Flulaval Prescribing Information

2.1 Dosage and Schedule

The dose and schedule for FLULAVAL 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.

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 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) may occur in association with administration of injectable vaccines, including FLULAVAL. Procedures should be in place to avoid injury from fainting.

5.3 Preventing and Managing Allergic Vaccine Reactions

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

5.4 Altered Immunocompetence

If FLULAVAL 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 may not protect all susceptible individuals.

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 could reveal adverse reactions not observed in clinical trials.

FLULAVAL has been administered in 3 trials to 5,114 individuals aged 18 years and older, and 1 trial to 987 individuals aged 3 through 17 years. FLULAVAL QUADRIVALENT has been administered in 1 trial to 1,207 individuals aged 6 through 35 months.

FLULAVAL in Adults

Safety data were obtained from 3 randomized, controlled trials, one of which was a placebo-controlled efficacy trial. In these trials, 9,836 subjects were randomized to receive either FLULAVAL (5,114 subjects in the safety analysis), FLUZONE, a U.S.‑licensed trivalent, inactivated influenza vaccine, manufactured by Sanofi Pasteur Inc. (894 subjects in the safety analysis), or placebo (3,828 subjects in the safety analysis), intramuscularly. In these trials, solicited reactions were collected for 4 days (i.e., 30 minutes post-vaccination through the next 3 days). Unsolicited adverse events that occurred within 22 days of vaccination (Day 0 to 21) were recorded based on spontaneous reports or in response to queries about changes in health status.

Trial 1 (NCT01389479): Safety information was collected in a randomized, controlled US trial. This trial included 1,000 adults aged 18 through 64 years who were randomized to receive FLULAVAL (n = 721) or a U.S. ‑licensed trivalent, inactivated influenza vaccine (n = 279). Among recipients of FLULAVAL, 57% were female; 91% of subjects were white and 9% were of other racial/ethnic groups. The mean age of subjects was 38 years; 80% were aged 18 through 49 years and 20% were aged 50 through 64 years.

Trial 2 (NCT00232947): Safety information was collected in a randomized, double-blind, active-controlled U.S. trial. The trial included 1,225 adults aged ≥50 years randomized to receive FLULAVAL (n = 610) or a U.S.‑licensed trivalent, inactivated influenza vaccine (n = 615). In the total population, 57% were female; 95% of subjects were white and 5% were of other racial/ethnic groups. The mean age of subjects was 66 years; 46% were aged 50 through 64 years, 41% were aged 65 through 79 years, and 13% were aged ≥80 years.

Trial 3 (NCT00216242): Safety information was collected in a double-blind, placebo-controlled U.S. trial. The trial included 7,658 adults aged 18 through 49 years randomized to receive FLULAVAL (n = 3,807) or placebo (n = 3,851). In the total population, 61% were female; 84% of subjects were white, 10% black, 2% Asian, and 4% were of other racial/ethnic groups. The mean age of subjects was 33 years.

Solicited Adverse Reactions: Solicited adverse reactions collected in trials 1, 2, and 3 for 4 days (day of vaccination and the next 3 days) are presented in Table 2.

a Four days included day of vaccination and the subsequent 3 days.

b Trial 1: NCT01389479; Trial 2: NCT00232947; Trial 3: NCT00216242.

c U.S.‑ licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.).

d Grade 3 pain, headache, fatigue, muscle aches, malaise, sore throat, cough, chills, chest tightness: Defined as prevented work/school/normal activities.
Grade 3 redness, swelling: Defined as >50 mm. Grade 3 fever: Defined as >103.1°F (39.5°C).
Grade 3 reddened eyes: Defined as very reddened, interfered with vision or caused a doctor’s visit. Grade 3 facial swelling: Defined as very swollen, prevented work/school/normal activities or caused a doctor’s visit.

e For Trial 2 and Trial 3, includes muscle aches and arthralgia.

f Fever : Defined as ≥ 99.5 ° F (37.5 ° C) .

Unsolicited Adverse Events: The incidence of unsolicited adverse events in the 21 days post-vaccination was comparable for FLULAVAL and the active comparator in Trial 1 (16% and 15%, respectively) and in Trial 2 (18% and 21%, respectively). In Trial 3, the incidence of unsolicited adverse events was comparable for the groups (21% for FLULAVAL and 19% for placebo).

Unsolicited adverse events defined as reported with FLULAVAL in >1.0% of subjects are described as follows: Trial 1: Cough, headache, and pharyngolaryngeal pain; Trial 2: Diarrhea, headache, and nasopharyngitis; and Trial 3: Pharyngolaryngeal pain, headache, fatigue, cough, injection site pain, upper respiratory tract infection, musculoskeletal pain, nasopharyngitis, injection site erythema, and discomfort.

