Influenza Virus Vaccine (Inactivated)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = discontinued product

Suspension, Intramuscular:

Afluria Quadrivalent: (5 mL) [contains neomycin sulfate, thimerosal]

Flucelvax Quadrivalent: (5 mL) [contains polysorbate 80, thimerosal]

FluLaval Quadrivalent: (5 mL) [contains formaldehyde solution, polysorbate 80, thimerosal]

Fluvirin: (5 mL [DSC]) [contains egg white (egg protein), neomycin, polymyxin, thimerosal]

Fluzone: (5 mL [DSC]) [contains egg white (egg protein), formaldehyde solution, gelatin (pork), thimerosal]

Fluzone Quadrivalent: (5 mL) [contains formaldehyde solution, thimerosal]

Suspension, Intramuscular [preservative free]:

Fluzone Quadrivalent: (0.5 mL) [contains formaldehyde solution]

Suspension Pen-injector, Intradermal [preservative free]:

Fluzone Intradermal Quadrivalent: 9 mcg/strain (0.1 mL) [contains egg white (egg protein), formaldehyde solution]

Suspension Prefilled Syringe, Intramuscular [preservative free]:

Afluria: (0.5 mL [DSC]) [contains neomycin sulfate]

Afluria Quadrivalent: (0.25 mL, 0.5 mL) [contains neomycin sulfate]

Fluad: (0.5 mL) [contains formaldehyde solution, neomycin, polysorbate 80]

Fluarix Quadrivalent: (0.5 mL) [contains formaldehyde solution, gentamicin, polysorbate 80]

Flucelvax: (0.5 mL [DSC]) [contains polysorbate 80]

Flucelvax Quadrivalent: (0.5 mL) [contains polysorbate 80]

FluLaval Quadrivalent: (0.5 mL) [contains polysorbate 80, formaldehyde solution]

Fluvirin: (0.5 mL [DSC]) [contains egg white (egg protein), neomycin, polymyxin]

Fluzone High-Dose: (0.5 mL) [contains formaldehyde solution]

Fluzone Quadrivalent: (0.25 mL, 0.5 mL) [contains formaldehyde solution]

Pharmacology

Mechanism of Action

Promotes immunity to seasonal influenza virus by inducing specific antibody production. Preparations from previous seasons must not be used.

Pharmacokinetics/Pharmacodynamics

Onset of Action

Most adults have antibody protection within 2 weeks of vaccination (CDC/ACIP [Grohskopf 2019]).

Duration of Action

Vaccine effectiveness declines at a variable rate, depending on virus subtypes, patient age, and other confounding factors (CDC/ACIP [Grohskopf 2019]).

Use: Labeled Indications

Influenza disease prevention: Active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine in the following persons:

US labeling:

• ≥6 months of age (Afluria Quadrivalent, Fluarix Quadrivalent, FluLaval Quadrivalent, Fluzone Quadrivalent)
• ≥4 years of age (Flucelvax Quadrivalent)
• ≥65 years of age (Fluad, Fluzone High-Dose)

Canadian labeling:

• 6 months to <2 years (Fluad Pediatric)
• ≥6 months of age (Agriflu, FluLaval Tetra, Fluviral, Fluzone Quadrivalent)
• ≥5 years of age (Afluria Tetra)
• ≥18 years of age (Influvac Tetra)
• ≥65 years of age (Fluad, Fluzone High-Dose)

The Advisory Committee on Immunization Practices (ACIP) recommends routine annual vaccination with the seasonal influenza vaccine for all persons ≥6 months of age who do not otherwise have contraindications to the vaccine. The ACIP and American Academy of Pediatrics (AAP) recommend use of any age and risk factor appropriate product and do not have a preferential recommendation for an influenza vaccine product; in addition to inactivated influenza vaccines (IIV3, IIV4), the live attenuated vaccine (LAIV4) may be used for persons ≥2 years of age and recombinant influenza vaccine (RIV) can be used in persons ≥18 years of age (AAP 2019; CDC/ACIP [Grohskopf 2019]).

