NDC 70461-420 Flucelvax Quadrivalent (multi-dose Vial)

Influenza A Virus A/nebraska/14/2019 (h1n1) Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza A Virus A/delaware/39/2019 (h3n2) Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza B Virus B/singapore/inftt-16-0610/2016 Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza B Virus B/darwin/7/2019 Antigen (mdck Cell Derived, Propiolactone Inactivated)

NDC Product Code 70461-420

NDC CODE: 70461-420

Proprietary Name: Flucelvax Quadrivalent (multi-dose Vial) What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Influenza A Virus A/nebraska/14/2019 (h1n1) Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza A Virus A/delaware/39/2019 (h3n2) Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza B Virus B/singapore/inftt-16-0610/2016 Antigen (mdck Cell Derived, Propiolactone Inactivated), Influenza B Virus B/darwin/7/2019 Antigen (mdck Cell Derived, Propiolactone Inactivated) What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

  • 70461 - Seqirus Inc.

NDC 70461-420-10

Package Description: 1 VIAL, MULTI-DOSE in 1 CARTON > 5 mL in 1 VIAL, MULTI-DOSE (70461-420-11)

NDC Product Information

Flucelvax Quadrivalent (multi-dose Vial) with NDC 70461-420 is a a vaccine lable product labeled by Seqirus Inc.. The generic name of Flucelvax Quadrivalent (multi-dose Vial) is influenza a virus a/nebraska/14/2019 (h1n1) antigen (mdck cell derived, propiolactone inactivated), influenza a virus a/delaware/39/2019 (h3n2) antigen (mdck cell derived, propiolactone inactivated), influenza b virus b/singapore/inftt-16-0610/2016 antigen (mdck cell derived, propiolactone inactivated), influenza b virus b/darwin/7/2019 antigen (mdck cell derived, propiolactone inactivated). The product's dosage form is injection, suspension and is administered via intramuscular form.

Labeler Name: Seqirus Inc.

Dosage Form: Injection, Suspension - A liquid preparation, suitable for injection, which consists of solid particles dispersed throughout a liquid phase in which the particles are not soluble. It can also consist of an oil phase dispersed throughout an aqueous phase, or vice-versa.

Product Type: Vaccine What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Flucelvax Quadrivalent (multi-dose Vial) Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • INFLUENZA A VIRUS A/NEBRASKA/14/2019 (H1N1) ANTIGEN (MDCK CELL DERIVED, PROPIOLACTONE INACTIVATED) 15 ug/.5mL
  • INFLUENZA A VIRUS A/DELAWARE/39/2019 (H3N2) ANTIGEN (MDCK CELL DERIVED, PROPIOLACTONE INACTIVATED) 15 ug/.5mL
  • INFLUENZA B VIRUS B/SINGAPORE/INFTT-16-0610/2016 ANTIGEN (MDCK CELL DERIVED, PROPIOLACTONE INACTIVATED) 15 ug/.5mL
  • INFLUENZA B VIRUS B/DARWIN/7/2019 ANTIGEN (MDCK CELL DERIVED, PROPIOLACTONE INACTIVATED) 15 ug/.5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POTASSIUM CHLORIDE (UNII: 660YQ98I10)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • MAGNESIUM CHLORIDE (UNII: 02F3473H9O)
  • SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T)
  • POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)
  • WATER (UNII: 059QF0KO0R)
  • POTASSIUM CHLORIDE (UNII: 660YQ98I10)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • MAGNESIUM CHLORIDE (UNII: 02F3473H9O)
  • SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T)
  • POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)
  • THIMEROSAL (UNII: 2225PI3MOV)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intramuscular - Administration within a muscle.
  • Intramuscular - Administration within a muscle.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Seqirus Inc.
Labeler Code: 70461
FDA Application Number: BLA125408 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-02-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 07-31-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Flucelvax Quadrivalent (multi-dose Vial) Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

FLUCELVAX QUADRIVALENT is an inactivated vaccine indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLUCELVAX QUADRIVALENT is approved for use in persons 4 years of age and older. For children and adolescents 4 through 17 years of age, approval is based on the immune response elicited by FLUCELVAX QUADRIVALENT. Data demonstrating a decrease in influenza disease after vaccination of this age group with FLUCELVAX QUADRIVALENT are not available [see Clinical Studies (14)].

2 Dosage And Administration

For intramuscular injection only.

