Fluvirin (Influenza Virus Vaccine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Overall Adverse Reaction Profile

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

Clinical Trial Experience

Adverse event information from clinical trials provides a basis for identifying adverse events that appear to be related to vaccine use and for approximating the rates of these events. However, 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.

Adult and Geriatric Subjects

Safety data were collected in a total of 2768 adult and geriatric subjects (18 years of age and older) who have received FLUVIRIN^® in 29 clinical studies since 1982.

In 9 clinical studies since 1997, among 1261 recipients of FLUVIRIN^®, 745 (59%) were women; 1211 (96%) were White, 23 (2%) Asian, 15 (1%) Black and 12 (1%) other; 370 (29%) of subjects were elderly (≥65 years of age). All studies have been conducted in the UK, apart from a study run in the US in 2005-2006 where FLUVIRIN^® was used as a comparator for an unlicensed vaccine.

After vaccination, the subjects were observed for 30 minutes for hypersensitivity or other immediate reactions. Subjects were instructed to complete a diary card for three days following immunization (i.e. Day 1 to 4) to collect local and systemic reactions (see Tables 1 and 2). All local and systemic adverse events were considered to be at least possibly related to the vaccine. Local and systemic reactions mostly began between day 1 and day 2. The overall adverse events reported in clinical trials since 1998 in at least 5% of the subjects are summarized in Table 3.

TABLE 1 Solicited Adverse Events in the First 72-96 Hours After Administration of FLUVIRIN^® in Adult (18-64 years of age) and Geriatric (≥65 years of age) Subjects.

	1998-1999 *§		1999-2000 *§		2000-2001 *§
	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs
	N = 66	N = 44	N = 76	N = 34	N = 75	N = 35
Local Adverse Events
Pain	16 (24%)	4 (9%)	16 (21%)	-	9 (12%)	-
Mass	7 (11%)	1 (2%)	4 (5%)	-	8 (11%)	1 (3%)
Inflammation	5 (8%)	2 (5%)	6 (8%)	-	7 (9%)	1 (3%)
Ecchymosis	4 (6%)	1 (2%)	3 (4%)	1 (3%)	4 (5%)	-
Edema	2 (3%)	1 (2%)	1 (1%)	2 (6%)	3 (4%)	1 (3%)
Reaction	2 (3%)	-	2 (3%)	-	4 (5%)	1 (3%)
Hemorrhage	-	-	1 (1%)	-	-	-
Systemic Adverse Events
Headache	7 (11%)	1 (2%)	17 (22%)	3 (9%)	4 (5%)	-
Fatigue	3 (5%)	2 (5%)	4 (5%)	1 (3%)	3 (4%)	-
Malaise	2 (3%)	1 (2%)	2 (3%)	1 (3%)	1 (1%)	-
Myalgia	1 (2%)	-	2 (3%)	-	-	-
Fever	1 (2%)	-	1 (1%)	-	-	-
Arthralgia	-	1 (2%)	-	1 (3%)	-	-
Sweating	-	-	3 (4%)	-	1 (1%)	1 (3%)

Results reported to the nearest whole percent; Fever defined as >38°C
– not reported
* Solicited adverse events in the first 72 hours after administration of FLUVIRN®
§ Solicited adverse events reported by COSTART preferred term
^ Solicited adverse events reported by MEDDRA preferred term
	2001-2002 *^		2002-2003 *^		2004-2005 ^
	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs
	N = 75	N = 35	N = 107	N = 88	N = 74	N = 61
Local Adverse Events
Pain	12 (16%)	1 (3%)	14 (13%)	7 (8%)	15 (20%)	9 (15%)
Mass	4 (5%)	1 (3%)	-	-	-	-
Ecchymosis	2 (3%)	-	3 (3%)	3 (3%)	2 (3%)	1 (2%)
Edema	2 (3%)	1 (3%)	6 (6%)	2 (2%)	-	-
Erythema	5 (7%)	-	11 (10%)	5 (6%)	16 (22%)	5 (8%)
Swelling	-	-	-	-	11 (15%)	4 (7%)
Reaction	-	-	2 (2%)	-	-	-
Induration	-	-	14 (13%)	3 (3%)	11 (15%)	1 (2%)
Pruritus	-	-	1 (1%)	-	-	-
Systemic Adverse Events
Headache	8 (11%)	1 (3%)	12 (11%)	9 (10%)	14 (19%)	3 (5%)
Fatigue	1 (1%)	1 (3%)	-	-	5 (7%)	2 (3%)
Malaise	3 (4%)	-	3 (3%)	4 (5%)	1 (1%)	1 (2%)
Myalgia	3 (4%)	-	5 (5%)	3 (3%)	8 (11%)	1 (2%)
Fever	-	-	-	1 (1%)	-	-
Arthralgia	-	-	2 (2%)	-	1 (1%)	-
Sweating	3 (4%)	1 (3%)	-	2 (2%)	-	-
Shivering	-	-	-	1 (1%)	-	-

TABLE 2 Solicited Adverse Events in the First 72 Hours After Administration of FLUVIRIN^® in Adult Subjects (18-49 years of age).

