INACTIVATED
INFLUENZA
VACCINE
WHAT YOU NEED TO KNOW 1
Why get vaccinated?
3
Influenza (“flu”) is a contagious disease. It is caused by the influenza virus, which spreads from infected persons to the nose or throat of others. Other illnesses can have the same symptoms and are often mistaken for influenza. But only an illness caused by the influenza virus is really influenza.
2007-08
Who should get inactivated influenza vaccine?
People 6 months of age and older can receive inactivated influenza vaccine. It is recommended for anyone who is at risk of complications from influenza or more likely to require medical care: • All children from 6 months up to 5 years of age. • Anyone 50 years of age or older.
Anyone can get influenza, but rates of infection are highest among children. For most people, it lasts only a few days. It can cause:
• Anyone 6 months to 18 years of age on long-term aspirin treatment (they could develop Reye Syndrome if they got influenza).
· fever · cough
• Women who will be pregnant during influenza season.
· sore throat · headache
· chills · muscle aches
· fatigue
Some people get much sicker. Influenza can lead to pneumonia and can be dangerous for people with heart or breathing conditions. It can cause high fever and seizures in children. On average, 226,000 people are hospitalized every year because of influenza and 36,000 die – mostly elderly. Influenza vaccine can prevent influenza.
• Anyone with long-term health problems with: - heart disease - kidney disease - lung disease - metabolic disease, such as diabetes - asthma - anemia, and other blood disorders • Anyone with a weakened immune system due to: - HIV/AIDS or other diseases affecting the immune system - long-term treatment with drugs such as steroids - cancer treatment with x-rays or drugs
There are two types of influenza vaccine:
• Anyone with certain muscle or nerve disorders (such as seizure disorders or severe cerebral palsy) that can lead to breathing or swallowing problems.
Inactivated (killed) vaccine, or the “flu shot” is given by injection into the muscle.
• Residents of nursing homes and other chronic-care facilities.
2
Inactivated Influenza vaccine
Live, attenuated (weakened) influenza vaccine, called LAIV, is sprayed into the nostrils. This vaccine is described in a separate Vaccine Information Statement. For most people influenza vaccine prevents serious influenzarelated illness. But it will not prevent “influenza-like” illnesses caused by other viruses. Influenza viruses are always changing. Because of this, influenza vaccines are updated every year, and an annual vaccination is recommended. Protection lasts up to a year. It takes up to 2 weeks for protection to develop after the vaccination. Some inactivated influenza vaccine contains thimerosal, a preservative that contains mercury. Some people believe thimerosal may be related to developmental problems in children. In 2004 the Institute of Medicine published a report concluding that, based on scientific studies, there is no evidence of such a relationship. If you are concerned about thimerosal, ask your doctor about thimerosal-free influenza vaccine.
Influenza vaccine is also recommended for anyone who lives with or cares for people at high risk for influenzarelated complications: • Health care providers. • Household contacts and caregivers of children from birth up to 5 years of age. • Household contacts and caregivers of people 50 years and older, and those with medical conditions that put them at higher risk for severe complications from influenza. A yearly influenza vaccination should be considered for: • People who provide essential community services. • People living in dormitories or under other crowded conditions, to prevent outbreaks. • People at high risk of influenza complications who travel to the Southern hemisphere between April and September, or to the tropics or in organized tourist groups at any time. Influenza vaccine is also recommended for anyone who wants to reduce the likelihood of becoming ill with influenza or spreading influenza to others.
4
When should I get influenza vaccine?
Plan to get influenza vaccine in October or November if you can. But getting vaccinated in December, or even later, will still be beneficial in most years. You can get the vaccine as soon as it is available, and for as long as illness is occurring. Influenza illness can occur any time from November through May. Most cases usually occur in January or February. Most people need one dose of influenza vaccine each year. Children younger than 9 years of age getting influenza vaccine for the first time should get 2 doses. For inactivated vaccine, these doses should be given at least 4 weeks apart. Influenza vaccine may be given at the same time as other vaccines, including pneumococcal vaccine.
5
Some people should talk with a doctor before getting influenza vaccine
Some people should not get inactivated influenza vaccine or should wait before getting it. • Tell your doctor if you have any severe (life-threatening) allergies. Allergic reactions to influenza vaccine are rare. - Influenza vaccine virus is grown in eggs. People with a severe egg allergy should not get the vaccine. - A severe allergy to any vaccine component is also a reason to not get the vaccine. - If you have had a severe reaction after a previous dose of influenza vaccine, tell your doctor. • Tell your doctor if you ever had Guillain-Barré Syndrome (a severe paralytic illness, also called GBS). You may be able to get the vaccine, but your doctor should help you make the decision. • People who are moderately or severely ill should usually wait until they recover before getting flu vaccine. If you are ill, talk to your doctor or nurse about whether to reschedule the vaccination. People with a mild illness can usually get the vaccine.
6
What are the risks from inactivated influenza vaccine?
A vaccine, like any medicine, could possibly cause serious problems, such as severe allergic reactions. The risk of a vaccine causing serious harm, or death, is extremely small. Serious problems from influenza vaccine are very rare. The viruses in inactivated influenza vaccine have been killed, so you cannot get influenza from the vaccine.
Severe problems: • Life-threatening allergic reactions from vaccines are very rare. If they do occur, it is usually within a few minutes to a few hours after the shot. • In 1976, a certain type of influenza (swine flu) vaccine was associated with Guillain-Barré Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS. However, if there is a risk of GBS from current flu vaccines, it would be no more than 1 or 2 cases per million people vaccinated. This is much lower than the risk of severe influenza, which can be prevented by vaccination.