Serious Adverse Events (SAEs): In Trial 1, no SAEs were reported. In Trial 2, 3% of subjects receiving FLULAVAL and 3% of subjects receiving the active comparator reported SAEs. In Trial 3, 1% of subjects receiving FLULAVAL and 1% of subjects receiving placebo reported SAEs. In the 3 clinical trials, the rates of SAEs were comparable between groups and none of the SAEs were considered related to vaccination.

FLULAVAL in Children

Trial 4 (NCT00980005) (Immunogenicity Non-Inferiority): An observer-blind, active-controlled U.S. trial evaluated subjects aged 3 through 17 years who received FLULAVAL (n = 1,055) or FLUZONE (n = 1,061), a U.S.‑licensed trivalent, inactivated influenza vaccine, manufactured by Sanofi Pasteur Inc. In the overall population, 53% were male; 78% of subjects were white, 12% were black, 2% were Asian, and 8% were of other racial/ethnic groups. The mean age of subjects was 8 years. 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 adverse reactions were collected for 4 days (day of vaccination and the next 3 days) (Table 3).

a Four days included day of vaccination and the subsequent 3 days.

b Trial 4: NCT00980005.

c U.S.‑ licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.).

d Grade 3 pain: Defined as cried when limb was moved/spontaneously painful (children <5years), or pain that prevented normal activity (children ≥5 years).
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 irritability, drowsiness, muscle aches, headache, fatigue, arthralgia, shivering: Defined as prevented normal activity.
Grade 3 loss of appetite: Defined as not eating at all.
Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C).

e Fever: Defined as ≥100.4°F (38.0°C)

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

The incidence of unsolicited adverse events that occurred within 28 days (Day 0 to 27) of any vaccination reported in subjects who received FLULAVAL (n = 1,055) or FLUZONE (n = 1,061) was 40% and 37%, respectively. The unsolicited adverse events that occurred most frequently (≥0.1% of subjects for FLULAVAL) and considered possibly related to vaccination included diarrhea, influenza-like illness, injection site hematoma, injection site rash, injection site warmth, rash, upper abdominal pain, and vomiting. The rates of SAEs were comparable between groups (0.9% and 0.6% for FLULAVAL and the comparator, respectively); none of the SAEs were considered related to vaccination.

FLULAVAL QUADRIVALENT in Children

Safety data were obtained with FLULAVAL QUADRIVALENT in children aged 6 through 35 months. Data with FLULAVAL QUADRIVALENT are relevant to FLULAVAL because both vaccines are manufactured using the same process and have overlapping compositions.

Trial 5 (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 adverse reactions were collected for 7 days (day of vaccination and the next 6 days) postvaccination. The incidence of solicited adverse reactions occurring within 7 days of vaccination in children are shown in Table 4.

a Seven days included day of vaccination and the subsequent 6 days.

b Trial 5: NCT02242643 .

c U.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.).

d Grade 3 pain: Defined as cried when limb was moved/spontaneously painful.
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity.
Grade 3 drowsiness: Defined as prevented normal activity.
Grade 3 loss of appetite: Defined as not eating at all.
Grade 3 (or higher) fever: Defined as >102.2°F (39.0°C).

e Fever: Defined as ≥100.4°F (38.0°C).

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of FLULAVAL or FLUAVAL QUADRIVALENT. 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, abnormal gait, injection site bruising, injection site sterile abscess, influenza-like symptoms.

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, pruritus, sweating, localized or generalized rash.

Vascular Disorders

Flushing, pallor.

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 in pregnant women to inform vaccine-associated risks.

A developmental toxicity study was performed in female rats administered FLULAVAL prior to mating and during gestation. Animals were administered a total dose of 0.2 mL on each of five occasions (a single human dose is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to FLULAVAL [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 by intramuscular injection 4 weeks prior to mating, and on gestation Days 6, 8, 11, and 15. 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 post-natal Day 25 were observed. There were no vaccine-related fetal malformations or variations, or vaccine-related effects on female fertility.

8.2 Lactation

Risk Summary

It is not known whether FLULAVAL is excreted in human milk. Data are not available to assess the effects of FLULAVAL 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 and any potential adverse effects on the breastfed child from FLULAVAL 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 in children younger than 6 months have not been established.

8.5 Geriatric Use

In clinical trials, there were 330 subjects aged 65 years and older who received FLULAVAL; 142 of these subjects were aged 75 years and older. Hemagglutination inhibition antibody responses were lower in geriatric subjects than younger subjects after administration of FLULAVAL. [See Clinical Studies (14.2).] Solicited adverse events were similar in frequency to those reported in younger subjects [see Adverse Reactions (6.1)].

12.1 Mechanism of Action

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14.1 Efficacy against Influenza

Efficacy Trial in Children

The efficacy of FLULAVAL QUADRIVALENT was evaluated in Trial 6, 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 (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. 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. Data for FLULAVAL QUADRIVALENT are relevant to FLULAVAL because both vaccines are manufactured using the same process and have overlapping compositions.