2.1 Dosage And Schedule

Administer FLUCELVAX QUADRIVALENT as a single 0.5 mL intramuscular injection preferably in the region of the deltoid muscle of the upper arm. Do not inject the vaccine in the gluteal region or areas where there may be a major nerve trunk.
Table 1: Dosage and Schedule
1 1 or 2 doses depends on vaccination history as per Advisory Committee on Immunization Practices annual recommendations on prevention and control of influenza with vaccines.
AgeDoseSchedule4 through 8 years of age
One or two doses1, 0.5 mL each
If 2 doses, administer at least 4 weeks apart
9 years of age and older
One dose, 0.5 mL
Not Applicable

2.2 Administration

Shake the syringe vigorously before administering and shake the multi-dose vial preparation each time before withdrawing a dose of vaccine. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit [see Description (11)]. If either condition exists, do not administer the vaccine. Between uses, return the multi-dose vial to the recommended storage conditions between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen.
Attach a sterile needle to the pre-filled syringe.
For the multi-dose vial, a separate sterile syringe and needle must be used for each injection to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and not recapped. It is recommended that small syringes (0.5 mL or 1 mL) should be used to minimize any product loss.
Administer intramuscularly only. Do not administer this product intravenously, intradermally or subcutaneously.

3 Dosage Forms And Strengths

  • FLUCELVAX QUADRIVALENT is a suspension for injection supplied in two presentations:
  • A 0.5 mL single-dose pre-filled Luer Lock syringe
  • A 5 mL multi-dose vial containing 10 doses (each dose is 0.5 mL)

4 Contraindications

Do not administer FLUCELVAX QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine [see Description (11)].

5.1 Guillain-Barré Syndrome

The 1976 swine influenza vaccine was associated with an elevated risk of Guillain-Barré syndrome (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 If GBS has occurred after receipt of a prior influenza vaccine, the decision to give FLUCELVAX QUADRIVALENT should be based on careful consideration of the potential benefits and risks.

5.2 Preventing And Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

5.3 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including Flucelvax. 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 by maintaining a supine or Trendelenburg position.

5.4 Altered Immunocompetence

After vaccination with FLUCELVAX QUADRIVALENT, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced immune response.

5.5 Limitations Of Vaccine Effectiveness

Vaccination with FLUCELVAX QUADRIVALENT may not protect all vaccine recipients against influenza disease.

6.1 Clinical Trials Experience

The most common (≥10%) local and systemic reactions in adults 18 through 64 years of age were injection site pain (45.4%), headache (18.7%), fatigue (17.8%) and myalgia (15.4%), injection site erythema (13.4%), and induration (11.6%).
The most common (≥10%) local and systemic reactions in adults ≥65 years of age were injection site pain (21.6%) and injection site erythema (11.9%).
The most common (≥10%) local and systemic reactions in children 4 through 5 years of age after first dose of vaccine were tenderness at the injection site (46%), injection site erythema (18%), sleepiness (19%), irritability (16%), injection site induration (13%) and change in eating habits (10%).
The most common (≥10%) local and systemic reactions in children 6 through 8 years of age after first dose of vaccine were pain at the injection site (54%), injection site erythema (22%), injection site induration (16%), headache (14%), fatigue (13%) and myalgia (12%).
The most common (≥10%) local and systemic reactions in children and adolescents 9 through 17 years of age were pain at the injection site (58%), headache (22%), injection site erythema (19%), fatigue (18%) and myalgia (16%), and injection site induration (15%).
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to rates in clinical studies of another vaccine and may not reflect rates observed in clinical practice.