The Canadian National Advisory Committee on Immunization (NACI) recommends the following (NACI 2019): Annual vaccination with seasonal influenza vaccine for all persons ≥6 months who do not otherwise have contraindications to the vaccine. Healthy, nonpregnant persons aged 2 to 59 years may receive vaccination with the seasonal live, attenuated influenza vaccine (LAIV) (nasal spray). The following influenza vaccine preferences should be considered:

• Persons 6 to 23 months of age: Quadrivalent inactivated influenza vaccine (IIV4) is preferred or trivalent inactivated influenza vaccine (IIV3) if IIV4 is not available.
• Persons 2 to 17 years of age: Either IIV4 or LAIV is preferred (IIV3 may be considered if neither IIV4 nor LAIV are available).
• Persons ≥65 years of age: IIV3-HD (high dose) is preferred over IIV3-SD (standard dose); however, any available IIV3 or IIV4 vaccine may be used for public health program-level decision making.
• Health care workers: Either IIV4 or IIV3 are recommended; LAIV should not be used.

When vaccine supply is limited, target groups for vaccination (those at higher risk of complications from influenza infection and their close contacts) include the following (CDC/ACIP [Grohskopf 2019]):

• All infants and children 6 to 59 months of age
• Persons ≥50 years of age
• Infants, children, and adolescents (6 months to 18 years of age) who are receiving long-term aspirin or salicylate therapy, and therefore, may be at risk for developing Reye syndrome after influenza
• Women who are or will be pregnant during the influenza season
• Patients with chronic pulmonary disorders (including asthma) or cardiovascular systems disorders (except isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)
• Persons who have immunosuppression due to any cause (including immunosuppression caused by medications or HIV)
• Residents of nursing homes and other long-term care facilities
• American Indians/Alaska Natives
• Extremely obese (BMI ≥40)
• Health care personnel, including students in these professions, who will have contact with patients and other persons not directly involved in patient care but may be exposed to infectious agents (eg, clerical, housekeeping, volunteers)
• Household contacts (including children) and caregivers of neonates, infants, and children <5 years (particularly neonates and infants <6 months) and adults ≥50 years
• Household contacts (including children) and caregivers of persons with medical conditions which put them at higher risk of severe complications from influenza infection

In addition, the NACI also recommends vaccination of patients with neurologic or neurodevelopment conditions including neuromuscular/neurovascular/neurodegenerative conditions, seizure disorders (including febrile seizures in pediatric patients and isolated developmental delay) but excluding migraines and psychiatric conditions without neurological conditions (NACI 2018).

Contraindications

Severe allergic reaction (eg, anaphylaxis) to a previous influenza vaccination or to any component of the formulation

Additional manufacturer contraindications for Afluria Quadrivalent, Fluad, Fluarix Quadrivalent, FluLaval Quadrivalent, Fluzone High-Dose, Fluzone Quadrivalent: History of severe allergic reaction (eg, anaphylaxis) to egg protein

Additional manufacturer contraindications for Canadian products: Agriflu, Fluad, Fluad Pediatric, FluLaval Tetra, Fluviral, Fluzone High-Dose, Fluzone Quadrivalent, Influvac Tetra: Hypersensitivity to egg protein; hydrocortisone (Fluad and Fluad Pediatric only).

Note: Both ACIP and NACI do not consider egg allergy a contraindication to influenza vaccination (CDC/ACIP [Grohskopf 2019]; NACI 2019).

