2.1 Dosage and Schedule

The dose and schedule for FLULAVAL QUADRIVALENT are presented in Table 1.

2.2 Administration Instructions

Shake well before administration. 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 exists, the vaccine should not be administered.

Attach a sterile needle to the prefilled syringe and administer intramuscularly.

The preferred sites for intramuscular injection are the anterolateral thigh for children aged 6 through 11 months and the deltoid muscle of the upper arm for persons aged 12 months and older. Do not inject in the gluteal area or areas where there may be a major nerve trunk.

Do not administer this product intravenously, intradermally, or subcutaneously.

5.1 Guillain-Barré Syndrome

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLULAVAL QUADRIVALENT 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/1 million persons vaccinated.

5.2 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including FLULAVAL QUADRIVALENT. 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.

5.3 Preventing and Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of FLULAVAL QUADRIVALENT.

5.4 Altered Immunocompetence

If FLULAVAL QUADRIVALENT is administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the immune response may be lower than in immunocompetent persons.

5.5 Limitations of Vaccine Effectiveness

Vaccination with FLULAVAL QUADRIVALENT may not protect all susceptible individuals.

5.6 Persons at Risk of Bleeding

As with other intramuscular injections, FLULAVAL QUADRIVALENT should be given with caution in individuals with bleeding disorders such as hemophilia or on anticoagulant therapy to avoid the risk of hematoma following the injection.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. There is the possibility that broad use of FLULAVAL QUADRIVALENT could reveal adverse reactions not observed in clinical trials.

In adults who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (60%); the most common (≥10%) solicited systemic adverse reactions were muscle aches (26%), headache (22%), fatigue (22%), and arthralgia (15%).

In children aged 6 through 35 months who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (40%); the most common (≥10%) solicited systemic adverse reactions were irritability (49%), drowsiness (37%), and loss of appetite (29%).

In children aged 3 through 17 years who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (65%). In children aged 3 through 4 years, the most common (≥10%) solicited systemic adverse reactions were irritability (26%), drowsiness (21%), and loss of appetite (17%). In children aged 5 through 17 years, the most common (≥10%) systemic adverse reactions were muscle aches (29%), fatigue (22%), headache (22%), arthralgia (13%), and gastrointestinal symptoms (10%).

FLULAVAL QUADRIVALENT has been administered in 8 clinical trials to 1,384 adults aged 18 years and older, 1,965 children aged 6 through 35 months, and 3,516 children aged 3 through 17 years.

FLULAVAL QUADRIVALENT in Adults

Trial 1 (NCT01196975) was a randomized, double-blind, active-controlled, safety and immunogenicity trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,272), or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 213 or TIV-2, n = 218), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 18 years and older (mean age: 50 years) and 61% were female; 61% of subjects were white, 3% were black, 1% were Asian, and 35% were of other racial/ethnic groups. Solicited adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of solicited adverse reactions occurring within 7 days of vaccination in adults are shown in Table 2.

Unsolicited adverse events occurring within 21 days of vaccination were reported in 19%, 23%, and 23% of subjects who received FLULAVAL QUADRIVALENT (n = 1,272), TIV-1 (B Victoria) (n = 213), or TIV-2 (B Yamagata) (n = 218), respectively. The unsolicited adverse reactions that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included nasopharyngitis, upper respiratory tract infection, headache, cough, and oropharyngeal pain. Serious adverse events occurring within 21 days of vaccination were reported in 0.4%, 0%, and 0% of subjects who received FLULAVAL QUADRIVALENT, TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively.

FLULAVAL QUADRIVALENT in Children

Trial 4 (NCT02242643) was a randomized, observer-blind, active-controlled immunogenicity and safety trial. The trial included subjects aged 6 through 35 months who received FLULAVAL QUADRIVALENT (n = 1,207) or FLUZONE QUADRIVALENT, a U.S.-licensed inactivated influenza vaccine (n = 1,217) used as comparator, manufactured by Sanofi Pasteur Inc. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or the comparator vaccine approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or the comparator vaccine. In the overall population, 53% were male; 64% were white, 16% were black, 3% were Asian, and 17% were of other racial/ethnic groups. The mean age of subjects was 20 months. Subjects were followed for safety for 6 months; solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days) post vaccination. The incidence of solicited adverse reactions occurring within 7 days of vaccination in children are shown in Table 3.

In children who received a second dose of FLULAVAL QUADRIVALENT or the comparator vaccine, the incidences of solicited adverse reactions following the second dose were generally similar or lower than those observed after the first dose.