Other

Adults 18 years of age and older:The safety of FLUCELVAX QUADRIVALENT in adults was evaluated in a randomized, double-blind, controlled study conducted in the US (Study 1). The safety population included a total of 2680 adults 18 years of age and older; 1340 adults 18 through 64 years of age and 1340 adults 65 years of age and older.
In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (TIV1c and TIV2c) (FLUCELVAX QUADRIVALENT (N=1335), TIV1c, N=676 or TIV2c, N= 669). The mean age of subjects who received FLUCELVAX QUADRIVALENT was 57.4 years of age; 54.8% of subjects were female and 75.6% were Caucasian, 13.4% were Black, 9.1% were Hispanic, 0.7% were American Indian and 0.3%, 0.1% and 0.7% were Asian, Native Hawaiian and others, respectively. The safety data observed are summarized in Table 2.
In this study, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination.
Solicited adverse reactions for FLUCELVAX QUADRIVALENT and comparator are summarized in Table 2.
Table 2: Incidence of Solicited Adverse Reactions in the Safety Population1 Reported Within 7 Days of Vaccination (Study 1)
18 through 64 years of age≥ 65 years of agePercentages (%)2FLUCELVAX QUADRIVALENT N=663Trivalent Influenza VaccineFLUCELVAX QUADRIVALENTN=656Trivalent Influenza VaccineTIV1c N=330TIV2c N=327TIV1c N=340TIV2c N=3361Safety population: all subjects in the exposed population who provided post-vaccination safety data.
2Percentage of severe adverse reactions are presented in parenthesis.
Study 1: NCT01992094
Local Adverse ReactionsInjection site induration
11.6 (0)
9.7 (0.3)
10.4 (0)
8.7 (0)
6.8 (0)
7.7 (0)
Injection site erythema
13.4 (0)
13.3 (0)
10.1 (0)
11.9 (0)
10.6 (0)
10.4 (0)
Injection site ecchymosis
3.8 (0)
3.3 (0.3)
5.2 (0)
4.7 (0)
4.4 (0)
5.4 (0)
Injection site pain
45.4 (0.5)
37.0 (0.3)
40.7 (0)
21.6 (0)
18.8 (0)
18.5 (0)
Systemic Adverse ReactionsChills
6.2 (0.2)
6.4 (0.6)
6.4 (0)
4.4 (0.3)
4.1 (0.3)
4.5 (0.6)
Nausea
9.7 (0.3)
7.3 (0.9)
8.9 (1.2)
3.8 (0.2)
4.1 (0)
4.2 (0.3)
Myalgia
15.4 (0.8)
14.5 (0.9)
15.0 (1.2)
8.2 (0.2)
9.4 (0.3)
8.3 (0.6)
Arthralgia
8.1 (0.5)
8.2 (0)
9.5 (0.9)
5.5 (0.5)
5.0 (0.3)
6.8 (0.9)
Headache
18.7 (0.9)
18.5 (0.9)
18.7 (0.6)
9.3 (0.3)
8.5 (0.6)
8.3 (0.6)
Fatigue
17.8 (0.6)
22.1 (0.3)
15.6 (1.5)
9.1 (0.8)
10.6 (0.3)
8.9 (0.6)
Vomiting
2.6 (0)
1.5 (0.3)
0.9 (0)
0.9 (0.2)
0.3 (0)
0.6 (0)
Diarrhea
7.4 (0.6)
7.6 (0)
7.6 (0.6)
4.3 (0.5)
5.0 (0.9)
5.1 (0.3)
Loss of appetite
8.3 (0.3)
8.5 (0.3)
8.3 (0.9)
4.0 (0.2)
5.0 (0)
3.6 (0.3)
Fever: ≥38.0 °C (≥40.0°C)
0.8 (0)
0.6 (0)
0.3 (0)
0.3 (0)
0.9 (0)
0.6 (0)
Unsolicited adverse events were collected for 21 days after vaccination. In adults 18 years of age and older, unsolicited adverse events were reported in 16.1% of subjects who received FLUCELVAX QUADRIVALENT, within 21 days after vaccination.
In adults 18 years of age and older, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after vaccination) and were reported by 3.9% of the subjects who received FLUCELVAX QUADRIVALENT. None of the SAEs were assessed as being related to study vaccine.