7
What if there is a severe reaction?
What should I look for? Any unusual condition, such as a high fever or behavior changes. Signs of a serious allergic reaction can include difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, a fast heart beat or dizziness. What should I do? Call a doctor, or get the person to a doctor right away. • Tell your doctor what happened, the date and time it happened, and when the vaccination was given. • Ask your doctor, nurse, or health department to report the reaction by filing a Vaccine Adverse Event Reporting System (VAERS) form. Or you can file this report through the VAERS web site at www.vaers.hhs.gov, or by calling 1-800-822-7967. VAERS does not provide medical advice.
8
The National Vaccine Injury Compensation Program
In the event that you or your child has a serious reaction to a vaccine, a federal program has been created to help pay for the care of those who have been harmed. For details about the National Vaccine Injury Compensation Program, call 1-800-338-2382 or visit their website at www.hrsa.gov/vaccinecompensation.
9
How can I learn more?
• Ask your immunization provider. They can give you the vaccine package insert or suggest other sources of information. • Call your local or state health department. • Contact the Centers for Disease Control and Prevention (CDC): - Call 1-800-232-4636 (1-800-CDC-INFO) - Visit CDC’s website at www.cdc.gov/flu
Mild problems: • soreness, redness, or swelling where the shot was given • fever • aches If these problems occur, they usually begin soon after the shot and last 1-2 days. Vaccine Information Statement Inactivated Influenza Vaccine (7/16/07) 42 U.S.C. §300aa-26
department of health and human services Centers for Disease Control and Prevention
INACTIVATED
INFLUENZA
VACCINE
WHAT YOU NEED TO KNOW
2008-09
Many Vaccine Information Statements are available in Spanish and other languages. See www.immunize.org/vis.
1
Why get vaccinated?
3
Influenza (“flu”) is a contagious disease.
Who should get inactivated influenza vaccine?
All children 6 months and older and all older adults:
It is caused by the influenza virus, which can be spread by coughing, sneezing, or nasal secretions.
• All children from 6 months through 18 years of age.
Other illnesses can have the same symptoms and are often mistaken for influenza. But only an illness caused by the influenza virus is really influenza.
Anyone who is at risk of complications from influenza, or more likely to require medical care:
Anyone can get influenza, but rates of infection are highest among children. For most people, it lasts only a few days. It can cause: · fever · cough
· sore throat · headache
· chills · muscle aches
· fatigue
Some people get much sicker. Influenza can lead to pneumonia and can be dangerous for people with heart or breathing conditions. It can cause high fever, diarrhea and seizures in children. On average, 226,000 people are hospitalized every year because of influenza and 36,000 die – mostly elderly. Influenza vaccine can prevent influenza.
2
Inactivated influenza vaccine
There are two types of influenza vaccine: 1. Inactivated (killed) vaccine, or the “flu shot” is given by injection into the muscle. 2. Live, attenuated (weakened) influenza vaccine is sprayed into the nostrils. This vaccine is described in a separate Vaccine Information Statement. Influenza viruses are always changing. Because of this, influenza vaccines are updated every year, and an annual vaccination is recommended. Each year scientists try to match the viruses in the vaccine to those most likely to cause flu that year. When there is a close match the vaccine protects most people from serious influenzarelated illness. But even when the there is not a close match, the vaccine provides some protection. Influenza vaccine will not prevent “influenza-like” illnesses caused by other viruses. It takes up to 2 weeks for protection to develop after the shot. Protection lasts up to a year. Some inactivated influenza vaccine contains a preservative called thimerosal. Some people have suggested that thimerosal may be related to developmental problems in children. In 2004 the Institute of Medicine reviewed many studies looking into this theory and concluded that there is no evidence of such a relationship. Thimerosal-free influenza vaccine is available.
• Anyone 50 years of age or older.
• Women who will be pregnant during influenza season. • Anyone with long-term health problems with: - heart disease - kidney disease - liver disease - lung disease - metabolic disease, such as diabetes - asthma - anemia, and other blood disorders • Anyone with a weakened immune system due to: - HIV/AIDS or other diseases affecting the immune system - long-term treatment with drugs such as steroids - cancer treatment with x-rays or drugs • Anyone with certain muscle or nerve disorders (such as seizure disorders or cerebral palsy) that can lead to breathing or swallowing problems. • Anyone 6 months through 18 years of age on long-term aspirin treatment (they could develop Reye Syndrome if they got influenza). • Residents of nursing homes and other chronic-care facilities. Anyone who lives with or cares for people at high risk for influenza-related complications: • Health care providers. • Household contacts and caregivers of children from birth up to 5 years of age. • Household contacts and caregivers of - people 50 years and older, or - anyone with medical conditions that put them at higher risk for severe complications from influenza. Health care providers may also recommend a yearly influenza vaccination for: • People who provide essential community services. • People living in dormitories, correctional facilities, or under other crowded conditions, to prevent outbreaks. • People at high risk of influenza complications who travel to the Southern hemisphere between April and September, or to the tropics or in organized tourist groups at any time. Influenza vaccine is also recommended for anyone who wants to reduce the likelihood of becoming ill with influenza or spreading influenza to others.
4
When should I get influenza vaccine?