Results reported to the nearest whole percent
– not reported
	2005-2006 US Trial
	FLUVIRIN ®
	N = 304
Local Adverse Events
Pain	168 (55%)
Erythema	48 (16%)
Ecchymosis	22 (7%)
Induration	19 (6%)
Swelling	16 (5%)
Systemic Adverse Events
Headache	91 (30%)
Myalgia	64 (21%)
Malaise	58 (19%)
Fatigue	56 (18%)
Sore throat	23 (8%)
Chills	22 (7%)
Nausea	21 (7%)
Arthralgia	20 (7%)
Sweating	17 (6%)
Cough	18 (6%)
Wheezing	4 (1%)
Chest tightness	4 (1%)
Other difficulties breathing	3 (1%)
Facial edema	-

TABLE 3 Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998

	1998-1999 §		1999-2000 §		2000-2001 §
	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs
	N = 66	N = 44	N = 76	N = 34	N = 75	N = 35
Adverse Events
Fatigue	8 (12%)	2 (5%)	8 (11%)	2 (6%)	5 (7%)	-
Back pain	4 (6%)	3 (7%)	-	-	-	-
Cough increased	2 (3%)	2 (5%)	-	-	-	-
Ecchymosis	4 (6%)	1 (2%)	4 (5%)	1 (3%)	5 (7%)	-
Fever	3 (5%)	-	-	-	-	-
Headache	12 (18%)	5 (11%)	22 (29%)	5 (15%)	14 (19%)	2 (6%)
Infection	3 (5%)	2 (5%)	-	-	-	-
Malaise	4 (6%)	4 (9%)	4 (5%)	1 (3%)	-	-
Migraine	4 (6%)	1 (2%)	-	-	-	-
Myalgia	4 (6%)	1 (2%)	-	-	-	-
Sweating	5 (8%)	1 (2%)	-	-	-	-
Rhinitis	3 (5%)	1 (2%)	-	-	5 (7%)	2 (6%)
Pharingitis	6 (9%)	1 (2%)	10 (13%)	-	6 (8%)	-
Arthralgia	-	-	-	2 (6%)	-	-
Injection site pain	16 (24%)	4 (9%)	16 (21%)	-	9 (12%)	-
Injection site ecchymosis	4 (6%)	1 (2%)	-	-	4 (5%)	-
Injection site mass	7 (11%)	1 (2%)	4 (5%)	-	8 (11%)	1 (3%)
Injection site edema	-	-	1 (1%)	2 (6%)	-	-
Injection site      inflammation	5 (8%)	2 (5%)	6 (8%)	-	7 (9%)	1 (3%)
Injection site reaction	-	-	-	-	4 (5%)	1 (3%)

Results reported to the nearest whole percent; Fever defined as >38°C
– not reaching the cut-off of 5%
§ Solicited adverse events reported by COSTART preferred term
^ Solicited adverse events reported by MEDDRA preferred term
	2001-2002 ^		2002-2003 ^		2004-2005 ^
	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs	18-64 yrs	≥ 65 yrs
	N = 75	N = 35	N = 107	N = 88	N = 74	N = 61
Adverse Events
Fatigue	5 (7%)	4 (11%)	11 (10%)	8 (9%)	4 (5%)	2 (3%)
Hypertension	-	-	1 (1%)	4 (5%)	-	-
Rinorrhea	-	-	2 (2%)	5 (6%)	-	-
Headache	20 (27%)	2 (6%)	35 (33%)	18 (20%)	12 (16%)	1 (2%)
Malaise	6 (8%)	1 (3%)	13 (12%)	8 (9%)	-	-
Myalgia	4 (5%)	1 (3%)	10 (9%)	4 (5%)	-	-
Sweating	3 (4%)	3 (9%)	2 (2%)	5 (6%)	-	-
Rhinitis	4 (5%)	-	-	-	-	-
Pharingitis	-	-	-	-	6 (8%)	-
Arthralgia	-	-	5 (5%)	4 (5%)	-	-
Sore throat	4 (5%)	1 (3%)	5 (5%)	4 (5%)	-	-
Injection site pain	13 (17%)	3 (9%)	14 (13%)	7 (8%)	6 (8%)	2 (3%)
Injection site ecchymosis	4 (5%)	1 (3%)	4 (4%)	4 (5%)	-	-
Injection site erythema	5 (7%)	2 (6%)	11 (10%)	5 (6%)	4 (5%)	-
Injection site mass	4 (5%)	1 (3%)	-	-	-	-
Injection site edema	-	-	6 (6%)	2 (2%)	4 (5%)	1 (2%)
Injection site induration	-	-	14 (13%)	3 (3%)	7 (9%)	-