Children and Adolescents 4 through 17 years of age:The safety of FLUCELVAX QUADRIVALENT in children was evaluated in a randomized, double-blind, controlled study conducted in the US (Study 2). The safety population included a total of 2332 children 4 through 17 years of age; 1161 children 4 through 8 years of age and 1171 children 9 through 17 years of age.
In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (FLUCELVAX QUADRIVALENT N=1159, TIV1c, N=593 or TIV2c, N= 580). Children 9 through 17 years of age received a single dose of FLUCELVAX QUADRIVALENT or comparator vaccine. Children 4 through 8 years of age received one or two doses (separated by 4 weeks) of FLUCELVAX QUADRIVALENT or comparator vaccine based on determination of the subject's prior influenza vaccination history. The mean age of subjects who received FLUCELVAX QUADRIVALENT was 9.6 years of age; 48% of subjects were female and 53% were Caucasian. The safety data observed are summarized in Table 3 and Table 4.
In this study, solicited local injection site and systemic adverse reactions were collected from subjects who completed a symptom diary card for 7 days following vaccination.
Solicited adverse reactions for FLUCELVAX QUADRIVALENT and comparator are summarized in Table 3 and Table 4.
Table 3: Incidence of Solicited Adverse Reactions in the Safety Population1 (4 through 5 years of age) Reported Within 7 Days of the First dose of Vaccination (Study 2)
Children 4 through 5 yearsPercentages (%)2FLUCELVAX QUADRIVALENTN=182Trivalent Influenza VaccineTIV1cN=91TIV2cN=931Safety population: all subjects in the exposed population who provided post-vaccination safety data.
2Percentage of subjects with severe adverse reactions are presented in parenthesis.
Study 2: NCT01992107
Local Adverse ReactionsInjection site induration
13 (1)
20 (2)
13 (0)
Injection site erythema
18 (1)
23 (1)
17 (0)
Injection site ecchymosis
9 (0)
11 (0)
8 (0)
Injection site tenderness
46 (1)
45 (1)
43 (0)
Systemic Adverse ReactionsChange in eating habits
10 (1)
7
6
Sleepiness
19 (1)
12 (3)
10 (0)
Irritability
16 (2)
10 (2)
10 (1)
Chills
5 (1)
2 (0)
1 (0)
Vomiting
4 (0)
2 (0)
2 (0)
Diarrhea
4 (0)
2 (0)
2 (0)
Fever: ≥38.0 °C (≥40.0 °C)
4 (0)
4 (0)
3 (0)
Table 4: Incidence of Solicited Adverse Reactions in the Safety Population1 (Children 6 through 17 years of age) Reported Within 7 Days of Vaccination (Study 2)
Children 6 through 8 years (after first dose)Children 9 through 17 yearsPercentages (%)2FLUCELVAX QUADRIVALENT N=371-372Trivalent Influenza vaccineFLUCELVAX QUADRIVALENT N=579Trivalent Influenza VaccineTIV1c N=185TIV2c N=186TIV1c N=294TIV2c N=281-2821Safety population: all subjects in the exposed population who provided post-vaccination safety data.
2Percentage of subjects with severe adverse reactions are presented in parenthesis.
Study 2: NCT 01992107
Local Adverse ReactionsInjection site induration
16 (0)
19 (1)
13 (0)
15 (0)
15 (0)
13 (<1)
Injection site erythema
22 (0)
23 (1)
20 (0)
19 (<1)
17 (0)
15 (<1)
Injection site ecchymosis
9 (0)
9 (0)
8 (0)
4 (0)
5 (0)
5 (0)
Injection site pain
54 (1)
57 (1)
58 (2)
58 (1)
51 (<1)
50 (0)
Systemic Adverse ReactionsChills
4 (1)
3 (0)
4 (0)
7 (0)
6 (1)
4 (1)
Nausea
8 (1)
5 (0)
5 (1)
9 (<1)
8 (1)
7 (1)
Myalgia
12 (1)
14 (0)
10 (0)
16 (<1)
17 (<1)
15 (<1)
Arthralgia
4 (0)
5 (0)
4 (0)
6 (0)
6 (0)
8 (<1)
Headache
14 (1)
13 (0)
12 (0)
22 (1)
23 (2)
18 (1)
Fatigue
13 (2)
14 (0)
18 (0)
18 (<1)
16 (1)
16 (<1)
Vomiting
3 (1)
3 (0)
3 (0)
2 (0)
1 (0)
2 (0)
Diarrhea
3 (<1)
6 (1)
5 (0)
4 (0)
4 (0)
3 (<1)
Loss of appetite
9 (<1)
5 (0)
8 (1)
9 (0)
9 (<1)
9 (0)
Fever: ≥38.0 °C (≥40.0 °C)
4 (0)
3 (0)
2 (0)
1 (<1)
3 (0)
1 (0)
In children who received a second dose of FLUCELVAX QUADRIVALENT, TIV1c, or TIV2c, the incidence of adverse reactions following the second dose of vaccine were similar to those observed with the first dose.
Unsolicited adverse events were collected for 21 days after last vaccination. In children 4 through 17 years of age, unsolicited adverse events were reported in 24.3% of subjects who received FLUCELVAX QUADRIVALENT, within 3 weeks after last vaccination.
In children 4 through 17 years of age, serious adverse events (SAEs) were collected throughout the study duration (until 6 months after last vaccination) and were reported by 0.5% of the subjects who received FLUCELVAX QUADRIVALENT. None of the SAEs were assessed as being related to study vaccine.

Pregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FLUCELVAX QUADRIVALENT during pregnancy. Women who are vaccinated with FLUCELVAX QUADRIVALENT during pregnancy are encouraged to enroll in the registry by calling 1-855-358-8966 or sending an email to Seqirus at us.medicalinformation@seqirus.com.

Risk SummaryAll 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 for FLUCELVAX QUADRIVALENT in pregnant women to inform vaccine-associated risks in pregnancy.
There were no developmental toxicity studies of FLUCELVAX QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUCELVAX (trivalent formulation) prior to mating and during gestation. The dose was 0.5 mL on each occasion (a single human dose is 0.5 mL). This study revealed no evidence of harm to the fetus due to FLUCELVAX (trivalent formulation) [see Use in Specific Populations (8.1)].

Clinical Considerations

Disease-associated Maternal and/or Embryo-Fetal RiskPregnant women are at increased risk for severe illness due to influenza 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 DataIn a developmental toxicity study, female rabbits were administered of FLUCELVAX (trivalent formulation) by intramuscular injection 1, 3, and 5 weeks prior to mating, and on gestation days 7 and 20. The dose was 0.5 mL on each occasion (a single human dose is 0.5 mL). No vaccine-related fetal malformations or variations and no adverse effects on pre-weaning development were observed in the study.

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

6.2 Postmarketing Experience

The following additional adverse events have been identified during post-approval use of FLUCELVAX 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 the vaccine.
Immune system disorders: Allergic or immediate hypersensitivity reactions, including anaphylactic shock.
Nervous systems disorders: Syncope, presyncope, paresthesia.
Skin and subcutaneous tissue disorders: Generalized skin reactions including pruritus, urticaria or non-specific rash.
General disorders and administration site conditions: Extensive swelling of injected limb.

8.4 Pediatric Use

Safety and effectiveness have not been established in children less than 4 years of age.

8.5 Geriatric Use

Of the total number of subjects who received one dose of FLUCELVAX QUADRIVALENT in clinical studies and included in the safety population (2493), 26.47% (660) were 65 years of age and older and 7.7% (194) were 75 years of age or older.
Antibody responses to FLUCELVAX QUADRIVALENT were lower in the geriatric (adults 65 years and older) population than in younger subjects [see Clinical Studies (14.3)].

11 Description

FLUCELVAX QUADRIVALENT (Influenza Vaccine) is a subunit influenza vaccine manufactured using cell culture derived candidate vaccine viruses (CVV) that are propagated in Madin Darby Canine Kidney (MDCK) cells, a continuous cell line. These cells were adapted to grow freely in suspension in culture medium. The virus is inactivated with β-propiolactone, disrupted by the detergent cetyltrimethylammonium bromide and purified through several process steps. Each of the 4 virus strains is produced and purified separately then pooled to formulate the quadrivalent vaccine.
FLUCELVAX QUADRIVALENT is a sterile, slightly opalescent suspension in phosphate buffered saline. FLUCELVAX QUADRIVALENT is standardized according to United States Public Health Service requirements for the 2020-2021 influenza season and is formulated to contain a total of 60 micrograms (mcg) hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA of each of the following four influenza strains:
A/Nebraska/14/2019 (an A/Hawaii/70/2019 (H1N1)pdm09-like virus)
A/Delaware/39/2019 (an A/Hong Kong/45/2019 (H3N2)-like virus)
B/Darwin/7/2019 (a B/Washington/02/2019-like virus)
B/Singapore/INFTT-16-0610/2016 (a B/Phuket/3073/2013-like virus)
Each dose of FLUCELVAX QUADRIVALENT may contain residual amounts of MDCK cell protein (≤ 25.2 mcg), protein other than HA (≤ 240 mcg), MDCK cell DNA (≤ 10 ng), polysorbate 80 (≤ 1500 mcg), cetyltrimethlyammonium bromide (≤ 18 mcg), and β-propiolactone (<0.5 mcg), which are used in the manufacturing process.
FLUCELVAX QUADRIVALENT contains no egg protein or antibiotics.
FLUCELVAX QUADRIVALENT 0.5 mL pre-filled syringes contain no preservative.
FLUCELVAX QUADRIVALENT 5 mL multi-dose vials contain thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose from the multi-dose vial contains 25 mcg mercury.
The tip caps and plungers of the prefilled syringes and the multi-dose vial stopper are not made with natural rubber latex.