Plan to get influenza vaccine in October or November if you can. But getting vaccinated in December, or even later, will still be beneficial in most years. You can get the vaccine as soon as it is available, and for as long as illness is occurring in your community. Influenza can occur any time from November through May, but it most often peaks in January or February. Most people need one dose of influenza vaccine each year. Children younger than 9 years of age getting influenza vaccine for the first time – or who got influenza vaccine for the first time last season but got only one dose – should get 2 doses, at least 4 weeks apart, to be protected. Influenza vaccine may be given at the same time as other vaccines, including pneumococcal vaccine.
5
Some people should talk with a doctor before getting influenza vaccine
Some people should not get inactivated influenza vaccine or should wait before getting it. • Tell your doctor if you have any severe (life-threatening) allergies. Allergic reactions to influenza vaccine are rare. - Influenza vaccine virus is grown in eggs. People with a severe egg allergy should not get the vaccine. - A severe allergy to any vaccine component is also a reason to not get the vaccine. - If you have had a severe reaction after a previous dose of influenza vaccine, tell your doctor. • Tell your doctor if you ever had Guillain-Barré Syndrome (a severe paralytic illness, also called GBS). You may be able to get the vaccine, but your doctor should help you make the decision. • People who are moderately or severely ill should usually wait until they recover before getting flu vaccine. If you are ill, talk to your doctor or nurse about whether to reschedule the vaccination. People with a mild illness can usually get the vaccine.
6
What are the risks from inactivated influenza vaccine?
A vaccine, like any medicine, could possibly cause serious problems, such as severe allergic reactions. The risk of a vaccine causing serious harm, or death, is extremely small. Serious problems from influenza vaccine are very rare. The viruses in inactivated influenza vaccine have been killed, so you cannot get influenza from the vaccine.
Severe problems: • Life-threatening allergic reactions from vaccines are very rare. If they do occur, it is usually within a few minutes to a few hours after the shot. • In 1976, a type of influenza (swine flu) vaccine was associated with Guillain-Barré Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS. However, if there is a risk of GBS from current flu vaccines, it would be no more than 1 or 2 cases per million people vaccinated. This is much lower than the risk of severe influenza, which can be prevented by vaccination.
7
What if there is a severe reaction?
What should I look for? • Any unusual condition, such as a high fever or behavior changes. Signs of a serious allergic reaction can include difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, a fast heart beat or dizziness. What should I do? • Call a doctor, or get the person to a doctor right away. • Tell your doctor what happened, the date and time it happened, and when the vaccination was given. • Ask your doctor, nurse, or health department to report the reaction by filing a Vaccine Adverse Event Reporting System (VAERS) form. Or you can file this report through the VAERS web site at www.vaers.hhs.gov, or by calling 1-800-822-7967. VAERS does not provide medical advice.
8
The National Vaccine Injury Compensation Program
A federal program exists to help pay for the care of anyone who has a serious reaction to a vaccine. For more information about the National Vaccine Injury Compensation Program, call 1-800-338-2382 or visit their website at www.hrsa.gov/vaccinecompensation.
9
How can I learn more?
• Ask your immunization provider. They can give you the vaccine package insert or suggest other sources of information. • Call your local or state health department. • Contact the Centers for Disease Control and Prevention (CDC): - Call 1-800-232-4636 (1-800-CDC-INFO) - Visit CDC’s website at www.cdc.gov/flu
Mild problems: • soreness, redness, or swelling where the shot was given • fever • aches If these problems occur, they usually begin soon after the shot and last 1-2 days. Vaccine Information Statement Inactivated Influenza Vaccine (7/24/08) 42 U.S.C. §300aa-26
department of health and human services Centers for Disease Control and Prevention
Novartis Vaccines and Diagnostics Limited July 2008
BLA 1750
Influenza Virus Vaccine Fluvirin® 2008-2009 FORMULA HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUVIRIN® (Influenza Virus Vaccine) safely and effectively. See full prescribing information for FLUVIRIN®. FLUVIRIN® (Influenza Virus Vaccine) Suspension for Intramuscular Injection 2008-2009 Formula Initial US Approval: 1988 INDICATIONS AND USAGE • FLUVIRIN® is an inactivated influenza virus vaccine indicated for active immunization of persons 4 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine (1). • FLUVIRIN® is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group (8.4). DOSAGE AND ADMINISTRATION Children • 4 to 8 years of age: 0.5-mL dose via intramuscular injection, one or two doses. Previously unvaccinated children 4 to 8 years of age should receive two 0.5-mL doses, one on day 1 followed by another 0.5-mL injection at least 1 month later (2.2). Children 4 to 8 years of age who have been previously vaccinated with one or two doses of any influenza virus vaccine should receive only one 0.5-mL dose (2.2). • 9 years and older: A single 0.5-mL intramuscular injection (2.2). Adults • A single 0.5-mL intramuscular injection (2.2). DOSAGE FORMS AND STRENGTHS FLUVIRIN®, a sterile suspension for intramuscular injection, is supplied in two presentations: • Prefilled syringe, 0.5-mL. Thimerosal, a mercury derivative used during manufacture, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose). (3, 11) • Multidose vial, 5-mL. Contains thimerosal, a mercury derivative (25 mcg mercury per 0.5-mL dose). Thimerosal is added as a preservative. (3,11) Each 0.5-mL dose contains a total of 45 micrograms (mcg) of influenza virus hemagglutinin (HA) from each of the following 3 strains: A/Brisbane/59/2007 (H1N1); A/Uruguay/716/2007 (H3N2), an A/Brisbane/10/2007-like strain; and B/Florida/4/2006. (3, 11)