Dosage and Administration

Dosing: Adult

Influenza seasons vary in the timing and duration from year to year. In general, vaccination should begin preferably in September and October (in the United States) to ensure optimal immunity prior to onset and for the full duration of influenza activity in the community. Early vaccination (in July or August) for an upcoming influenza season has been associated with suboptimal immunity before the end of an influenza season, particularly in older adults. Vaccination should continue throughout the influenza season as long as vaccine is available. The Centers for Disease Control and Prevention does not recommend revaccination later in the season for those persons who have already been fully vaccinated. Advisory Committee on Immunization Practices does not have a preference for any inactivated influenza vaccine (IIV) formulation when used within their specified age indications (CDC/ACIP [Grohskopf 2019]). International considerations: Products with similar names but containing different strains may be circulating globally due to differences in recommendations between northern and southern hemisphere countries. In addition, recommendations related to use of influenza vaccines and approved ages may vary per country.

Immunization:

Afluria Quadrivalent:

Adults ≤64 years: IM or via PharmaJet Stratis Needle-Free Injection System: 0.5 mL per dose as a single dose (1 dose per season)

Adults >64 years: IM: 0.5 mL per dose as a single dose (1 dose per season)

Fluarix Quadrivalent, Flucelvax Quadrivalent, FluLaval Quadrivalent, Fluzone Quadrivalent: IM: 0.5 mL/dose (1 dose per season)

Canadian labeling:

Afluria Tetra, Agriflu, FluLaval Tetra, Fluviral, Fluzone Quadrivalent: IM: 0.5 mL/dose (1 dose per season)

Influvac Tetra: IM, SubQ: 0.5 mL/dose (1 per season)

Dosing: Geriatric

Influenza seasons vary in the timing and duration from year to year. In general, vaccination should begin preferably in September and October (in the United States) to ensure optimal immunity prior to onset and for the full duration of influenza activity in the community. Early vaccination (in July or August) for an upcoming influenza season has been associated with suboptimal immunity before the end of an influenza season, particularly in older adults. Vaccination should continue throughout the influenza season as long as vaccine is available. The Centers for Disease Control and Prevention does not recommend revaccination later in the season for those persons who have already been fully vaccinated. The high-dose inactivated influenza vaccine (IIV), Fluzone High-Dose, contains 60 mcg of each vaccine antigen per 0.5 mL dose compared to 15 mcg of each vaccine antigen per 0.5 mL dose. The high-dose IIV formulation was shown to elicit a higher antibody response and may provide better protection against influenza illness compared to standard dose IIV3 formulations. However, the Advisory Committee on Immunization Practices does not have a preference for any given IIV formulation in older adults when used within their specified age indications (CDC/ACIP [Grohskopf 2019]).

Immunization: Adults ≥65 years of age:

Afluria Quadrivalent, Fluad, Fluarix Quadrivalent, Flucelvax Quadrivalent, FluLaval Quadrivalent, Fluzone High-Dose, Fluzone Quadrivalent: IM: 0.5 mL/dose (1 dose per season).

Canadian labeling:

Afluria Tetra, Agriflu, Fluad, FluLaval Tetra, Fluviral, Fluzone Quadrivalent, Fluzone High-Dose: IM: 0.5 mL/dose (1 dose per season)

Influvac Tetra: IM, SubQ: 0.5 mL/dose (1 per season)

Dosing: Pediatric

Influenza seasons vary in the timing and duration from year to year. In general, vaccination should begin preferably in September and October (in US) to ensure optimal immunity prior to onset and for the full duration of influenza activity in the community. Early vaccination (in July or August) for an upcoming influenza season has been associated with suboptimal immunity before the end of an influenza season, particularly in older adults. Vaccination should continue throughout the influenza season as long as vaccine is available. ACIP and AAP do not have a preference for any given inactivated influenza vaccine (IIV) formulation when used within their specified age indications and appropriate risk factor selection (if applicable) (AAP 2019; CDC/ACIP [Grohskopf 2019]). According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (ACIP [Kroger 2017]).

International considerations: Products with similar names but containing different strains may be circulating globally due to differences in recommendations between northern and southern hemisphere countries. In addition, recommendations related to use of influenza vaccines and approved ages may vary per country.