Unsolicited adverse events occurring within 28 days of vaccination were reported in 46% and 44% of subjects who received FLULAVAL QUADRIVALENT (n = 1,207) and the comparator vaccine (n = 1,217), respectively. The unsolicited adverse reactions that occurred most frequently (≥1%) for FLULAVAL QUADRIVALENT included upper respiratory tract infection, cough, diarrhea, pyrexia, vomiting, and rash. Serious adverse events occurring during the study period (approximately 6 months) were reported in 2% of subjects who received FLULAVAL QUADRIVALENT and in 2% of subjects who received the comparator vaccine. There were no deaths reported during the study period.

Trial 2 (NCT01198756) was a randomized, double-blind, active-controlled trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 932) or one of 2 formulations of a comparator trivalent influenza vaccine [FLUARIX (Influenza Vaccine), TIV-1 (B Victoria), n = 929 or TIV-2 (B Yamagata), n = 932], each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 3 through 17 years (mean age: 9 years) and 53% were male; 65% were white, 13% were Asian, 9% were black, and 13% were of other racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccination received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of influenza vaccination and children aged 9 years and older received one dose. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of solicited adverse reactions occurring within 7 days of vaccination in children are shown in Table 4.

In children who received a second dose of FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), the incidences of adverse reactions following the second dose were generally lower than those observed after the first dose.

Unsolicited adverse events occurring within 28 days of vaccination were reported in 30%, 31%, and 30% of subjects who received FLULAVAL QUADRIVALENT (n = 932), FLUARIX TIV-1 (B Victoria) (n = 929), or TIV-2 (B Yamagata) (n = 932), respectively. The unsolicited adverse reactions that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included vomiting, pyrexia, bronchitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.1%, 0.2%, and 0.2% of subjects who received FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively.

Trial 3 (NCT01218308) was a randomized, observer-blind, non-influenza vaccine-controlled trial evaluating the efficacy of FLULAVAL QUADRIVALENT. The trial included subjects aged 3 through 8 years who received FLULAVAL QUADRIVALENT (n = 2,584) or HAVRIX (Hepatitis A Vaccine) (n = 2,584) as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart (this dosing regimen for HAVRIX is not a U.S.-licensed schedule). Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of solicited adverse reactions occurring within 7 days of vaccination in children are shown in Table 5.

In children who received a second dose of FLULAVAL QUADRIVALENT or HAVRIX, the incidences of adverse reactions following the second dose were generally lower than those observed after the first dose.

The frequency of unsolicited adverse events occurring within 28 days of vaccination was similar in both groups (33% for both FLULAVAL QUADRIVALENT and HAVRIX). The unsolicited adverse reactions that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included diarrhea, pyrexia, gastroenteritis, nasopharyngitis, upper respiratory tract infection, varicella, cough, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.7% of subjects who received FLULAVAL QUADRIVALENT and in 0.2% of subjects who received HAVRIX.

6.2 Postmarketing Experience

Beyond those events reported in the clinical trials for FLULAVAL QUADRIVALENT or FLULAVAL, the following adverse reactions have been identified during postapproval use of FLULAVAL QUADRIVALENT or FLULAVAL (trivalent influenza vaccine). Because these reactions 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.

Blood and Lymphatic System Disorders

Lymphadenopathy.

Eye Disorders

Eye pain, photophobia.

Gastrointestinal Disorders

Dysphagia, vomiting.

General Disorders and Administration Site Conditions

Chest pain, injection site inflammation, asthenia, injection site rash, influenza-like symptoms, abnormal gait, injection site bruising, injection site sterile abscess.

Immune System Disorders

Allergic reactions including anaphylaxis, angioedema.

Infections and Infestations

Rhinitis, laryngitis, cellulitis.

Musculoskeletal and Connective Tissue Disorders

Muscle weakness, arthritis.

Nervous System Disorders

Dizziness, paresthesia, hypoesthesia, hypokinesia, tremor, somnolence, syncope, Guillain-Barré syndrome, convulsions/seizures, facial or cranial nerve paralysis, encephalopathy, limb paralysis.

Psychiatric Disorders

Insomnia.

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnea, dysphonia, bronchospasm, throat tightness.

Skin and Subcutaneous Tissue Disorders

Urticaria, localized or generalized rash, pruritus, sweating.

Vascular Disorders

Flushing, pallor.

7.1 Concomitant Administration with Other Vaccines

FLULAVAL QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial.

There are insufficient data to assess the concomitant administration of FLULAVAL QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites.

7.2 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 FLULAVAL QUADRIVALENT.

8.1 Pregnancy

Risk Summary

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.

There are insufficient data on FLULAVAL QUADRIVALENT in pregnant women to inform vaccine-associated risks.

