be based on careful consideration of the potential benefits and risks.

The 1976 swine influenza vaccine was associated with an elevated risk of 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⁾

Syncope (fainting) has been reported following vaccination with Fluzone. Procedures should be in place to avoid injury from fainting.

In two postmarketing observational studies, an increased risk of seizures was observed in the first day following vaccination among children 6 months to <5 years of age [see Adverse Reactions (6.2)].

If Fluzone is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.

Vaccination with Fluzone may not protect all recipients.

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trial(s) of a vaccine cannot be directly compared to rates in the clinical trial(s) of another vaccine and may not reflect the rates observed in practice.

The following adverse events have been spontaneously reported during the post-approval use of Fluzone 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 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 Disorders: Dyspnea, oropharyngeal pain, rhinorrhea, cough, wheezing, throat tightness
• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
• General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in extremities, chest pain
• Gastrointestinal Disorders: Vomiting

It is not known if Fluzone is excreted in human milk. Data are not available to assess the effects of Fluzone 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 and any potential adverse effects on the breastfed child from Fluzone 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 in children below the age of 6 months have not been established. Safety and effectiveness of Fluzone in children 9 through 17 years of age is based on safety and effectiveness in children 6 months through 8 years of age and adults 18 years of age and older.

Safety and immunogenicity of Fluzone were evaluated in adults 65 years of age and older. [see Adverse Reactions (6.1) and Clinical Studies (14.3)] Antibody responses to Fluzone are lower in persons ≥65 years of age than in younger adults. [see Clinical Studies (14.5, 14.6)]

Specific levels of hemagglutination inhibition (HI) antibody titer postvaccination 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.^{(3), (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.

Fluzone has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility in males.

Study 6 (NCT not available) was a randomized, double-blind, placebo-controlled study conducted at a single US center during the 1999–2000 (Year 1) and 2000–2001 (Year 2) influenza seasons. The intent-to-treat analysis set included a total of 786 children 6 through 24 months of age. Participants received two 0.25ml doses of either Fluzone (N = 525) or a placebo (N = 261) 4 weeks apart. Among all randomized participants in both years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were Black, and 7.2% were of other racial groups. Cases of influenza were identified through active and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary endpoint and is presented in Table 10.

Study 7 (NCT00538512) was a randomized, double-blind, placebo-controlled study conducted in a single US center during the 2007–2008 influenza season. Participants received one dose of either Fluzone vaccine (N = 813), an active comparator (N = 814), or placebo (N = 325). The intent-to-treat analysis set included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% were of other racial/ethnic groups. Cases of influenza were identified through active and passive surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR). Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 11.

In Study 1, a multi-center study conducted in the US, 68 children 6 months through 35 months of age given two 0.25 mL doses of Fluzone and 120 children 3 years through 8 years of age given two 0.5 mL doses of Fluzone were included in the per-protocol analysis set. The two doses (2006–2007 formulation) were administered 26 to 30 days apart. Females accounted for 42.6% of the participants in the 6 months through 35 months age group and 53.3% of the participants in the 3 years through 8 years age group. Most participants in the 6 months through 35 months and 3 years through 8 years age groups, respectively, were Caucasian (70.6% and 79.2%), followed by Hispanic (19.1% and 13.3%), and Black (7.4% and 4.2%).

The percentage of participants who received influenza vaccination during the previous influenza season was 54.4% for the 6 months through 35 months age group and 27.5% for the 3 years through 8 years age group. Table 12 shows seroconversion rates and the percentage of participants with an HI titer ≥1:40 prevaccination and one month following the second dose of Fluzone.

In Study 3 (NCT02915302) [see Adverse Reactions (6.1)], 1027 children, 6 months through 35 months of age, were included in the per-protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis set [see Adverse Reactions (6.1)].

In this study, children 6 months through 35 months of age received one or two doses of either 0.25 mL or 0.5 mL of Fluzone Quadrivalent. Non-inferiority of the 0.5 mL dose(s) relative to the 0.25 mL dose(s) of Fluzone Quadrivalent was demonstrated for all four strains based on pre- specified criteria (lower limit of the 2-sided 95% CI of the ratio of GMTs between groups >0.667; lower limit of the 2-sided 95% CI of the difference in seroconversion rates >-10%). GMT ratios (GMT_{0.5-mL dose} divided by GMT_{0.25-mL dose)} for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 1.42 (95% CI: 1.16; 1.74), 1.48 (95% CI: 1.21; 1.82), 1.33 (95% CI: 1.09; 1.62), and 1.41 (95% CI: 1.17; 1.70), respectively. Seroconversion rate (SCR) differences (SCR_{0.5-mL dose} minus SCR_{0.25-mL dose}) for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 4.6% (95% CI: -0.4%; 9.6%), 5.1% (95% CI: 0.4%; 9.8%), 1.3% (95% CI: -2.9%; 5.6%), and 2.6% (95% CI: -1.4%; 6.5%). Data for Fluzone Quadrivalent are relevant to Fluzone because both vaccines are manufactured using the same process and have overlapping compositions.

Adults 18 through 64 years of age received Fluzone (2008–2009 formulation) in Study 4, a multi-center trial conducted in the US. For immunogenicity analyses, there were 1287 participants who received Fluzone in the per-protocol analysis set. There were fewer males (35.8%) than females. The mean age was 42.6 years (ranged from 18.2 through 65.0 years). Most participants were Caucasian (80.0%), followed by Hispanic (11.0%), and Black (6.3%). Table 13 shows seroconversion rates at 28 days following vaccination and the percentage of participants with an HI titer ≥1:40 prior to vaccination and 28 days following vaccination.

Adults 65 years of age and older received Fluzone (2006–2007 formulation) in Study 5, a multi-center trial conducted in the US. For immunogenicity analyses, there were 1275 participants who received Fluzone in the immunogenicity analysis set. Females accounted for 54.7% of participants. The mean age was 72.9 years (ranged from 65 through 94 years of age); 36% of participants were 75 years of age or older. Most participants were Caucasian (92.9%), followed by Hispanic (3.7%), and Black (2.7%). Table 14 shows seroconversion rates at 28 days following vaccination and the percentage of participants with an HI titer ≥1:40 prior to vaccination and 28 days following vaccination.

Multiple-dose vial, 5 mL (NDC 49281-645-78) (not made with natural rubber latex). Supplied as package of one (NDC 49281-645-15). A maximum of ten doses can be withdrawn from the multiple-dose vial.

Single-dose, prefilled syringe (clear plunger rod), without needle, 0.5 mL (NDC 49281-426-88) (not made with natural rubber latex). Supplied as package of 10 (NDC 49281-426-50).

Store all Fluzone presentations refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen.

Between uses, return the multiple-dose vial to the recommended storage conditions at 2° to 8°C (35° to 46°F).

Do not use after the expiration date shown on the label.