Immunization, annual: Note: Age is age at the time of the first dose.

Infants ≥6 months and Children <9 years: The number of doses needed per flu season is dependent upon vaccination history (see below) (AAP 2019; CDC/ACIP [Grohskopf 2019]).

One dose: If the patient received ≥2 doses of trivalent or quadrivalent influenza vaccine prior to July 1 preceding the current flu season start. The 2 doses need not have been received during the same season or consecutive seasons.

Two doses (separated by ≥4 weeks) if any of the following:

• It is the patient's first season of vaccination.
• Patient received ≤1 dose of trivalent or quadrivalent influenza vaccine prior to July 1 preceding the current flu season start.
• If vaccination status cannot be determined.

Note: A child turning 9 years of age between the first and second dose should still receive 2 doses.

Children ≥9 years and Adolescents: A single dose per season is needed.

Product-specific dosing: Note: In infants and young children, the dose volume may be different for some formulations (eg, 0.25 mL vs 0.5 mL per dose); use precaution when verifying product selection and dose volume.

Afluria Quadrivalent: IM:

Infants 6 months to Children 35 months: 0.25 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children 3 to 8 years: 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children ≥9 years and Adolescents <18 years: 0.5 mL per dose as a single dose per season.

Adolescents ≥18 years: IM or via PharmaJet Stratis Needle-Free Injection System: 0.5 mL per dose as a single dose per season.

Fluzone Quadrivalent: IM:

Infants ≥6 months and Children ≤35 months: 0.25 mL or 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history. If 2 doses required, the schedule can be completed as any combination of 0.25 mL or 0.5 mL doses administered ≥4 weeks apart (see Note).

Children 3 to 8 years: 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children ≥9 years and Adolescents: 0.5 mL per dose as a single dose per season.

FluLaval Quadrivalent: IM:

Infants ≥6 months and Children <9 years: 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children ≥9 years and Adolescents: 0.5 mL per dose as a single dose per season.

Fluarix Quadrivalent: IM:

Infants ≥6 months and Children <9 years: 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children ≥9 years and Adolescents: 0.5 mL per dose as a single dose per season.

Flucelvax Quadrivalent: IM:

Children 4 to 8 years: 0.5 mL per dose for a total of 1 or 2 doses per season, dependent upon vaccination history (see Note).

Children ≥9 years and Adolescents: 0.5 mL per dose as a single dose per season.

Canadian labeling:

Afluria Tetra: IM:

Children 5 to 8 years: 0.5 mL per dose (1 dose per season); a second dose should be administered 4 weeks after the first in previously unvaccinated patients.

Children ≥9 years and Adolescents: 0.5 mL per dose (1 dose per season).

Agriflu, Fluzone Quadrivalent: IM:

Infants and Children 6 to 35 months: 0.25 mL or 0.5 mL per dose; NACI recommendation: 0.5 mL per dose (NACI 2019) (1 dose per season); a second dose should be administered 4 weeks after the first in previously unvaccinated patients (NACI 2019).

Children 3 to 8 years: 0.5 mL per dose (1 dose per season); a second dose should be administered 4 weeks after the first in previously unvaccinated patients.

Children ≥9 years and Adolescents: 0.5 mL per dose (1 dose per season).

Fluad Pediatric: IM: Infants and Children 6 months to <2 years: 0.25 mL per dose (1 dose per season); a second dose should be administered 4 weeks after the first in previously unvaccinated patients and in patients who were vaccinated for the first time last season and only 1 dose was received.

FluLaval Tetra, Fluviral: IM:

Infants ≥6 months and Children <9 years: 0.5 mL per dose (1 dose per season); a second dose should be administered 4 weeks after the first in previously unvaccinated patients.

Children ≥9 years and Adolescents: 0.5 mL per dose (1 dose per season).

Influvac Tetra: IM, SubQ: Adolescents ≥18 years: 0.5 mL per dose (1 dose per season).

