Fluvirin

Fluvirin is an inactivated influenza virus vaccine for persons 4 years of age and older against influenza virus disease caused by influenza virus.

Fluvirin is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group.

This vaccine may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Novartis Vaccines and Diagnostics Limited

Fluvirin is part of the drug class:

• Influenza vaccines

Medications can interact with certain foods in your diet. In some cases, this may be harmful and your doctor may advise you to avoid eating certain foods. In the case of Fluvirin, there are no specific foods that you must exclude from your diet when receiving this vaccination.

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.

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 2 and 3). 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 4.

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 2 and 3) 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 4).

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 2 and 3). 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

TABLE 2 : 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

TABLE 3 : Solicited Adverse Events in the First 72 Hours After Administration of FLUVIRIN® in Adult Subjects (18-49 years of age).

TABLE 4 : Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998

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.

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 FLUVIRIN®. 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), presyncope, syncope shortly after vaccination.
• Digestive disorders: Diarrhea; nausea; vomiting; abdominal pain.
• Blood and lymphatic disorders: Local lymphadenopathy; thrombocytopenia (some very rare cases were severe with platelet counts less than 5,000 per mm³).
• 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 nonspecific, maculopapular, and vesiculobulbous).
• General disorders and administration site conditions: Injection site cellulitis- like reaction (very rare cases of swelling, pain, and redness were large and extended to the entire arm)

Other Adverse Reactions Associated With Influenza Vaccination

Anaphylaxis has been reported after administration of FLUVIRIN®. Although FLUVIRIN® contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS].

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barr� 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 polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination.

Read the entire FDA prescribing information for Fluvirin (Influenza Virus Vaccine)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• A burning, numbness, or tingling feeling that is not normal.
• Not able to move face muscles as much.
• Trouble controlling body movements.
• Very bad dizziness or passing out.
• Muscle weakness.
• Seizures.
• Very bad headache.
• Change in eyesight.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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.

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-Barré 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).

Other Adverse Reactions Associated with Influenza Vaccination

Anaphylaxis has been reported after administration of Fluvirin®. Although Fluvirin® contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS (4)].

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

Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some human studies, antibody titer of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects [see REFERENCES (15.1, 15.2)].

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year [see REFERENCES (15.3)].

15.1      Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004; 103:133-138.

15.2      Hobson D, Curry RL, Beare A, et. al. The role of serum hemagglutinin-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.

15.3      Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008; 57(RR-7):1-64.