12.1 Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance and analysis of influenza virus isolates permits identification of yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers induced by vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some studies, HI antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.2,3Antibody against one influenza virus type or subtype confers little or no protection against another. 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 virologic basis for seasonal epidemics and the reason for the usual change of one or more strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains representing the influenza viruses likely to circulate in the United States in the upcoming winter.
Annual influenza vaccination is recommended by the Advisory Committee on Immunization Practices because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.4

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

FLUCELVAX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals.
FLUCELVAX (trivalent formulation) administered to female rabbits had no effect on fertility [see Use in Specific Populations (8.1)].

14.1 Efficacy Against Culture-Confirmed Influenza

The efficacy experience with FLUCELVAX is relevant to FLUCELVAX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions.
A multinational (US, Finland, and Poland), randomized, observer-blind, placebo-controlled trial was performed to assess clinical efficacy and safety of FLUCELVAX during the 2007-2008 influenza season in adults aged 18 through 49 years. A total of 11,404 subjects were enrolled to receive FLUCELVAX (N=3828), AGRIFLU (N=3676) or placebo (N=3900) in a 1:1:1 ratio. Among the overall study population enrolled, the mean age was 33 years, 55% were female, 84% were Caucasian, 7% were Black, 7% were Hispanic, and 2% were of other ethnic origin.
FLUCELVAX efficacy was assessed by the prevention of culture-confirmed symptomatic influenza illness caused by viruses antigenically matched to those in the vaccine and prevention of influenza illness caused by all influenza viruses compared to placebo. Influenza cases were identified by active and passive surveillance of influenza-like illness (ILI). ILI was defined as a fever (oral temperature ≥100.0°F / 38°C) and cough or sore throat. Nose and throat swab samples were collected for analysis within 120 hours of onset of an influenza-like illness in the period from 21 days to 6 months after vaccination. Overall vaccine efficacy against all influenza viral subtypes and vaccine efficacy against individual influenza viral subtypes were calculated (see Tables 5 and 6, respectively).
Table 5: Vaccine Efficacy against Culture-Confirmed Influenza
1Efficacy against influenza was evaluated over a 9-month period in 2007/2008.
2Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %.
3VE success criterion: the lower limit of the one-sided 97.5% CI for the estimate of the VE relative to placebo is >40%.
Study: NCT00630331
Number of subjects per protocolNumber of subjects with influenzaAttack Rate(%)Vaccine Efficacy (VE)1,2%Lower Limit of One-Sided 97.5% CI of VE2, 3Antigenically Matched Strains
FLUCELVAX
3776
7
0.19
83.8
61.0
    Placebo
3843
44
1.14
--
--
All Culture-Confirmed Influenza
FLUCELVAX
3776
42
1.11
69.5
55.0
    Placebo
3843
140
3.64
--
--
Table 6: Efficacy of FLUCELVAX against Culture-Confirmed Influenza by Influenza Viral Subtype
1No VE success criterion was prespecified in the protocol for each individual influenza virus subtype.
2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %.
3 There were too few cases of influenza due to vaccine-matched influenza A/H3N2 or B to adequately assess vaccine efficacy.
Study: NCT00630331
FLUCELVAX(N=3776)Placebo(N=3843)Vaccine Efficacy (VE)2Attack Rate(%)Number of Subjects with InfluenzaAttack Rate(%)Number of Subjects with Influenza%Lower Limit of One-Sided 97.5% CI of VE1,2Antigenically Matched Strains
A/H3N230. 05
2
0
0
--
--
A/H1N1
0.13
5
1.12
43
88.2
67.4
B30
0
0.03
1
--
--
All Culture-Confirmed Influenza
A/H3N2
0.16
6
0.65
25
75.6
35.1
A/H1N1
0.16
6
1.48
57
89.3
73.0
B
0.79
30
1.59
61
49.9
18.2
There are no data demonstrating prevention of influenza disease after vaccination with FLUCELVAX in the pediatric age group.