Administration

Afluria Quadrivalent, Afluria Tetra [Canadian product], Fluad, Fluarix Quadrivalent, Flucelvax Quadrivalent, FluLaval Quadrivalent, Fluzone High-Dose, Fluzone Quadrivalent, Agriflu [Canadian product], FluLaval Tetra [Canadian product], Fluviral [Canadian product]: For IM administration only. Suspensions should be shaken well prior to use. Inspect for particulate matter and discoloration prior to administration. Some manufacturers recommend avoiding use if visible particles or discoloration are present in the suspension after shaking. See manufacturer labeling for specific recommendations. Adults should be vaccinated in the deltoid muscle. Do not inject into the gluteal region or areas where there may be a major nerve trunk.

Afluria Quadrivalent via PharmaJet Stratis Needle-free Injection System: For IM administration in adults 18 to 64 years of age only. For detailed instructions on preparation and administration of a dose, refer to the information available online at www.pharmajet.com.

Influvac Tetra [Canadian product]: May be administered by IM or deep subcutaneous injection. Shake well prior to use. Allow to warm to room temperature prior to use.

Unless otherwise indicated in product labeling, jet injectors should not be used to administer inactivated influenza vaccines. Currently, Afluria Quadrivalent is the only influenza vaccine licensed in the United States with data about use with a jet-injector device.

Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection. To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2017]). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, and the administering person's name, title, and address be entered into the patient's permanent medical record.

If a pediatric vaccine (0.25 mL) is inadvertently administered to a patient who should have received a 0.5 mL dose, an additional 0.25 mL should be administered to provide the full 0.5 mL dose. If the error is discovered after the patient has left the health care setting, a 0.5 mL dose should be given as soon as the patient can return (CDC/ACIP [Grohskopf 2019]).

Note: For patients at risk of hemorrhage following IM injection, the vaccine should be administered IM if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23 gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (ACIP [Kroger 2017]).

Storage

Store all products between 2°C to 8°C (36°F to 46°F). Do not freeze. Potency is destroyed by freezing; do not use if product has been frozen.

Afluria Quadrivalent, Afluria Tetra [Canadian product], Flucelvax Quadrivalent, FluLaval Quadrivalent, FluLaval Tetra [Canadian product]: Protect from light. Discard multiple dose vials 28 days after initial entry (excluding Flucelvax Quadrivalent). Between uses, the multiple-dose vial should be stored at 2°C to 8°C (36°F to 46°F). The number of needle punctures should not exceed 10 per multiple-dose vial.

Agriflu [Canadian product]: Protect from light. May be used if exposed to temperatures between 8°C to 25°C for less than 2 hours. Discard multiple-dose vials 28 days after initial entry. Between uses, the multiple-dose vial should be stored at 2°C to 8°C (36°F to 46°F). The number of needle punctures should not exceed 10 per multi-dose vial.

Fluad, Fluarix Quadrivalent, Fluzone High-Dose (Canadian labeling), Fluzone Quadrivalent (Canadian labeling), Influvac Tetra: Protect from light.

Fluad (Canadian labeling), Fluad Pediatric [Canadian product]: Protect from light. May be used if exposed to temperatures between 8°C to 25°C for less than 2 hours.

Fluviral [Canadian product]: Discard multiple dose vials 28 days after initial entry. Protect from light.

Drug Interactions

Doxofylline: Influenza Virus Vaccine (Inactivated) may increase the serum concentration of Doxofylline. Monitor therapy

Fingolimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Consider therapy modification

Immunosuppressants: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Exceptions: Cytarabine (Liposomal). Consider therapy modification

Pneumococcal Conjugate Vaccine (13-Valent): Influenza Virus Vaccine (Inactivated) may diminish the therapeutic effect of Pneumococcal Conjugate Vaccine (13-Valent). Pneumococcal Conjugate Vaccine (13-Valent) may diminish the therapeutic effect of Influenza Virus Vaccine (Inactivated). Monitor therapy

Siponimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Consider therapy modification

Venetoclax: May diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy

Adverse Reactions

Frequency not defined. Adverse reactions in adults ≥65 years of age may be greater using the high-dose vaccine, but are typically mild and transient.