Adults (18 to 64 years of age)

In adult subjects, solicited local adverse events occurred with similar frequency in all trials. The most common solicited adverse events occurring in the first 96 hours after administration (Tables 1 and 2) were associated with the injection site (such as pain, erythema, mass, induration and swelling) but were generally mild/moderate and transient. The most common solicited systemic adverse events were headache and myalgia.

The most common overall events in adult subjects (18-64 years of age) were headache, fatigue, injection site reactions (pain, mass, erythema, and induration) and malaise (Table 3).

Geriatric Subjects (65 years of age and older)

In geriatric subjects, solicited local and systemic adverse events occurred less frequently than in adult subjects. The most common solicited local and systemic adverse events were injection site pain, and headache (Tables 1 and 2). All were considered mild/moderate and were transient.

The most common overall events in elderly subjects (≥65 years of age) were headache and fatigue.

Only 11 serious adverse events in adult and geriatric subjects (18 years and older) have been reported to date from all the trials performed. These serious adverse events were a minor stroke experienced by a 67 year old subject 14 days after vaccination (1990), death of an 82 year old subject 35 days after vaccination (1990) in very early studies; death of a 72 year old subject 19 days after vaccination (1998-1999), a hospitalization for hemorrhoidectomy of a 38 year old male subject (1999-2000), a severe respiratory tract infection experienced by a 74 year old subject 12 days after vaccination (2002-2003), a planned transurethral resection of the prostate in a subject with prior history of prostatism (2004-2005), two cases of influenza (2005-2006), a drug overdose (2005-2006), cholelithiasis (2005-2006) and a nasal septal operation (2005-2006). None of these events were considered causally related to vaccination.

Clinical Trial Experience in Pediatric Subjects

In 1987 a clinical study was carried out in 38 "at risk" children aged between 4 and 12 years (17 females and 21 males). To record the safety of FLUVIRIN^®, participants recorded their symptoms on a diary card during the three days after vaccination and noted any further symptoms they thought were attributable to the vaccine. The only reactions recorded were tenderness at the site of vaccination in 21% of the participants on day 1, which was still present in 16% on day 2 and 5% on day 3. In one child, the tenderness was also accompanied by redness at the site of injection for two days. The reactions were not age-dependent and there was no bias towards the younger children.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6 - 47 months). Of these, 285 healthy subjects plus 41 "at risk" subjects received FLUVIRN^®. No serious adverse events were reported.

FLUVIRIN^® should only be used for the immunization of persons aged 4 years and over.

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use of FLUVIRIN^®. Because these reactions 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. Adverse events described here are included because: a) they represent reactions which are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) the frequency of reporting.

• Body as a whole: Local injection site reactions (including pain, pain limiting limb movement, redness, swelling, warmth, ecchymosis, induration), hot flashes/flushes; chills; fever; malaise; shivering; fatigue; asthenia; facial edema.
• Immune system disorders: Hypersensitivity reactions (including throat and/or mouth edema). In rare cases, hypersensitivity reactions have lead to anaphylactic shock and death.
• Cardiovascular disorders: Vasculitis (in rare cases with transient renal involvement), syncope shortly after vaccination.
• Digestive disorders: Diarrhea; nausea; vomiting; abdominal pain.
• Blood and lymphatic disorders: Local lymphadenopathy; transient thrombocytopenia.
• Metabolic and nutritional disorders: Loss of appetite.
• Musculoskeletal: Arthralgia; myalgia; myasthenia.
• Nervous system disorders: Headache; dizziness; neuralgia; paraesthesia; confusion; febrile convulsions; Guillain-Barr© Syndrome; myelitis (including encephalomyelitis and transverse myelitis); neuropathy (including neuritis); paralysis (including Bell's Palsy).
• Respiratory disorders: Dyspnea; chest pain; cough; pharyngitis; rhinitis.
• Skin and appendages: Stevens-Johnson syndrome; sweating; pruritus; urticaria; rash (including non-specific, maculopapular, and vesiculobulbous).