Vaccine Information: Flublok Quadrivalent (Page 2 of 4)

6.2 Postmarketing Experience

There is no post-marketing experience with Flublok Quadrivalent.

The following events have been spontaneously reported during post-approval use of Flublok (trivalent formulation). They are described because of the temporal relationship, the biologic plausibility of a causal relationship to Flublok (trivalent formulation), and their potential seriousness. 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.

Immune system disorders: anaphylaxis, anaphylactoid reactions, allergic reactions, and other forms of hypersensitivity.

7 DRUG INTERACTIONS

Data evaluating the concomitant administration of Flublok Quadrivalent with other vaccines are not available.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure

Pregnancy outcomes in women who have been exposed to Flublok Quadrivalent during pregnancy are being monitored. Sanofi Pasteur Inc. is maintaining a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with Flublok Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive Flublok Quadrivalent during pregnancy in Sanofi Pasteur Inc.’s vaccination pregnancy registry by calling 1-800-822-2463.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Available data on Flublok Quadrivalent and Flublok (trivalent formulation) administered to pregnant women are insufficient to inform vaccine-associated risks in pregnant women.

There were no developmental studies of Flublok Quadrivalent formulation performed in animals. The developmental effects of Flublok (trivalent formulation) are relevant to Flublok Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions. A developmental study of Flublok (trivalent formulation) has been performed in rats administered 0.5 mL divided of Flublok (trivalent formulation) prior to mating and during gestation. This study revealed no evidence of harm to the fetus due to Flublok (trivalent formulation) (see Data [8.1]).

Clinical Considerations

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 with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.

Data

Animal

In a developmental toxicity study, female rats were administered 0.5 mL divided of Flublok (trivalent formulation) by intramuscular injection twice prior to mating (35 days and 14 days prior to mating) and on gestation Day 6. No vaccine-related fetal malformations or variations and no adverse effects on pre-weaning development were observed in the study.

8.2 Lactation

Risk Summary

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

8.4 Pediatric Use

Data from a randomized, controlled trial demonstrated that children 6 months to less than 3 years of age had diminished hemagglutinin inhibition (HI) responses to Flublok (trivalent formulation) as compared to a U.S.-licensed influenza vaccine approved for use in this population, strongly suggesting that Flublok (trivalent formulation) would not be effective in children younger than 3 years of age. Safety and effectiveness of Flublok Quadrivalent have not been established in children 3 years to less than 18 years of age.

8.5 Geriatric Use

Data from an efficacy study (Study 2), which included 1759 subjects ≥ 65 years and 525 subjects ≥ 75 years who received Flublok Quadrivalent, are insufficient to determine whether elderly subjects respond differently from younger subjects (see Clinical Trials Experience [6.1] and Clinical Studies [14]).

11 DESCRIPTION

Flublok Quadrivalent [Quadrivalent Influenza Vaccine] is a sterile, clear, colorless solution of recombinant hemagglutinin (HA) proteins from four influenza viruses for intramuscular injection. It contains purified HA proteins produced in a continuous insect cell line (expres SF+®) that is derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda (which is related to moths, caterpillars and butterflies), and grown in serum-free medium composed of chemically-defined lipids, vitamins, amino acids, and mineral salts. Each of the four HAs is expressed in this cell line using a baculovirus vector (Autographa californica nuclear polyhedrosis virus), extracted from the cells with Triton X-100 and further purified by column chromatography. The purified HAs are then blended and filled into single-dose syringes.

Flublok Quadrivalent is standardized according to United States Public Health Service (USPHS) requirements. For the 2019-2020 influenza season it is formulated to contain 180 mcg HA per 0.5 mL dose, with 45 mcg HA of each of the following 4 influenza virus strains: A/Brisbane/02/2018 (H1N1), A/Kansas/14/2017 (H3N2), B/Maryland/15/2016 (a B/Colorado/6/2017-like virus) and B/Phuket/3073/2013.

A single 0.5 mL dose of Flublok Quadrivalent contains sodium chloride (4.4 mg), monobasic sodium phosphate (0.195 mg), dibasic sodium phosphate (1.3 mg), and polysorbate 20 (Tween® 20) (27.5 mcg). Each 0.5 mL dose of Flublok Quadrivalent may also contain residual amounts of baculovirus and Spodoptera frugiperda cell proteins (≤ 19 mcg), baculovirus and cellular DNA (≤ 10 ng), and Triton X-100 (≤ 100 mcg).