Cardiovascular: Chest tightness, hypertension

Central nervous system: Chills, drowsiness, fatigue, headache, irritability, malaise, migraine, shivering

Dermatologic: Diaphoresis, ecchymoses

Gastrointestinal: Abdominal pain, anorexia, diarrhea, gastroenteritis, nausea, sore throat, vomiting

Infection: Infection, varicella

Local: Injection site reactions (including bruising, erythema, hematoma at injection site, induration, inflammation, itching at injection site, pain, rash, soreness, swelling at injection site, tenderness at injection site)

Neuromuscular & skeletal: Arthralgia, back pain, myalgia (may start within 6 to 12 hours and last 1 to 2 days; incidence generally equal to placebo in adults; occurs more frequently than placebo in children)

Respiratory: Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngolaryngeal pain, rhinitis, rhinorrhea, upper respiratory tract infection, wheezing

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Abnormal gait, anaphylactic shock, anaphylaxis, angioedema, arthritis, asthma, Bell's palsy, brachial plexopathy, brain disease, bronchospasm, cellulitis, chest pain, confusion, constriction of the pharynx, cranial nerve palsy, dizziness, dysphagia, eye pain, facial paralysis, febrile seizures, flu-like symptoms, flushing, Guillain-Barre syndrome, Henoch-Schönlein purpura (immunoglobulin A vasculitis), hot flash, hypersensitivity reaction (including oculorespiratory syndrome, an acute, self-limited reaction with ocular and respiratory symptoms) (CDC/ACIP [Grohskopf 2013]), hypoesthesia, hypokinesia, insomnia, laryngitis, limb pain, lymphadenopathy, maculopapular rash, microscopic polyangiitis, myasthenia, myelitis (including encephalomyelitis), neuralgia, neuritis (including brachial), ocular hyperemia, optic neuritis, optic neuropathy, pallor, paralysis (including limb), paresthesia, pharyngeal edema, photophobia, presyncope, pruritus, seizure, serum sickness, skin rash, Stevens-Johnson syndrome, swelling of injected limb (lasting >1 week), syncope, thrombocytopenia, transverse myelitis, tremor, urticaria, vasculitis (including transient renal involvement), vasodilation, vesicobullous rash, voice disorder, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2017]).
• Oculorespiratory syndrome: Oculorespiratory syndrome (ORS) is an acute, self-limiting reaction to inactivated influenza vaccine (IIV) with one or more of the following symptoms appearing within 2 to 24 hours after the dose: chest tightness, cough, difficulty breathing, facial swelling, red eyes, sore throat, or wheezing. Symptoms resolve within 48 hours of onset. The cause of ORS has not been established, but studies have suggested that it is not IgE mediated. However, because ORS symptoms may be similar to those of an IgE-mediated hypersensitivity reaction, health care providers unsure of etiology of symptoms should seek advice from an allergist/immunologist when determining whether a patient may be revaccinated in subsequent seasons (Demicheli 2018; Skowronski 2005).
• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2017]).

Disease-related concerns:

• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2017]).
• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2017]).
• Febrile seizures: Based on information from the Centers for Disease Control and Prevention (CDC), an increased rate of febrile seizures has been reported in young children 6 to 23 months of age who received vaccination with IIV and the 13-valent pneumococcal conjugate vaccine (PCV13), 7-valent pneumococcal conjugate vaccine (PCV7), or diphtheria, tetanus, and pertussis (DTaP)-containing vaccines. However, due to the risks associated with delaying either vaccine, administering them at separate visits or deviating from the recommended vaccine schedule is not currently recommended (CDC/ACIP [Grohskopf 2019]). Antipyretics have not been shown to prevent febrile seizures; antipyretics may be used to treat fever or discomfort following vaccination (ACIP [Kroger 2017]). One study reported that routine prophylactic administration of acetaminophen to prevent fever prior to vaccination decreased the immune response of some vaccines; the clinical significance of this reduction in immune response has not been established (Prymula 2009).
• Guillain-Barré syndrome: Use with caution in patients with history of Guillain-Barré syndrome (GBS); patients with history of GBS have a greater likelihood of developing GBS than those without. As a precaution, the Advisory Committee on Immunization Practices (ACIP) recommends that patients with a history of GBS and who are at low risk for severe influenza complications, and patients known to have experienced GBS within 6 weeks following previous vaccination should generally not be vaccinated (consider influenza antiviral chemoprophylaxis in these patients). The benefits of vaccination may outweigh the potential risks in persons with a history of GBS who are also at higher risk for severe complications of influenza (CDC/ACIP [Grohskopf 2019]). Recent studies of patients who received the trivalent inactivated influenza vaccine or the monovalent H1N1 influenza vaccine have shown the risk of GBS is lower with vaccination than with influenza infection (Baxter 2013; Greene 2013; Kwong 2013).
• Neurologic disorders: Some Canadian product labeling recommends delaying therapy in patients with active neurologic disorders.

Concurrent drug therapy issues:

• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2017]).
• Vaccines: In order to maximize vaccination rates, the ACIP, as well as the Canadian National Advisory Committee on Immunization (NACI), recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist. The ACIP prefers each dose of a specific vaccine in a series come from the same manufacturer when possible; however, vaccination should not be deferred because a specific brand is unavailable (ACIP [Kroger 2017]; NACI 2018).

Special populations:

• Altered immunocompetence: Consider deferring immunization during periods of immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high-dose corticosteroid]); may have a reduced response to vaccination. Inactivated vaccine (IIV or recombinant influenza vaccine [RIV]) is preferred over live virus vaccine for immunocompromised persons, household members, health care workers, and others coming in close contact with severely immunosuppressed persons requiring care in a protected environment. Refer to annual immunization schedule for additional information (ACIP [Kroger 2017]; CDC/ACIP [Grohskopf 2019]). Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2017]; IDSA [Rubin 2014]).
• Elderly: Antibody responses may be lower and decline faster in older adults ≥65 years of age compared to younger adults; however, deferral to later in the season may result in missed vaccination opportunities or early season infection (CDC/ACIP [Grohskopf 2019]). Fluzone High-Dose contains 4 times the amount of each influenza antigen compared to other inactivated virus vaccines and was shown to elicit a higher antibody response and may provide better protection against influenza illness in older adults compared to standard dose IIV3 formulations (DiazGranados 2014). However, the ACIP does not have a preference for any one vaccine (IIV [standard or high dose] or RIV4) (CDC/ACIP [Grohskopf 2019]).

Dosage form specific issues:

• Chicken egg protein: Most products are manufactured with chicken egg protein (expressed as ovalbumin content when content is disclosed on prescribing information). The ovalbumin content may vary from season to season and lot to lot of vaccine. Allergy to eggs must be distinguished from allergy to the vaccine. Recommendations are available from the ACIP and NACI regarding influenza vaccination to persons who report egg allergies; however, ACIP states a prior severe allergic reaction to influenza vaccine, regardless of the component suspected, is a contraindication to vaccination. Per ACIP, patients with a history of egg allergy who have experienced only hives following egg exposure should receive influenza vaccine if otherwise appropriate. Patients with a history of egg allergy other than hives (eg, angioedema, respiratory distress) or who required emergency medical attention (eg, epinephrine) may receive influenza vaccine if otherwise appropriate and administered in an inpatient or outpatient medical setting with health care supervision able to recognize and manage severe allergic conditions (CDC/ACIP [Grohskopf 2019]). However, the American Academy of Pediatrics (AAP); American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology; and NACI state that patients may receive vaccination regardless of severity of egg allergy and no special precautions are required (AAP 2019; Greenhawt 2018; NACI 2019). Flucelvax Quadrivalent (ccIIV4) is an inactivated influenza vaccine manufactured using cell-culture technology and provides an alternative to vaccines cultured with chicken egg protein (CDC/ACIP [Grohskopf 2019]).
• Gentamicin: Some products are manufactured with gentamicin.
• Kanamycin: Some products are manufactured with kanamycin.
• Latex: Packaging may contain natural latex rubber.
• Neomycin: Some products are manufactured with neomycin.
• Polymyxin: Some products are manufactured with polymyxin.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
• Thimerosal: Some products contain thimerosal; hypersensitivity reactions may occur.