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CONTRAINDICATIONS • History of systemic hypersensitivity reactions to egg proteins, or any other component of FLUVIRIN®, or life-threatening reactions to previous influenza vaccinations. (4.1, 11) WARNINGS AND PRECAUTIONS • If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUVIRIN® should be based on careful consideration of the potential benefits and risks. (5.1) • Immunocompromised persons may have a reduced immune response to FLUVIRIN®. (5.2) ADVERSE REACTIONS The most frequently reported adverse reactions are mild hypersensitivity reactions (such as rash), local reactions at the injection site, and influenza-like symptoms. (6) To report SUSPECTED ADVERSE REACTIONS contact Novartis Vaccines at 1800-244-7668, or VAERS at 1-800-822-7967 and www.vaers.hhs.gov. DRUG INTERACTIONS • Do not mix with any other vaccine in the same syringe or vial. (7.1) • Immunosuppressive therapies may reduce immune response to FLUVIRIN®. (7.2) USE IN SPECIFIC POPULATIONS • Safety and effectiveness of FLUVIRIN® have not been established in pregnant women, nursing mothers or children less than 4 years of age. (8.1, 8.3, 8.4) • Antibody responses were lower in the geriatric population than in younger subjects. (8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: July 2008
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FULL PRESCRIBING INFORMATION: CONTENTS* 1 2 3 4 5
6
7 8
11 12 13 14
15 16 17
INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Recommended Dose and Schedule DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS 4.1 Hypersensitivity WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome 5.2 Altered Immunocompetence 5.3 Preventing and Managing Allergic Reactions 5.4 Limitations of Vaccine Effectiveness ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile 6.2 Clinical Trial Experience 6.3 Postmarketing Experience 6.4 Other Adverse Reactions Associated with Influenza Vaccination DRUG INTERACTIONS 7.1 Concomitant Administration with Other Vaccines 7.2 Concurrent Use with Immunosuppressive Therapies USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1 Immunogenicity in Adults (18 to 64 years of age) 14.2 Immunogenicity in Geriatric Subjects (65 years of age and over) 14.3 Immunogenicity in Pediatric Subjects REFERENCES HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
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FULL PRESCRIBING INFORMATION 1
INDICATIONS AND USAGE FLUVIRIN® is an inactivated influenza virus vaccine indicated for immunization of persons 4 years of age and older against influenza virus disease caused by influenza virus subtypes A and type B contained in the vaccine. [see DOSAGE FORMS AND STRENGTHS (3)] FLUVIRIN® is not indicated for children less than 4 years of age because there is evidence of diminished immune response in this age group. 2 2.1
DOSAGE AND ADMINISTRATION Preparation for Administration Inspect FLUVIRIN® syringes and multidose vials visually for particulate matter and/or discoloration prior to administration. If either of these conditions exists, the vaccine should not be administered. Shake the syringe vigorously before administering the vaccine and shake the multidose vial preparation each time before withdrawing a dose of vaccine. Between uses, return the multidose vial to the recommended storage conditions between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen. A separate syringe and needle or a sterile disposable unit should be used for each injection to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and not recapped. It is recommended that small syringes (0.5-mL or 1-mL) should be used to minimize any product loss. 2.2
Recommended Dose and Schedule Children (4 to 17 years of age): For children 4 to 8 years of age, who have not previously been vaccinated with an influenza vaccine, FLUVIRIN® should be given as a 0.5-mL intramuscular injection on day 1 followed by another 0.5-mL intramuscular injection at least 1 month later. If a child between the ages of 4 and 8 years does not receive a second dose of vaccine within the same season, only one dose of vaccine should be administered the following season. (15.3) Children, 4 to 8 years of age, who have been vaccinated in preceding year(s) with one or two doses of any influenza virus vaccine should receive only one dose. (15.3) Children over the age of 9 should receive a single 0.5-mL intramuscular injection. The needle size may range from 7/8 to 1¼ inches, depending on the size of the child’s deltoid muscle, and should be of sufficient length to penetrate the muscle tissue. The anterolateral thigh can be used, but the needle should be longer, usually 1 inch. Adults (18 years and older): FLUVIRIN® should be administered as a single 0.5-mL intramuscular injection preferably in the region of the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal region or areas where there may be a major nerve trunk. A needle of ≥1 inch is preferred because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults.
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3
DOSAGE FORMS AND STRENGTHS FLUVIRIN® is a sterile, suspension for intramuscular injection. Each 0.5-mL dose contains a total of 45 mcg hemagglutinin from the 3 influenza virus types in the vaccine. [see DESCRIPTION (11)] FLUVIRIN® is available in two presentations: 1) Prefilled syringe, 0.5-mL. Thimerosal, a mercury derivative used during manufacture, is removed by subsequent purification steps to a trace amount (≤1 mcg mercury per 0.5-mL dose). 2) Multidose vial, 5-mL. Contains thimerosal, a mercury derivative, added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury. 4 4.1
CONTRAINDICATIONS Hypersensitivity FLUVIRIN® should not be administered to anyone with known systemic hypersensitivity reactions to egg proteins (eggs or egg products), or to any component of FLUVIRIN®, or who has had a life-threatening reaction to previous influenza vaccinations. 5 5.1
WARNINGS AND PRECAUTIONS Guillain-Barré Syndrome If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUVIRIN® should be based on careful consideration of the potential benefits and risks. 5.2
Altered Immunocompetence If FLUVIRIN® is administered to immunocompromised persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained. 5.3
Preventing and Managing Allergic Reactions Prior to administration of any dose of FLUVIRIN®, the healthcare provider should review the patient’s prior immunization history for possible adverse events, to determine the existence of any contraindication to immunization with FLUVIRIN® and to allow an assessment of benefits and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.
