FLUARIX has been administered to 1,271 adults in clinical trials. Study FLUARIX-US-001 was a randomized, double-blinded, placebo-controlled study that evaluated a total of 952 subjects: FLUARIX n = 760, placebo n = 192. The population was 18 to 64 years of age (mean 39.1), 54% were female and 80% were Caucasian. Solicited adverse events were collected for 4 days (day of vaccination and the next 3 days). Unsolicited events that occurred within 21 days of vaccination (day 0-20) were recorded using diary cards supplemented by spontaneous reports and a medical history as reported by subjects.

Most events reported were considered by the subjects as mild and self-limiting. Table 2 provides the incidence of solicited adverse events for the FLUARIX and placebo groups from Study FLUARIX-US-001.

The adverse event information from clinical trials provides a basis for identifying adverse events that appear to be related to vaccine use and for approximating rates. However, because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice.

Table 2. Percentage of Subjects With Solicited Local or Systemic Adverse Events Within 4 Days* of Vaccination From Study FLUARIX-US-001 (Total Vaccinated Cohort)

Solicited and unsolicited adverse events following administration of FLUARIX were collected in 3 additional studies. One randomized study enrolled adults >60 years of age. Two studies enrolled adults ≥ 18 years of age. From these 3 studies, a post-hoc analysis of solicited adverse events observed in the subsets of subjects ≥ 65 years of age (n = 245), pain was observed in 12.2%, redness in 15.9%, swelling in 16.7%, muscle aches in 10.2%, fatigue in 12.2%, headache in 14.3%, arthralgias in 11.0%, shivering in 6.9%, and fever in 0.4% of subjects.

Unsolicited adverse events from Study FLUARIX-US-001 that occurred in ≥ 1% of recipients of FLUARIX and at a rate greater than placebo included upper respiratory tract infection (3.9% vs. 2.6%), nasopharyngitis (2.5% vs. 1.6%), nasal congestion (2.2% vs. 2.1%), diarrhea (1.6% vs. 0%), influenza-like illness (1.6% vs. 0.5%), vomiting (1.4% vs. 0%), and dysmenorrhea (1.3% vs. 1.0%). One death due to atherosclerotic cardiovascular disease occurred 17 days after administration of FLUARIX.

Incidence of Adverse Events of 1% to 10% in Non-US Clinical Trials With FLUARIX: The following additional adverse events have been observed in non-US clinical trials with FLUARIX.

General Disorders and Administrative Site Conditions: Malaise.

Local Reactions at Injection Site: Ecchymosis, induration.

Skin and Subcutaneous Tissue Disorders: Sweating.

Two deaths were reported in non-US trials with FLUARIX: one death due to acute pancreatitis occurred 10 months after administration of FLUARIX and one death due to abdominal neoplasm occurred 9 months after administration of FLUARIX.

As with any vaccine, there is the possibility that broad use of FLUARIX could reveal adverse events not observed in clinical trials.

Postmarketing Reports: Worldwide voluntary reports of adverse events received for FLUARIX since market introduction of this vaccine are listed below. This list includes serious events or events which have causal connection to components of this or other vaccines or drugs. 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.

Blood and Lymphatic System Disorders: Autoimmune hemolytic anemia, lymphadenopathy, thrombocytopenia.

Cardiac Disorders: Tachycardia.

Ear and Labyrinth Disorders: Vertigo.

Eye Disorders: Conjunctivitis, eye irritation, eye pain, eye redness, eye swelling, eyelid swelling.

Gastrointestinal Disorders: Abdominal pain or discomfort, nausea, swelling of the mouth, throat, and/or tongue.

General Disorders and Administrative Site Conditions: Asthenia, chest pain, chills, feeling hot, injection site mass, injection site reaction, injection site warmth, pain.

Immune System Disorders: Anaphylactic reaction including shock, anaphylactoid reaction, hypersensitivity, serum sickness.

Infections and Infestations: Injection site abscess, injection site cellulitis, pharyngitis, rhinitis, tonsillitis.

Musculoskeletal and Connective Tissue Disorders: Pain in extremity.

Nervous System Disorders: Convulsion, dizziness, encephalomyelitis, facial palsy, facial paresis, Guillain-Barré syndrome, hypoesthesia, myelitis, neuritis, neuropathy, paresthesia.

Respiratory, Thoracic and Mediastinal Disorders: Asthma, bronchospasm, cough, dyspnea, pneumonia, respiratory distress, stridor.

Skin and Subcutaneous Tissue Disorders: Angioneurotic edema, erythema, erythema multiforme, facial swelling, pruritus, rash, Stevens-Johnson syndrome, urticaria.

Vascular disorders: Henoch-Schönlein purpura, vasculitis.

Other Adverse Events: Immediate, presumably allergic, reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. Two subjects experienced urticaria in clinical trials of FLUARIX. These reactions probably result from hypersensitivity to certain vaccine components, such as residual egg protein. Although FLUARIX contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy (see CONTRAINDICATIONS).³

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain- Barré syndrome (GBS).^3,10 Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear.³ If influenza vaccine does pose a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated.³

Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy have been reported.^11,12

Microscopic polyangitis (vasculitis) has been reported temporally associated with influenza vaccination.¹³

Reporting of Adverse Events: The US Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986.¹⁴ The VAERS toll-free number is 1-800-822-7967. Reporting forms may also be obtained at the VAERS website at www.vaers.hhs.gov.

Although it has been reported that influenza vaccination may inhibit the clearance of warfarin, theophylline, and phenytoin, controlled studies have yielded inconsistent results regarding pharmacokinetic interactions between influenza vaccine and these medications.^4-9 Nevertheless, clinicians should consider the potential for an interaction when influenza vaccine is administered to persons receiving these drugs.

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines.

FLUARIX should not be mixed with any other vaccine in the same syringe or vial.

REFERENCES

3. Centers for Disease Control and Prevention. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2004;53(RR-6):1-44.

4. Renton KW, Gray JD, Hall RI. Decreased elimination of theophylline after influenza vaccination. Can Med Assoc J 1980;123:288-290.

5. Fischer RG, Booth BH, Mitchell DQ, et al. Influence of trivalent influenza vaccine on serum theophylline levels. Can Med Assoc J 1982;126:1312-1313.

6. Lipsky BA, Pecoraro RE, Roben NJ, et al. Influenza vaccination and warfarin anticoagulation. Ann Intern Med 1984;100(6):835-837.

7. Kramer P, Tsuru M, Cook CE, et al. Effect of influenza vaccine on warfarin anticoagulation. Clin Pharmacol Ther 1984;35(3):416-418.

8. Patriarca PA, Kendal AP, Stricof RL, et al. Influenza vaccination and warfarin or theophylline toxicity in nursing-home residents. New Engl J Med 1983;308(26):1601-1602.

9. Levine M, Jones MW, and Gribble M. Increased serum phenytoin concentration following influenza vaccination. Clin Pharm 1984;3:505-509.

10. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976-1977. Am J Epidemiol 1979;110(2):105-123.

11. Hull TP and Bates JH. Optic neuritis after influenza vaccination. Am J Ophthalmol 1997;124(5):703-704.

12. Kawasaki A, Purvin VA, Tang R. Bilateral anterior ischemic optic neuropathy following influenza vaccination. J Neuro- Ophthalmol 1998;18(1):56-59.

13. Kelsall JT, Chalmers A, Sherlock CH, et al. Microscopic polyangitis after influenza vaccination. J Rheumatol 1997;1198-1202.

14. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR-2):1-35.

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