Other warnings/precautions:

• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for use of this vaccine in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the Infectious Diseases Society of America (Rubin 2014).
• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2017]).
• Other influenza vaccines: Influenza vaccines from previous seasons must not be used. Vaccines formulated for the northern hemisphere may differ in composition from the southern hemisphere vaccine; consult CDC Yellow Book for more information regarding travel vaccines (CDC/ACIP [Grohskopf 2019]).

Monitoring Parameters

Monitor for anaphylaxis and syncope for 15 minutes following administration (ACIP [Kroger 2017]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion.

Pregnancy

Pregnancy Considerations

Inactivated influenza vaccine (IIV) has not been shown to cause fetal harm when given to pregnant women, although information related to use in the first trimester is relatively limited (CDC/ACIP [Grohskopf 2019]).

Following maternal immunization with IIV, vaccine-specific antibodies are observed in the newborn (CDC 2018). Most studies evaluating the use of inactivated influenza vaccines during pregnancy have not shown an increased risk of adverse pregnancy events (CDC/ACIP [Grohskopf 2019]).

The risk for severe illness and complications from influenza infection is increased during pregnancy, particularly during the second and third trimesters (CDC/ACIP [Grohskopf 2019]). Influenza vaccination decreases the risk of laboratory-confirmed influenza in pregnant women (Thompson 2014) and infants <6 months of age whose mothers have been vaccinated (CDC 2018).

Influenza vaccination with any licensed, recommended, age-appropriate vaccine is recommended for all females who are or may become pregnant during the influenza season and who do not otherwise have contraindications to the vaccine (CDC/ACIP [Grohskopf 2019]). Use of an inactivated vaccine is recommended; vaccination may be done during any trimester of pregnancy (ACOG 732 2018).

Pregnant females should observe the same precautions as nonpregnant patients to reduce the risk of exposure to influenza and other respiratory infections (CDC/HHS 2019). When vaccine supply is limited, focus on delivering the vaccine should be given to females who are pregnant or will be pregnant during the flu season, as well as mothers of newborns and contacts or caregivers of children <5 years of age (CDC/ACIP [Grohskopf 2019]).

Women exposed to FluLaval Quadrivalent or Fluarix Quadrivalent vaccine during pregnancy or their health care provider may contact the GlaxoSmithKline registry at 888-452-9622.

Women exposed to Afluria Quadrivalent or Flucelvax Quadrivalent vaccine during pregnancy may contact the Seqirus registry at 855-358-8966 or via email at us.medicalinformation@seqirus.com.

Health care providers may enroll women exposed to Fluzone Quadrivalent during pregnancy in the Sanofi Pasteur vaccination registry at 800-822-2463.

Patient Education

• Discuss specific use of vaccine and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience injection site pain or irritation, muscle pain, joint pain, loss of strength and energy, nausea (children), vomiting (children), diarrhea (children), lack of appetite (children), abdominal pain (children), fatigue (children), abnormal crying (children), or irritability (children). Have patient report immediately to prescriber burning or numbness feeling, facial paralysis, abnormal movements, severe dizziness, passing out, muscle weakness, seizures, severe headache, or vision changes (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.