5.4
Limitations of Vaccine Effectiveness Vaccination with FLUVIRIN® may not protect all individuals.
6 6.1
ADVERSE REACTIONS Overall Adverse Reaction Profile Serious allergic reactions, including anaphylactic shock, have been observed in individuals receiving FLUVIRIN® during postmarketing surveillance.
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6.2
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.
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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. *§
Local Adverse Events Pain Mass Inflammation Ecchymosis Edema Reaction Hemorrhage Systemic Adverse Events Headache Fatigue Malaise Myalgia Fever Arthralgia Sweating
*§
*§
1998-1999 18-64 yrs ≥ 65 yrs N = 66 N = 44
1999-2000 18-64 yrs ≥ 65 yrs N = 76 N = 34
16 (24%) 7 (11%) 5 (8%) 4 (6%) 2 (3%) 2 (3%) -
4 (9%) 1 (2%) 2 (5%) 1 (2%) 1 (2%) -
16 (21%) 4 (5%) 6 (8%) 3 (4%) 1 (1%) 2 (3%) 1 (1%)
1 (3%) 2 (6%) -
9 (12%) 8 (11%) 7 (9%) 4 (5%) 3 (4%) 4 (5%) -
1 (3%) 1 (3%) 1 (3%) 1 (3%) -
7 (11%) 3 (5%) 2 (3%) 1 (2%) 1 (2%) -
1 (2%) 2 (5%) 1 (2%) 1 (2%) -
17 (22%) 4 (5%) 2 (3%) 2 (3%) 1 (1%) 3 (4%)
3 (9%) 1 (3%) 1 (3%) 1 (3%) -
4 (5%) 3 (4%) 1 (1%) 1 (1%)
1 (3%)
*^
2001-2002 18-64 yrs ≥ 65 yrs N = 75 N = 35
*^
2002-2003 18-64 yrs ≥ 65 yrs N = 107 N = 88
2000-2001 18-64 yrs ≥ 65 yrs N = 75 N = 35
^
2004-2005 18-64 yrs ≥ 65 yrs N = 74 N = 61
Local Adverse Events Pain 12 (16%) 1 (3%) 14 (13%) 7 (8%) 15 (20%) Mass 4 (5%) 1 (3%) Ecchymosis 2 (3%) 3 (3%) 3 (3%) 2 (3%) Edema 2 (3%) 1 (3%) 6 (6%) 2 (2%) Erythema 5 (7%) 11 (10%) 5 (6%) 16 (22%) Swelling 11 (15%) Reaction 2 (2%) Induration 14 (13%) 3 (3%) 11 (15%) Pruritus 1 (1%) Systemic Adverse Events Headache 8 (11%) 1 (3%) 12 (11%) 9 (10%) 14 (19%) Fatigue 1 (1%) 1 (3%) 5 (7%) Malaise 3 (4%) 3 (3%) 4 (5%) 1 (1%) Myalgia 3 (4%) 5 (5%) 3 (3%) 8 (11%) Fever 1 (1%) Arthralgia 2 (2%) 1 (1%) Sweating 3 (4%) 1 (3%) 2 (2%) Shivering 1 (1%) 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 Vial and Syringe leaflet text
9 (15%) 1 (2%) 5 (8%) 4 (7%) 1 (2%) 3 (5%) 2 (3%) 1 (2%) 1 (2%) -
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TABLE 2 Solicited Adverse Events in the First 72 Hours After Administration of FLUVIRIN® in Adult Subjects (18-49 years of age). 2005-2006 US Trial FLUVIRIN® N = 304 Local Adverse Events Pain Erythema Ecchymosis Induration Swelling Systemic Adverse Events Headache Myalgia Malaise Fatigue Sore throat Chills Nausea Arthralgia Sweating Cough Wheezing Chest tightness Other difficulties breathing Facial edema Results reported to the nearest whole percent – not reported
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168 (55%) 48 (16%) 22 (7%) 19 (6%) 16 (5%) 91 (30%) 64 (21%) 58 (19%) 56 (18%) 23 (8%) 22 (7%) 21 (7%) 20 (7%) 17 (6%) 18 (6%) 4 (1%) 4 (1%) 3 (1%) -
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TABLE 3 Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998 §
Adverse Events Fatigue Back pain Cough increased Ecchymosis Fever Headache Infection Malaise Migraine Myalgia Sweating Rhinitis Pharingitis Arthralgia Injection site pain Injection site ecchymosis Injection site mass Injection site edema Injection site inflammation Injection site reaction
§
§
1998-1999 18-64 yrs ≥ 65 yrs N = 66 N = 44
1999-2000 18-64 yrs ≥ 65 yrs N = 76 N = 34
2000-2001 18-64 yrs ≥ 65 yrs N = 75 N = 35
8 (12%) 4 (6%) 2 (3%) 4 (6%) 3 (5%) 12 (18%) 3 (5%) 4 (6%) 4 (6%) 4 (6%) 5 (8%) 3 (5%) 6 (9%) 16 (24%) 4 (6%) 7 (11%) 5 (8%)
2 (5%) 3 (7%) 2 (5%) 1 (2%) 5 (11%) 2 (5%) 4 (9%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 4 (9%) 1 (2%) 1 (2%) 2 (5%)
8 (11%) 4 (5%) 22 (29%) 4 (5%) 10 (13%) 16 (21%) 4 (5%) 1 (1%) 6 (8%)
2 (6%) 1 (3%) 5 (15%) 1 (3%) 2 (6%) 2 (6%) -
5 (7%) 5 (7%) 14 (19%) 5 (7%) 6 (8%) 9 (12%) 4 (5%) 8 (11%) 7 (9%)
2 (6%) 2 (6%) 1 (3%) 1 (3%)
-
-
-
-
4 (5%)
1 (3%)
^
2001-2002 18-64 yrs ≥ 65 yrs N = 75 N = 35
^
2002-2003 18-64 yrs ≥ 65 yrs N = 107 N = 88
Adverse Events Fatigue 5 (7%) 4 (11%) 11 (10%) 8 (9%) Hypertension 1 (1%) 4 (5%) Rinorrhea 2 (2%) 5 (6%) Headache 20 (27%) 2 (6%) 35 (33%) 18 (20%) 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 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%) Injection site ecchymosis 4 (5%) 1 (3%) 4 (4%) 4 (5%) Injection site erythema 5 (7%) 2 (6%) 11 (10%) 5 (6%) Injection site mass 4 (5%) 1 (3%) Injection site edema 6 (6%) 2 (2%) Injection site induration 14 (13%) 3 (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 Vial and Syringe leaflet text
^
2004-2005 18-64 yrs ≥ 65 yrs N = 74 N = 61 4 (5%) 12 (16%) 6 (8%) 6 (8%) 4 (5%) 4 (5%) 7 (9%)
2 (3%) 1 (2%) 2 (3%) 1 (2%) -
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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. 6.3
Postmarketing Experience The following additional adverse reactions have been reported during postapproval use of FLUVIRIN®. Because these reactions are reported voluntarily from a Vial and Syringe leaflet text