14.2 Immunogenicity Of Flucelvax Quadrivalent In Adults 18 Years Of Age And Above

Immunogenicity of FLUCELVAX QUADRIVALENT was evaluated in adults 18 years of age and older in a randomized, double-blind, controlled study conducted in the US (Study 1). In this study, subjects received FLUCELVAX QUADRIVALENT or one of the two formulations of comparator trivalent influenza vaccine (FLUCELVAX QUADRIVALENT (N=1334), TIV1c, N=677 or TIV2c, N= 669). In the per protocol set, the mean age of subjects who received FLUCELVAX QUADRIVALENT was 57.5 years; 55.1% of subjects were female and 76.1% of subjects were Caucasian, 13% were black and 9% were Hispanic. The immune response to each of the vaccine antigens was assessed, 21 days after vaccination.
The immunogenicity endpoints were geometric mean antibody titers (GMTs) of hemagglutination inhibition (HI) antibodies response and percentage of subjects who achieved seroconversions, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or a pre-vaccination HI titer >1:10 and at least 4-fold increase in serum HI antibody titer.
FLUCELVAX QUADRIVALENT was noninferior to TIVc. Noninferiority was established for all 4 influenza strains included in the QIVc, as assessed by ratios of GMTs and the differences in the percentages of subjects achieving seroconversion at 3 weeks following vaccination. The antibody response to influenza B strains contained in FLUCELVAX QUADRIVALENT was superior to the antibody response after vaccination with TIVc containing an influenza B strain from the alternate lineage. There was no evidence that the addition of the second influenza B strain resulted in immune interference to other strains included in the vaccine (see Table 7).
Table 7: Noninferiority of FLUCELVAX QUADRIVALENT relative to TIVc in adults 18 Years of Age and Above– Per Protocol Analysis Set (Study 1)
Abbreviations: HI = hemagglutination inhibition. PPS = per protocol set. GMT = geometric mean titer. CI = confidence interval.
1 Per protocol set: All subjects in Full Analysis Set, immunogenicity population, who has correctly received the assigned vaccine, have no major protocol deviations leading to exclusion as defined prior to unblinding/ analysis and are not excluded due to other reasons defined prior to unblinding or analysis.
2 The comparator vaccine for noninferiority comparisons for A/H1N1, A/H3N2 and B1 is TIV1c; for B2 it is TIV2c.
3 Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10 and post-vaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold increase in post-vaccination HI antibody titer.
Study 1: NCT01992094
FLUCELVAX QUADRIVALENTN = 1250TIV1c/TIV2c1N = 635/N =639Vaccine Group Ratio(95% CI)Vaccine Group Difference(95% CI)A/H1N1
GMT(95% CI)
302.8(281.8-325.5)
298.9(270.3-330.5)
1.0(0.9-1.1)
-
Seroconversion Rate2
(95% CI)
49.2%(46.4-52.0)
48.7%(44.7-52.6)
-
-0.5%(-5.3-4.2)
A/H3N2
GMT(95% CI)
372.3(349.2-396.9)
378.4(345.1-414.8)
1.0(0.9-1.1)
-
Seroconversion Rate2
(95% CI)
38.3%(35.6-41.1)
35.6%(31.9-39.5)
-
-2.7%(-7.2-1.9)
B1
GMT(95% CI)
133.2(125.3-141.7)
115.6(106.4-125.6)
0.9(0.8-1.0)
-
Seroconversion Rate2
(95% CI)
36.6%(33.9-39.3)
34.8%(31.1-38.7)
-
-1.8%(-6.2-2.8)
B2
GMT(95% CI)
177.2(167.6-187.5)
164.0(151.4-177.7)
0.9(0.9-1.0)
-
Seroconversion Rate2 (95% CI)
39.8%(37.0-42.5)
35.4%(31.7-39.2)
-
-4.4%(-8.9-0.2)