Flublok Quadrivalent contains no egg proteins, antibiotics, or preservatives. The single-dose, pre-filled syringes contain no natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Flublok Quadrivalent contains recombinant HA proteins of the four strains of influenza virus specified by health authorities for inclusion in the annual seasonal vaccine. These proteins function as antigens which induce a humoral immune response, measured by hemagglutination inhibition (HI) antibody.

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 (usually annual) development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual replacement of one or more influenza virus strains in each year’s influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (i.e., typically two type A and, in quadrivalent formulations, two type B), representing the influenza viruses likely to be circulating in the U.S. in the upcoming winter.

13 NONCLINICAL TOXICOLOGY

Flublok Quadrivalent has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. A developmental toxicity study conducted in rats vaccinated with Flublok (trivalent formulation) revealed no evidence of impaired female fertility (see Pregnancy [8.1]).

14 CLINICAL STUDIES

14.1 Efficacy Against Laboratory-Confirmed Influenza

The efficacy of Flublok (trivalent formulation) is relevant to Flublok Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions (see Description [11]).

The efficacy of Flublok (trivalent formulation) in protecting against influenza illness was evaluated in a randomized, observer-blind, placebo-controlled multicenter trial conducted in the U.S. during the 2007-2008 influenza season in adults 18-49 years of age (Study 3) .

Study 3 enrolled and vaccinated 4648 healthy adults (mean age 32.5 years) randomized in a 1:1 ratio to receive a single dose of Flublok (n=2344) or saline placebo (n=2304). Among enrolled subjects, 59% were female, 67% were white, 19% African-American, 2% Asian, < 1% other races, and 11% of Latino/Hispanic ethnicity. Culture-confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 7 months post- vaccination. ILI was defined as having at least 2 of 3 symptoms (no specified duration) in the following categories: 1) fever ≥ 100ºF; 2) respiratory symptoms (cough, sore throat, or runny nose/stuffy nose); or 3) systemic symptoms (myalgias, arthralgias, headache, chills/sweats, or tiredness/malaise). For subjects with an episode of ILI, nasal and throat swab samples were collected for viral culture.

The primary efficacy endpoint of Study 3 was Centers for Disease Control-defined influenza-like illness (CDC-ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok. CDC-ILI is defined as fever of ≥100°F oral accompanied by cough, sore throat, or both on the same day or on consecutive days. Attack rates and vaccine efficacy (VE), defined as the reduction in the influenza rate for Flublok relative to placebo, were calculated for the total vaccinated cohort (n=4648).

The pre-defined success criterion for the primary efficacy analysis was that the lower bound of the 95% confidence interval (CI) of VE should be at least 40%. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained from subjects in Study 3 were not antigenically matched to the strains represented in the vaccine. An exploratory analysis of VE of Flublok against all strains, regardless of antigenic match, isolated from any subject with an ILI, not necessarily meeting CDC- ILI criteria, demonstrated an efficacy estimate of 44.8% (95% CI 24.4, 60.0). See Table 3 for a presentation of VE by case definition and antigenic similarity.

Table 3: Vaccine Efficacy Against Culture-Confirmed Influenza in Healthy Adults 18-49 Years of Age, Study 3*
Case definition Flublok (trivalent)(N=2344) Saline Placebo(N=2304) Flublok Vaccine Efficacy , % 95% Confidence Interval
Cases, n Rate, % Cases, n Rate, %
*
In Study 3 (NCT00539981) vaccine efficacy analyses were conducted on the Total Vaccinated Cohort (all randomized subjects who received study vaccine according to the treatment actually received and who provided data). Vaccine efficacy (VE) = 1 minus the ratio of Flublok/placebo infection rates.
Determined under the assumption of Poisson event rates, according to Breslow and Day, 1987.
Meets CDC influenza-like illness (CDC-ILI) defined as fever of ≥100°F oral accompanied by cough and/or sore throat, on the same day or on consecutive days.
§
Primary endpoint of trial.
All culture-confirmed cases are considered, regardless of whether they qualified as CDC-ILI.
#
Secondary endpoint of trial.
Þ
Exploratory (prespecified) endpoint of trial.
Positive culture with a strain represented in the vaccine
CDC-ILI, all matched strains , § 1 0.04 4 0.2 75.4 (-148.0, 99.5)
Any ILI, all matched strains , # 2 0.1 6 0.3 67.2 (-83.2, 96.8)
Positive culture with any strain, regardless of match to the vaccine
CDC-ILI, all strains , Þ 44 1.9 78 3.4 44.6 (18.8, 62.6)
Sub-Type A 26 1.1 56 2.4 54.4 (26.1, 72.5)
Type B 18 0.8 23 1.0 23.1 (-49.0, 60.9)
Any ILI, all strains 64 2.7 114 4.9 44.8 (24.4, 60.0)
Sub-Type A 41 1.7 79 3.4 49.0 (24.7, 65.9)
Type B 23 1.0 36 1.6 37.2 (-8.9, 64.5)