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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).
6.4
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. 7 7.1
DRUG INTERACTIONS Concomitant Administration with Other Vaccines There are no data to assess the concomitant administration of FLUVIRIN® with other vaccines. If FLUVIRIN® is to be given at the same time as another injectable vaccine(s), the vaccines should always be administered at different injection sites. FLUVIRIN® should not be mixed with any other vaccine in the same syringe or vial. Vial and Syringe leaflet text
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7.2
Concurrent Use with Immunosuppressive Therapies Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to FLUVIRIN®.
8 8.1
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with FLUVIRIN®. It is also not known whether FLUVIRIN® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. FLUVIRIN® should be given to a pregnant woman only if clearly needed. 8.3
Nursing Mothers It is not known whether FLUVIRIN® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUVIRIN® is administered to a nursing woman. 8.4
Pediatric Use The safety and immunogenicity of FLUVIRIN® have not been established in children under 4 years of age. The safety and immunogenicity of FLUVIRIN® have been established in the age group 4 years to 16 years. The use of FLUVIRIN® in these age groups is supported by evidence from adequate and well controlled studies of FLUVIRIN® in adults that demonstrate the immunogenicity of FLUVIRIN® [see ADVERSE REACTIONS (6) and CLINICAL STUDIES (14)]. 8.5
Geriatric Use Since 1997, of the total number of geriatric subjects (n = 397) in clinical studies of FLUVIRIN®, 29% were 65 years and over, while 2.1% were 75 years and over. Antibody responses were lower in the geriatric population than in younger subjects. Adverse events occurred less frequently in geriatric subjects (≥65 years) than in younger adults. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. [See ADVERSE REACTION (6) and CLINICAL STUDIES (14)]. 11
DESCRIPTION FLUVIRIN® is a trivalent, sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with betapropiolactone. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of nonylphenol ethoxylate, a process which removes most of the internal proteins. The nonylphenol ethoxylate is removed from the surface antigen preparation. FLUVIRIN® is a homogenized, sterile, slightly opalescent suspension in a phosphate buffered saline. FLUVIRIN® has been standardized according to USPHS requirements for the 2008-2009 influenza season and is formulated to contain 45 mcg
Vial and Syringe leaflet text
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hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 strains: A/Brisbane/59/2007(H1N1); A/Uruguay/716/2007 (H3N2), an A/Brisbane/10/2007-like strain; and B/Florida/4/2006. The 0.5-mL prefilled syringe presentation is formulated without preservative. However, thimerosal, a mercury derivative used during manufacturing, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose). The 5-mL multidose vial formulation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury. Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), polymyxin (≤ 3.75 mcg), neomycin (≤ 2.5 mcg), betapropiolactone (not more than 0.5 mcg) and nonylphenol ethoxylate (not more than 0.015% w/v). The multidose vial stopper and the syringe stopper/plunger do not contain latex. 12 12.1
CLINICAL PHARMACOLOGY 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)]. 13 13.1
NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility FLUVIRIN® has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. 14
CLINICAL STUDIES Between 1982 and 1991, twelve clinical studies were conducted in healthy adult and geriatric subjects and one in children between 4 and 12 years of age who were considered to be ‘at risk’. Since 1991 an annual clinical study has been conducted in the UK in healthy adults aged 18 years or older. FLUVIRIN® was also used as a control in a US clinical trial in adults (18-49 years of age). In all the trials, blood samples were taken Vial and Syringe leaflet text
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prior to vaccination and approximately three weeks after vaccination to assess the immunogenic response to vaccination by measurement of anti-HA antibodies. Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-48 months). Of these, 285 healthy subjects plus 41 ‘at risk’ pediatric subjects, received FLUVIRIN®. FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. 14.1
Immunogenicity in Adults (18 to 64 years of age) Tables 4 and 5 show the immunogenicity data for the adult age group. The seven clinical studies presented enrolled a total of 774 adult subjects. In the adult group, for all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 40%; the geometric mean titer (GMT) increase was >2.5; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 70%.