A developmental toxicity study was performed in female rats administered FLULAVAL QUADRIVALENT prior to mating and during gestation and lactation periods. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to FLULAVAL QUADRIVALENT (see Data).

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women infected with seasonal influenza are at increased risk of severe illness associated with influenza infection compared with non-pregnant women. Pregnant women with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.

Data

Animal Data: In a developmental toxicity study, female rats were administered FLULAVAL QUADRIVALENT by intramuscular injection 4 and 2 weeks prior to mating, on Gestation Days 3, 8, 11, and 15, and on Lactation Day 7. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to Postnatal Day 25 were observed. There were no vaccine-related fetal malformations or variations.

8.2 Lactation

Risk Summary

It is not known whether FLULAVAL QUADRIVALENT is excreted in human milk. Data are not available to assess the effects of FLULAVAL 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 FLULAVAL QUADRIVALENT and any potential adverse effects on the breastfed child from FLULAVAL QUADRIVALENT or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of FLULAVAL QUADRIVALENT in children younger than 6 months have not been established.

8.5 Geriatric Use

In a randomized, double-blind, active-controlled trial, immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who received FLULAVAL QUADRIVALENT (n = 397); approximately one-third of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 to 64 years) and the frequencies of solicited and unsolicited adverse reactions were generally lower than in younger subjects [see Adverse Reactions (6.1), Clinical Studies (14.2)].

12.1 Mechanism of Action

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.

Public health authorities recommend influenza vaccine strains annually. Inactivated influenza vaccines are standardized to contain the hemagglutinins of strains representing the influenza viruses likely to circulate in the United States during the influenza season.

Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies, antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. 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 virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year’s influenza vaccine.

Annual revaccination is recommended because immunity declines during the year after vaccination and because circulating strains of influenza virus change from year to year.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

FLULAVAL QUADRIVALENT has not been evaluated for carcinogenic, mutagenic potential, or male infertility in animals. Vaccination of female rats with FLULAVAL QUADRIVALENT had no effect on fertility [see Use in Specific Populations (8.1)].

14.1 Efficacy against Influenza

The efficacy of FLULAVAL QUADRIVALENT was evaluated in Trial 3, a randomized, observer-blind, non-influenza vaccine-controlled trial conducted in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy subjects aged 3 through 8 years were randomized (1:1) to receive FLULAVAL QUADRIVALENT (n = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) influenza strains, or HAVRIX (n = 2,584), as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX [see Adverse Reactions (6.1)]. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years.

Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse transcriptase polymerase chain reaction (RT-PCR)-positive influenza A and/or B disease presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥100°F in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine efficacy was calculated based on the ATP cohort for efficacy (Table 6).

In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or B disease presenting as ILI was evaluated in subjects aged 3 through 4 years and 5 through 8 years; vaccine efficacy was 35.3% (95% CI: ‑1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), respectively. As the trial lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.

As a secondary objective in the trial, subjects with RT-PCR-positive influenza A and/or B were prospectively classified based on the presence of adverse outcomes that have been associated with influenza infection (defined as fever >102.2°F/39.0°C, physician-verified shortness of breath, pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary congestion, croup, and/or acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including myositis, encephalitis, seizure and/or myocarditis).

The risk reduction of fever >102.2°F/39.0°C associated with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 7.

14.2 Immunological Evaluation

Adults

Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial conducted in subjects aged 18 years and older. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,246) or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 204 or TIV-2, n = 211), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see Adverse Reactions (6.1)].

Immune responses, specifically hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoint was GMTs adjusted for baseline, performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results were available after vaccination. FLULAVAL QUADRIVALENT was non‑inferior to both TIVs based on adjusted GMTs (Table 8). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 8).

Children

Trial 4 was a randomized, observer-blind, active-controlled trial in children aged 6 through 35 months which was conducted in the United States and Mexico. In this trial, subjects received 0.5 mL of FLULAVAL QUADRIVALENT containing 15 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,207); or 0.25 mL of control vaccine FLUZONE QUADRIVALENT (Influenza Vaccine) containing 7.5 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,217) [see Adverse Reactions (6.1)].

Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following completion of vaccination regimen. Previously vaccinated children received one dose and previously unvaccinated children (i.e., unprimed individuals) received 2 doses 4 weeks apart of FLULAVAL QUADRIVALENT or the comparator. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4‑fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to the comparator for all 4 vaccine strains based on adjusted GMTs and seroconversion rates (Table 9).

Trial 2 was a randomized, double-blind, active-controlled trial conducted in children aged 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 878), or one of 2 formulations of a comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 871 or TIV-2 n = 878), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see Adverse Reactions (6.1)].

Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following one or 2 doses of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as at least a 4‑fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs and seroconversion rates (Table 10). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 10).