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 5).

a Trial 6: NCT01218308.

b According-to-protocol cohort for efficacy included subjects who met all eligibility criteria, were successfully contacted at least once post-vaccination, and complied with the protocol-specified efficacy criteria.

c Number of influenza cases.

d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% for the lower limit of the 2-sided 95% CI.

e Hepatitis A Vaccine used as a control vaccine.

f Of 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)].

g Since only 67% of cases could be typed, the clinical significance of this result is unknown.

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 6.

Efficacy Trial in Adults

The efficacy of FLULAVAL was evaluated in a randomized, double-blind, placebo-controlled trial conducted in the United States during the 2005-2006 and 2006-2007 influenza seasons (Trial 3). Efficacy of FLULAVAL was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects aged 18 through 49 years were randomized (1:1); a total of 3,783 subjects received FLULAVAL and 3,828 subjects received placebo [see Adverse Reactions (6.1)]. Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks post-vaccination and for duration of approximately 7 months thereafter. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as illness sufficiently severe to limit daily activity and including cough, and at least one of the following: Fever >99.9°F, nasal congestion or runny nose, sore throat, muscle aches or arthralgia, headache, feverishness or chills. After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated using the per protocol cohort (Table 7). Of note, the 1.2% attack rate in the placebo group for culture-confirmed, antigenically matched strains was lower than expected, contributing to a wide confidence interval for the estimate of vaccine efficacy.

14.2 Immunological Evaluation

Adults

Trial 1 was a randomized, blinded, active-controlled U.S. trial performed in healthy adults aged 18 through 64 years (N = 1,000). A total of 721 subjects received FLULAVAL, and 279 received a U.S.‑licensed trivalent, inactivated influenza vaccine, FLUZONE (manufactured by Sanofi Pasteur Inc.), intramuscularly; 959 subjects had complete serological data and no major protocol deviations [see Adverse Reactions(6.1)].

Analyses of immunogenicity (Table 8) were performed for each hemagglutinin (HA) antigen contained in the vaccine: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the proportion of subjects with HI antibody titers of ≥1:40 after vaccination, and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion (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). The pre-specified success criteria for HI titer ≥1:40 was 70% and for seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved an HI titer of ≥1:40 exceeded the pre-defined criteria for the A strains. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion exceeded the pre-defined criteria for all 3 strains.

a Results obtained following vaccination with FLULAVAL manufactured for the 2004–2005 season.

b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.

c The pre-specified success criteria for HI titer ≥1:40 was 70%.

d Seroconversion defined as a 4‑ fold increase in post-vaccination HI antibody titers from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

e The pre-specified success criteria for seroconversion rate was 40%.

Trial 2 (Immunogenicity Non-Inferiority): In a randomized, double-blind, active-controlled U.S. trial, immunological non-inferiority of FLULAVAL was compared with a U.S.‑licensed trivalent, inactivated influenza vaccine, FLUZONE, manufactured by Sanofi Pasteur Inc. A total of 1,225 adults aged 50 years and older in stable health were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [see Adverse Reactions (6.1)].

Analyses of immunogenicity were performed for each HA antigen contained in the vaccines: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the geometric mean antibody titer (GMT) ratio (FLULAVAL/comparator), and 2) assessment of the lower bounds of 2‑sided 95% confidence intervals for seroconversion rates (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). Non-inferiority of FLULAVAL to the comparator vaccine was established for all 6 co–primary endpoints (Table 9). Within each age stratum, immunogenicity results were similar between the groups.

Children

In Trial 4, the immune response of FLULAVAL (n = 987) was compared to FLUZONE, a U.S.‑licensed trivalent, inactivated influenza vaccine (n = 979), manufactured by Sanofi Pasteur Inc., in an observer-blind, randomized trial in children aged 3 through 17 years. The immune responses to each of the antigens contained in FLULAVAL formulated for the 2009-2010 season were evaluated in sera obtained after one or 2 doses of FLULAVAL and were compared with those following the comparator influenza vaccine [see Adverse Reactions (6.1)].

The non‑inferiority 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 According‑to‑Protocol (ATP) cohort. FLULAVAL was non-inferior to the comparator influenza for all strains based on adjusted GMTs and seroconversion rates (Table 10).

Trial 5 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 four 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 four 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 11).

a Trial 5: NCT02242643.

b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.

c A 0.5-mL dose containing 15 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).

d A 0.25-mL dose of U.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.) containing 7.5 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).

e Non‑ inferior to the comparator vaccine based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (comparator/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2‑ sided 95% CI on difference of comparator vaccine minus FLULAVAL QUADRIVALENT ≤10%).

f Seroconversion defined as a 4‑ fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.