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TABLE 4 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Adult Subjects Year/Strain
No. of subjects
Seroconversion ∞ % 95% CIφ
HI titer ≥1:40¥ % 95% CIφ
n N 1998-1999 A/H1N1 48 73 (62, 83) 50 76 (65, 86) A/H3N2 66 43 65 (54, 77) 47 71 (60, 82) B 42 64 (52, 75) 62 94 (88, 100) 1999-2000 A/H1N1 45 59 (48, 70) 50 66 (55, 76) A/H3N2 76 51 67 (57, 78) 66 87 (79, 94) B 53 70 (59, 80) 75 99 (96, 100) 2000-2001 A/H1N1 41 55 (44, 67) 41 55 (44, 67) A/H3N2 74 45 61 (50, 72) 52 84 (75, 92) B 50 68 (57, 78) 73 99 (96, 100) 2001-2002 A/H1N1 44 59 (48, 70) 48 64 (53, 75) A/H3N2 75 46 61 (50, 72) 68 91 (84, 97) B 42 56 (45, 67) 66 88 (81, 95) 2002-2003 A/H1N1 62 58 (49, 68) 73 69 (60, 78) A/H3N2 106 72 68 (59, 77) 93 88 (81, 94) B 78 74 (65, 82) 101 95 (91, 99) 2004-2005 A/H1N1 52 70 (59, 80) 66 89 (80, 95) A/H3N2 74 60 81 (70, 89) 73 99 (93, 100) B 57 77 (66, 86) 69 93 (85, 98) 2005-2006 A/H1N1 191 63 (57, 68) 296 98 (95, 99) A/H3N2 303 273 90 (86, 93) 294 97 (94, 99) B 213 70 (65, 75) 263 87 (82, 90) ∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a prevaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer. ¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥ 1:40. φ 95% CI: 95% confidence interval
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TABLE 5 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Pre- and Post-Immunization, for Adult Subjects Year/Strain
No. of subjects
Prevaccination
1998-1999 A/H1N1 A/H3N2 66 B 1999-2000 A/H1N1 A/H3N2 76 B 2000-2001 A/H1N1 A/H3N2 74 B 2001-2002 A/H1N1 A/H3N2 75 B 2002-2003 A/H1N1 A/H3N2 106 B 2004-2005 A/H1N1 A/H3N2 74 B 2005-2006 A/H1N1 A/H3N2 303 B * 95% CI: 95% confidence interval
Geometric Mean Titer (GMT) PostFold Increase vaccination
(95% CI)*
7.26 8.23 20.97
160.87 87.02 231.07
22.16 10.57 110.2
(14.25, 34.46) (6.91, 16.16) (6.90, 17.59)
7.43 15.29 25.70
58.95 122.83 254.76
7.93 8.03 9.91
(5.73, 10.97) (5.80, 11.13) (6.97, 14.10)
5.42 15.98 26.24
33.80 126.01 308.25
6.24 7.89 11.75
(4.49, 8.69) (5.61, 11.09) (7.73, 17.85)
7.76 23.67 19.91
54.78 153.81 107.53
7.06 6.50 5.40
(5.24, 9.52) (4.78, 8.84) (3.95, 7.38)
7.78 23.32 30.20
60.39 292.03 314.11
7.77 12.52 10.40
(5.81, 10.39) (8.77, 17.87) (7.54, 14.34)
13 37 15
159 658 156
12 18 11
(8.39, 17) (12, 26) (7.87, 14)
29 14 13
232 221 83
8 15 6.5
(6.68, 9.59) (14, 17) (5.73, 7.37)
14.2
Immunogenicity in Geriatric Subjects (65 years of age and older) Tables 6 and 7 show the immunogenicity of FLUVIRIN® in the geriatric age group. The six clinical studies presented enrolled a total of 296 geriatric subjects. For each of the influenza antigens, the percentage of subjects who achieved seroconversion and the percentage of subjects who achieved HI titers of ≥1:40 are shown, as well as the fold increase in GMT. For all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (postvaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 30%; the geometric mean titer (GMT) increase was >2.0; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 60%. The pre-specified efficacy criteria were met in each study, although a relatively
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lower immunogenicity of A/H1N1 strain was seen in the last four studies (the same strain was in each of the formulations). TABLE 6 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Geriatric Subjects Year/Strain
No. of subjects
Seroconversion ∞ % 95% CIφ
HI titer ≥1:40¥ % 95% CIφ
N N 1998-1999 A/H1N1 33 79 (66, 91) 38 90 (82, 99) A/H3N2 42 33 79 (66, 91) 36 86 (75, 96) B 13 31 (17, 45) 42 100 (100, 100) 1999-2000 A/H1N1 10 29 (14, 45) 23 68 (52, 83) A/H3N2 34 18 53 (36, 70) 31 91 (82, 100) B 9 26 (12, 41) 32 94 (86, 100) 2000-2001 A/H1N1 5 14 (3, 26) 10 29 (14, 44) A/H3N2 35 22 63 (47, 79) 31 89 (78, 99) B 13 37 (21, 53) 33 94 (87, 100) 2001-2002 A/H1N1 5 14 (3, 26) 14 40 (24, 56) A/H3N2 35 15 43 (26, 59) 33 94 (87, 100) B 6 17 (5, 30) 32 91 (82, 100) 2002-2003 A/H1N1 24 27 (18, 36) 52 58 (48, 69) A/H3N2 89 42 47 (37, 58) 85 96 (91, 100) B 41 46 (36, 56) 86 97 (93, 100) 2004-2005 A/H1N1 17 28 (17, 41) 46 75 (63, 86) A/H3N2 61 29 48 (35, 61) 60 98 (91, 100) B 38 62 (49, 74) 51 84 (72, 92) ∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a prevaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer ¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥1:40 φ 95% CI: 95% confidence interval