Study 2 evaluated the efficacy of Flublok Quadrivalent in a randomized, observer-blind, active-controlled, multi-center trial conducted during the 2014-2015 influenza season in adults 50 years of age and older. A total of 8963 healthy, medically stable adults (mean age 62.5 years) were randomized in a 1:1 ratio to receive a single dose of Flublok Quadrivalent (n=4474) or a U.S.-licensed quadrivalent inactivated influenza vaccine (Comparator, Fluarix Quadrivalent, manufactured by Glaxo SmithKline) (n=4489). Among randomized subjects, 58% were female, 80% white, 18% black/African-American, 2% other races, and 5% of Hispanic/Latino ethnicity. A total of 5186 (60%) subjects were 50-64 years of age and 3486 (40%) were ≥65 years of age. Real-time polymerase chain reaction (rtPCR) -confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 6 months post- vaccination. ILI was defined as having at least one symptom (no specified duration) in each of two categories of respiratory and systemic symptoms. Respiratory symptoms included sore throat, cough, sputum production, wheezing and difficulty breathing. Systemic symptoms included fever > 99°F (>37°C) oral, chills, fatigue, headache and myalgia. For subjects with an episode of ILI, a nasopharyngeal swab sample was collected for rtPCR testing and reflex viral culture of rtPCR-positive samples.

The primary efficacy endpoint of Study 2 was rtPCR-positive, protocol-defined ILI due to any strain of influenza. Attack rates and relative vaccine efficacy (rVE), defined as 1 – [Attack rate Flublok Quadrivalent/ Attack Rate Comparator], were calculated for the total efficacy population (n=8604) for the primary efficacy endpoint and for several alternative efficacy endpoints (Table 4). Antigenic and phylogenetic evaluations of the similarity (“matching”) of clinical isolates to vaccine antigens were not performed. CDC epidemiological data for the 2014-2015 influenza season indicated that Influenza A (H3N2) viruses predominated and that most influenza A/H3N2 viruses were antigenically dissimilar while A/H1N1 and B viruses were antigenically similar to vaccine antigens.

Table 4: Relative Vaccine Efficacy (rVE) of Flublok Quadrivalent versus Comparator against Laboratory-Confirmed Influenza, Regardless of Antigenic Similarity to Vaccine Antigens, Adults 50 Years of Age and Older, Study 2 (Efficacy Population)*,
Flublok Quadrivalent(N=4303) Comparator(N=4301) rVE %(95% CI)
n Attack Rate% (n/N) n Attack Rate% (n/N) RR
Abbreviations: rtPCR=reverse transcriptase polymerase chain reaction; Comparator=U.S.-licensed quadrivalent inactivated influenza vaccine, Fluarix Quadrivalent, manufactured by GlaxoSmithKline; n=number of influenza cases; N=number of subjects in treatment group; RR=relative risk (Attack Rate Flublok/Attack Rate IIV4); rVE = [(1-RR) × 100].
*
Study 2 is registered as NCT02285998.
Efficacy Population included all randomized subjects who received study vaccine and provided any follow-up documentation for influenza-like illness beginning at least 14 days postvaccination. Excluded subjects with protocol deviations that could adversely affect efficacy.
Primary Analysis. All cases of rtPCR-confirmed influenza are included. Antigenic characterization and genetic sequencing to determine similarity of isolates to vaccine antigens were not performed. CDC surveillance data indicated that the majority of influenza A/H3N2 wild type viruses were antigenically distinct whereas influenza A/H1N1 and type B viruses were antigenically similar to vaccine antigens during the 2014-2015 season. Study 2 met the pre-specified success criterion for the primary endpoint (lower limit of the 2-sided 95% CI of vaccine efficacy for Flublok Quadrivalent relative to Comparator should be not less than -20%).
§
Post hoc analyses. All cases of influenza A were A/H3N2. Cases of influenza B were not distinguished by lineage.
Culture of rtPCR-positive samples was performed in MDCK cells.
All rtPCR-positive Influenza 96 2.2 138 3.2 0.70 30 (10, 47)
All rtPCR-positive Influenza A § 73 1.7 114 2.7 0.64 36 (14, 53)
All rtPCR-positive Influenza B § 23 0.5 24 0.6 0.96 4 (-72, 46)
All Culture-confirmed Protocol-defined ILI §, 58 1.3 101 2.3 0.57 43 (21, 59)

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