14.3 Immunogenicity In Children And Adolescents 4 Through 17 Years Of Age

Immunogenicity of FLUCELVAX QUADRIVALENT was evaluated in children 4 through 17 years of age in a randomized, double-blind, controlled study conducted in the US (Study 2) [see Adverse Reactions (6.1)]. In this study, 1159 subjects received FLUCELVAX QUADRIVALENT. In the per protocol set, the mean age of subjects who received FLUCELVAX QUADRIVALENT was 9.8 years; 47% of subjects were female and 54% of subjects were Caucasian, 22% were black and 19% were Hispanic. The immune response to each of the vaccine antigens was assessed, 21 days after vaccination.
The immunogenicity endpoints were the percentage of subjects who achieved seroconversion, defined as a pre-vaccination hemagglutination inhibition (HI) titer of <1:10 with a post-vaccination HI titer ≥1:40 or at least a 4-fold increase in serum HI titer; and percentage of subjects with a post-vaccination HI titer ≥1:40.
In subjects receiving FLUCELVAX QUADRIVALENT, for all four influenza strains, the 95% LBCI seroconversion rates were ≥40% and the percentage of subjects who achieved HI titer ≥1:40 post vaccination were ≥70% (95% LBCI) (see Table 8).
Table 8: The Percentage of Children and Adolescents 4 through 17 years of Age with Seroconversion1 and HI Titers ≥ 1:40 post vaccination with FLUCELVAX QUADRIVALENT– Per-Protocol Analysis Set2 (Study 2)
FLUCELVAX QUADRIVALENT
Abbreviations: HI = hemagglutinin inhibition. CI = confidence interval.
Analyses are performed on data for day 22 for previously vaccinated subjects and day 50 for not previously vaccinated subjects.
1 Seroconversion rate = percentage of subjects with either a pre-vaccination HI titer < 1:10 and post-vaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold increase in post-vaccination HI titer. Immunogenicity success criteria were met if the lower limit of the 95% confidence interval (CI) of the percentage of subjects with HI titer ≥1:40 is ≥70%; and the lower limit of the 95% CI of the percentage of subjects with seroconversion is ≥40%.
2Per protocol set: All subjects in Full Analysis Set, immunogenicity population, who has correctly received the assigned vaccine, have no major protocol deviations leading to exclusion as defined prior to unblinding/ analysis and are not excluded due to other reasons defined prior to unblinding or analysis.
Study 2: NCT 01992107
A/H1N1
N = 1014
Seroconversion Rate1 (95% CI)
72% (69-75)
HI titer≥1:40
99% (98-100)
A/H3N2
N = 1013
Seroconversion Rate1 (95% CI)
47% (44-50)
HI titer≥1:40
100% (99-100)
B1
N = 1013
Seroconversion Rate1 (95% CI)
66% (63-69)
HI titer≥1:40
92% (91-94)
B2
N = 1009
Seroconversion Rate1 (95% CI)
73% (70-76)
HI titer≥1:40
91% (89-93)

15 References

  • Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998; 339(25):1797-1802.
  • Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004; 103:133-138.
  • Hobson D, Curry RL, Beare A, et al. The role of serum hemagglutinin-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.
  • Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(33): 1128-1132.

16 How Supplied/Storage And Handling

FLUCELVAX QUADRIVALENT product presentations are listed in Table 9 below.
Table 9: Flucelvax Quadrivalent Product Presentations
PresentationCarton NDC NumberComponentsPre-filled Syringe
70461-320-03
0.5 mL single dose pre-filled syringe, package of 10 syringes per carton [NDC 70461-320-04]
Multi-dose Vial
70461-420-10
5 mL multi-dose vial, individually packaged in a carton [NDC 70461-420-11]
Store this product refrigerated at 2°C to 8°C (36ºF to 46ºF). Between uses, return the multi-dose vial to the recommended storage conditions. Do not freeze. Protect from light. Do not use after the expiration date.

17 Patient Counseling Information

Inform vaccine recipients of the potential benefits and risks of immunization with FLUCELVAX QUADRIVALENT.
Educate vaccine recipients regarding the potential side effects; clinicians should emphasize that (1) FLUCELVAX QUADRIVALENT contains non-infectious particles and cannot cause influenza and (2) FLUCELVAX QUADRIVALENT is intended to provide protection against illness due to influenza viruses only and cannot provide protection against other respiratory illnesses.
Instruct vaccine recipients to report adverse reactions to their healthcare provider.
Encourage women who receive FLUCELVAX QUADRIVALENT while pregnant to enroll in the pregnancy registry.  Pregnant women can enroll in the pregnancy registry by calling 1-855-358-8966 or sending an email to Seqirus at us.medicalinformation@seqirus.com.
Provide vaccine recipients with the Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).
Inform vaccine recipients that annual vaccination is recommended.
FLUCELVAX QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.
Manufactured by: Seqirus Inc.
Holly Springs, NC 27540, USA
US License No. 2049
Distributed by: Seqirus USA Inc. 25 Deforest Avenue, Summit, NJ 07901, USA
1-855-358-8966

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