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Overall Adverse Reactions

The most common local (injection site) adverse reactions observed in clinical studies with AGRIFLU were pain, induration, swelling, and erythema. The most common systemic adverse reactions observed were headache, myalgia, and malaise. These reactions are typically mild.

Serious allergic reactions, including anaphylactic shock, have been observed during postmarketing surveillance in individuals receiving AGRIFLU.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction 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 rates observed in clinical practice. The most common local adverse reactions and general adverse reactions observed with AGRIFLU were pain and erythema at the injection site, headache, myalgia, and malaise.

Clinical safety data have been obtained from three randomized, controlled trials one of which was a placebo controlled efficacy study.1,2,3 In these trials, 13480 subjects were randomized to receive either AGRIFLU (5338 subjects included in the safety analysis), a U.S.-licensed comparator influenza vaccine (435 included in the safety analysis), an investigational inactivated influenza vaccine (3813 included in the safety analysis), or placebo (3894 included in the safety analysis). (see Clinical Studies). The overall enrolled population from the 3 studies was 18-64 years of age (mean 33 years), 57 % were female and 75% were Caucasian, 6% were Black, 18% were Hispanic and 1% were of other ethnic origin. The percentage of subjects who had a record of receiving a previous influenza vaccination was 13%. (see Clinical Studies). In all three studies, solicited local (injection site) and systemic reactions were collected from subjects who completed a symptom diary card for seven days following vaccination. Safety data are presented in Table 1.

Table 1: Percentage of Subjects Reporting Solicited Adverse Reactions in Days 1-7 After Vaccination With AGRIFLU or Comparators

  Percentage of Subjects with Adverse Reactions
Study 11 2007 NCT00464672 (18-64 years) Study 22 2007-2008 NCT00617851 (18-49 years) Study 33 2007-2008 NCT 00630331 (18-49 years)
AGRIFLU
N=460
Comparatora
N=233
AGRIFLU
N=1209
Comparatora
N=202
AGRIFLU
N=3669
Placebo
N=3895
Local Adverse Reactions
Injection site pain
Any pain 25 30 22 22 24 10
Severe painb < 1 0 < 1 < 1 < 1 < 1
Induration 2 1 1 1 6 3
Swelling < 1 1 1 < 1 5 3
Erythema < 1 1 < 1 < 1 13 10
Ecchymosis < 1 0 < 1 < 1 3 4
Systemic Adverse Reactions
Headache 23 18 24 24 15 15
Myalgia 14 16 18 20 10 7
Malaise 12 12 12 12 7 6
Fatigue 10 10 9 8 11 10
Chills 5 7 7 8 6 6
Arthralgia 7 6 6 7 3 3
Sweating 5 5 4 4 3 3
Fever ( ≥ 38°C) 2 3 4 3 < 1 < 1
aComparator is U.S.-licensed trivalent, inactivated influenza virus vaccine (Fluvirin).
bSevere injection site pain= local reaction leading to the inability to perform normal daily activities.

In the two studies with a U.S.-licensed influenza comparator vaccine, unsolicited adverse events were reported by subjects over a 3-week period after vaccination. Unsolicited adverse events that occurred in > 1% of subjects included influenza-like illness (4% of AGRIFLU subjects and 3% of active comparator subjects) and headache (2% of AGRIFLU and comparator subjects). A total of 17% of subjects in both the AGRIFLU and the comparator groups reported unsolicited adverse events: 15% and 16% of subjects in the AGRIFLU and in the comparator groups, respectively, had mild unsolicited adverse events, 2% and 1% of subjects had moderate adverse events, and < 1 % of subjects in both groups had severe adverse events.

In the placebo controlled efficacy study, all unsolicited adverse events were collected for 7 days after vaccination and selected adverse events (serious adverse events, onset of chronic illness, AEs that necessitated a physician consultation and/or led to withdrawal from the study) for up to 3 weeks after vaccination. A total of 13% and 14% of subjects in the AGRIFLU and the comparator groups reported unsolicited adverse events: in both the AGRIFLU and in the comparator groups, 7% of subjects had mild unsolicited adverse events, 5% of subjects had moderate adverse events, and 2% of subjects had severe adverse events. Unsolicited adverse events reported in the 3 week period that occurred in > 1% of subjects included pharyngolaryngeal pain (2% of both AGRIFLU and placebo subjects).

Postmarketing Experience

The following additional adverse events have been identified during postapproval use of AGRIFLU in Europe since 2003. 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.

Blood and Lymphatic System Disorders

Thrombocytopenia (some very rare cases were severe with platelet counts less than 5,000 per mm³).

Eye Disorders

Conjunctivitis, eyelid edema, eye redness

Gastrointestinal Disorders

Diarrhea, nausea, vomiting, abdominal pain

General Disorders and Administration Site Conditions

Local injection site reactions, including pain, pain limiting limb movement, redness, swelling, warmth, ecchymosis, induration, local lymphadenopathy, Injection-site cellulitis-like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than one week), Extensive swelling of injected limb lasting more than one week, and general disorders including, chills, fever, malaise, fatigue, asthenia, facial edema.

Immune System Disorders

Hypersensitivity reactions (including throat and/or mouth edema, anaphylaxis, and anaphylactic shock)

Musculoskeletal and Connective Tissue Disorders

Arthralgia, myalgia.

Nervous System Disorders

Headache, syncope shortly after vaccination, dizziness, neuralgia, paraesthesia, convulsion, myelitis (including encephalomyelitis and transverse myelitis), neuropathy (including neuritis and brachial plexus neuropathy), paralysis (including Bell's Palsy and other cranial nerve paralyses), Guillain-Barré Syndrome

Skin and Subcutaneous Disorders

Pruritus, urticaria and non-specific rash

Vascular Disorders

Vasculitis (in rare cases associated with transient renal involvement), hot flush

Adverse Events Associated With influenza Vaccines

Anaphylaxis has been reported after administration of AGRIFLU. AGRIFLU contains egg proteins, which can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS and DESCRIPTION].

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

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

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