Vaccine Information: Flulaval Quadrivalent 2019/2020 (Page 2 of 4)

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 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FLULAVAL QUADRIVALENT during pregnancy. Healthcare providers are encouraged to register women by calling 1-888-452-9622.

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)].

11 DESCRIPTION

FLULAVAL QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a quadrivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs. Each of the influenza viruses is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate.

FLULAVAL QUADRIVALENT is a sterile, opalescent, translucent to off-white suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension.

FLULAVAL QUADRIVALENT has been standardized according to U.S. Public Health Service (USPHS) requirements for the 2019-2020 influenza season and is formulated to contain 60 micrograms (mcg) hemagglutinin (HA) per 0.5‑mL dose in the recommended ratio of 15 mcg HA of each of the following 4 influenza virus strains (2 A strains and 2 B strains): A/Brisbane/02/2018 (H1N1) pdm09 (IVR-190), A/Kansas/14/2017 (H3N2) X-327, B/Maryland/15/2016 NYMC BX-69A (a B/Colorado/06/2017-like virus), and B/Phuket/3073/2013.

The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 0.5-mL dose from the multi-dose vial contains 50 mcg thimerosal (<25 mcg mercury); thimerosal, a mercury derivative, is added as a preservative.

Each 0.5‑mL dose of either presentation may also contain residual amounts of ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), α-tocopheryl hydrogen succinate (≤320 mcg), and polysorbate 80 (≤887 mcg) from the manufacturing process. Antibiotics are not used in the manufacture of this vaccine.

The tip caps and plungers of the prefilled syringes are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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).

Table 6. FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy against Influenza A and/or B in Children Aged 3 through 8 Yearsa (According-to-Protocol Cohort for Efficacy)
CI = Confidence Interval; RT-PCR = Reverse transcriptase polymerase chain reaction.a Trial 3: 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.

Nb

nc

Influenza Attack Rate % (n/N)

Vaccine Efficacy

% (CI)

All RT-PCR-Positive Influenza

FLULAVAL QUADRIVALENT

2,379

58

2.4

55.4d

(95% CI: 39.1, 67.3)

HAVRIXe

2,398

128

5.3

All Culture-Confirmed Influenzaf

FLULAVAL QUADRIVALENT

2,379

50

2.1

55.9

(97.5% CI: 35.4, 69.9)

HAVRIXe

2,398

112

4.7

Antigenically Matched Culture-Confirmed Influenza

FLULAVAL QUADRIVALENT

2,379

31

1.3

45.1g

(97.5% CI: 9.3, 66.8)

HAVRIXe

2,398

56

2.3

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.

Table 7. FLULAVAL QUADRIVALENT: Incidence of Adverse Outcomes Associated with RT-PCR-Positive Influenza in Children Aged 3 through 8 Yearsa (Total Vaccinated Cohort)b
a Trial 3: NCT01218308.b Total vaccinated cohort included all vaccinated subjects for whom data were available.c Hepatitis A Vaccine used as a control vaccine.d In subjects who presented with more than one adverse outcome, each outcome was counted in the respective category.e Number of subjects presenting with at least one event in each group.f One subject in each group had sequential influenza due to influenza type A and type B viruses.

FLULAVAL

QUADRIVALENT

n = 2,584

HAVRIXc

n = 2,584

Adverse Outcomed

Number of Events

Number of Subjectse

%

Number of Events

Number of Subjectse

%

Fever >102.2°F/39.0°C

16f

15

0.6

51f

50

1.9

Shortness of breath

0

0

0

5

5

0.2

Pneumonia

0

0

0

3

3

0.1

Wheezing

1

1

0

1

1

0

Bronchitis

1

1

0

1

1

0

Pulmonary congestion

0

0

0

1

1

0

Acute otitis media

0

0

0

1

1

0

Bronchiolitis

0

0

0

0

0

0

Croup

0

0

0

0

0

0

Encephalitis

0

0

0

0

0

0

Myocarditis

0

0

0

0

0

0

Myositis

0

0

0

0

0

0

Seizure

0

0

0

0

0

0

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