SIDE EFFECTS

In children 5 through 17 years of age, the most common injection-site reactions observed in clinical studies with AFLURIA were pain ( ≥ 60%), redness ( ≥ 20%) and swelling ( ≥ 10%). The most common systemic adverse events were headache, myalgia ( ≥ 20%), malaise and fever ( ≥ 10%).

In adults 18 through 64 years of age, the most common injection-site adverse reactions observed in clinical studies with AFLURIA were tenderness ( ≥ 60%) and pain ( ≥ 40%). The most common systemic adverse events observed were headache, malaise, and muscle aches ( ≥ 20%).

In adults 65 years of age and older, the most common injection-site adverse reactions observed in clinical studies with AFLURIA were tenderness ( ≥ 30%) and pain ( ≥ 10%).

Clinical Trials Experience

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 the clinical studies of another vaccine and may not reflect the rates observed in clinical practice.

Children

In clinical studies, AFLURIA has been administered to, and safety information collected for, 3,009 children ages 6 months to less than 18 years. Clinical safety data for AFLURIA in children is presented from three clinical studies (Studies 1, 2 and 3). Data from a comparator-controlled trial (Study 1) are presented, followed by pooled data from two open label studies (Studies 2 and 3). Subjects 6 months through 8 years of age received one or two vaccinations as determined by previous vaccination history (for further details on clinical study design, dosing and demographics see Clinical Studies).

Study 1 included 1,468 subjects for safety analysis, ages 6 months to less than 18 years, randomized to receive AFLURIA (735 subjects) or another U.S.-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur, Inc.) (733 subjects).

Study 2 included 1,976 subjects for safety analysis, ages 6 months to less than 18 years. All subjects received AFLURIA.

Study 3 included 298 subjects for safety analysis, ages 6 months to less than 9 years. All subjects received AFLURIA.

The safety assessment was similar for the three pediatric studies. Local (injection site) and systemic adverse events were solicited for 7 days post-vaccination (Tables 1 and 2). Unsolicited adverse events were collected for 30 days post-vaccination. All adverse events are presented regardless of any treatment causality assigned by study investigators.

Among the pediatric studies, there were no vaccine-related deaths or vaccine-related serious adverse events reported in children 5 years of age and older.

In the comparator-controlled trial (Study 1), the rate of fever after the first dose of AFLURIA in subjects aged 5 to less than 9 years was 16% as compared to 8% in subjects who received the comparator. The rate of fever in subjects aged 9 to less than 18 years following a single dose of AFLURIA was 6% as compared to 4% in subjects who received the comparator. In all three pediatric studies, the rates of fever in subjects aged 5 to less than 9 years who received AFLURIA were lower after dose 2 than dose 1.

Data in Tables 1 and 2 are presented for children 5 years and older.

Table 1: Proportion of Subjects 5 through 17 Years of Age with Solicited Local or Systemic Adverse Events within 7 Days after Administration of First or Second Dose of AFLURIA, Irrespective of Causality (Study 1)

Table 2: Proportion of Subjects 5 through 17 Years of Age with Solicited Local or Systemic Adverse Events Within 7 Days after Administration of AFLURIA, Irrespective of Causality (Studies 2 and 3)

In Study 1, unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 5 years to less than 9 years following the first or second dose included cough (15%) and pyrexia (9%). Unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 9 years to less than 18 years following the first dose included cough (7%), oropharyngeal pain (7%), headache (7%) and nasal congestion (6%).

In Studies 2 and 3, unsolicited adverse events that occurred in ≥ 5% subjects ages 5 years to less than 9 years after the first or second dose included the following: upper respiratory tract infection (13%), cough (10%), rhinorrhoea (7%), headache (5%), nasopharyngitis (5%) and pyrexia (5%). Unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA in ages 9 years to less than 18 years following the first dose included upper respiratory tract infection (9%) and headache (8%).

Adults

In clinical studies, a single dose of AFLURIA was administered to, and safety information collected for, 11,104 subjects ages 18 to

less than 65 years and 836 subjects ages 65 years and older. Clinical safety data for AFLURIA in adults are presented from three clinical studies (Studies 4 through 6). In all adult studies, there were no vaccine-related deaths or vaccine-related serious adverse events reported.

Study 4 included 1,357 subjects for safety analysis, ages 18 to less than 65 years, randomized to receive AFLURIA (1,089 subjects) or placebo (268 subjects) (see Clinical Studies).

Study 5 included 15,020 subjects for safety analysis, ages 18 to less than 65 years, randomized to receive AFLURIA (10,015 subjects) or placebo (5,005 subjects) (see Clinical Studies).

Study 6 included 1,266 subjects for safety analysis, ages 65 years and older, randomized to receive AFLURIA (630 subjects) or another U.S.-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur SA) as an active control (636 subjects) (see Clinical Studies).

The safety assessment was identical for the three adult studies. Local (injection-site) and systemic adverse events were solicited for 5 days post-vaccination (Table 3). Unsolicited adverse events were collected for 21 days post-vaccination. All adverse events are presented regardless of any treatment causality assigned by study investigators.

Table 3: Proportion of Subjects 18 Years of Age and Older with Solicited Local or Systemic Adverse Events within 5 Days after Administration of AFLURIA or Placebo, Irrespective of Causality (Studies 4, 5 and 6)

In Study 4, headache was the only unsolicited adverse event that occurred in ≥ 5% of subjects who received AFLURIA or placebo (8% versus 6%, respectively).

In Study 5, headache was the only unsolicited adverse event that occurred in ≥ 5% of subjects who received AFLURIA or placebo (12% versus 11%, respectively).

In Study 6, unsolicited adverse events that occurred in ≥ 5% of subjects who received AFLURIA included headache (8%), nasal congestion (7%), cough (5%), rhinorrea (5%), and pharyngolaryngeal pain (5%).

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. The adverse reactions described have been included in this section because they: 1) represent reactions that are known to occur following immunizations generally or influenza immunizations specifically; 2) are potentially serious; or 3) have been reported frequently. These adverse reactions reflect experience in both children and adults and include those identified during post-approval use of AFLURIA outside the US since 1985.

Blood and lymphatic system disorders

Transient thrombocytopenia

Immune system disorders

Allergic reactions including anaphylactic shock and serum sickness

Nervous system disorders

Neuralgia, paresthesia, convulsions (including febrile seizures), encephalopathy, neuritis or neuropathy, transverse myelitis, and GBS

Vascular disorders

Vasculitis with transient renal involvement

Skin and subcutaneous tissue disorders

Pruritus, urticaria, and rash

Adverse Reactions Associated With Influenza Vaccination

Anaphylaxis has been reported after administration of AFLURIA. Egg protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, asthma, and systemic anaphylaxis (see CONTRAINDICATIONS).

The 1976 swine influenza vaccine was associated with an increased frequency of 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 one additional case per 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 polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination.

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