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TABLE 7 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Pre- and Post-Immunization, for Geriatric Subjects Year/Strain
No. of subjects
Prevaccination
1998-1999 A/H1N1 A/H3N2 42 B 1999-2000 A/H1N1 A/H3N2 34 B 2000-2001 A/H1N1 A/H3N2 35 B 2001-2002 A/H1N1 A/H3N2 35 B 2002-2003 A/H1N1 A/H3N2 89 B 2004-2005 A/H1N1 A/H3N2 61 B * 95% CI: 95% confidence interval
Geometric Mean Titer (GMT) PostFold Increase vaccination
(95% CI)*
13.92 10.69 114.1
176.65 124.92 273.56
12.69 11.69 2.40
(8.24, 19.56) (7.02, 19.46) (1.82, 3.17)
15.82 28.00 57.16
50.58 133.19 127.86
3.20 4.76 2.24
(2.13, 4.80) (2.92, 7.76) (1.56, 3.20)
6.66 25.87 61.24
18.85 140.68 191.23
2.83 5.44 3.12
(1.91, 4.18) (3.72, 7.96) (2.13, 4.59)
12.69 47.33 45.49
26.65 114.26 91.89
2.10 2.41 2.02
(1.55, 2.84) (1.73, 3.38) (1.47, 2.78)
13.29 65.86 74.87
31.92 272.79 288.57
2.40 4.14 3.85
(1.90, 3.03) (3.09, 5.55) (2.89, 5.13)
21 72 20
64 320 114
3.13 4.43 5.69
(2.33, 4.2) (3.13, 6.27) (4.39, 7.38)
14.3
Immunogenicity in Pediatric Subjects A small-scale study, was conducted in 1987 to evaluate safety and immunogenicity of FLUVIRIN® in 38 ‘at risk’ children, with diabetes and/or asthma, or lymphoid leukemia. Thirty-eight participants aged between 4 and 12 years of age were assessed. Ten subjects had diabetes, 21 had asthma, two had both diabetes and asthma, and one had lymphoid leukemia. There were four healthy control subjects. All participants received a single 0.5-mL dose of FLUVIRIN®. Immunogenicity results were obtained for 19 of the 38 subjects enrolled in the study. The point estimate of the percentage of subjects achieving a titer of ≥ 1:40 was 84% for the A/H1N1 strain 79% for the B strain, and 53% for the A/H3N2 strain. The GMT fold increases were 5.8 for the A/H1N1 strain, 40 for the B strain and 17.7 for the A/H3N2 strain. 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’ pediatric subjects, received FLUVIRIN®. In a 1995/1996 clinical study, 41 subjects (aged 6-36 months) at increased risk for influenza-related complications received two 0.25-mL doses of FLUVIRIN®. At least 49% of subjects showed a ≥4-fold increase in HI antibody titer to all three strains. HI Vial and Syringe leaflet text
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antibody titers of 1:40 or greater were seen in at least 71% of the subjects for all three influenza strains, with increases in geometric mean titer of 6.0-fold or greater to all three strains. Two clinical studies (1999-2000 and 2004) indicated a lower immunogenicity profile for FLUVIRIN® compared with two commercial split vaccines; in a study in the age group 6-48 months the comparator was a US licensed vaccine, Fluzone®, and in another study in the age group 6-36 months the comparator was a non-US licensed inactivated influenza vaccine. Despite the small sample size (a total of 285 healthy subjects received FLUVIRIN® in these two clinical studies) the lower immunogenicity profile of FLUVIRIN® was greatest versus the comparator vaccines in children <36months but was also evident in those 36-48 months of age, though the differences were less. FLUVIRIN® should only be used for the immunization of persons aged 4 years and over. 15 15.1 15.2 15.3
REFERENCES Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138. 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 Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-10):1-42.
16 16.1
HOW SUPPLIED/STORAGE AND HANDLING How Supplied FLUVIRIN® is supplied as a 0.5-mL prefilled syringe, package of 10 prefilled syringes per carton. NDC 66521-111-01 FLUVIRIN® is supplied as a 5-mL multidose vial, individually packaged in a carton. NDC 66521-111-10 16.2 Storage and Handling Store FLUVIRIN® refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Do not use after the expiration date. Between uses, return the multidose vial to the recommended storage conditions. 17
PATIENT COUNSELING INFORMATION Vaccine recipients and guardians should be informed by their health care provider of the potential benefits and risks of immunization with FLUVIRIN®. When educating vaccine recipients and guardians regarding the potential side effects, clinicians should emphasize that (1) FLUVIRIN® contains non-infectious particles and cannot cause influenza and (2) FLUVIRIN® is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against all respiratory illness. Vaccine recipients and guardians should be instructed to report any severe or unusual adverse reactions to their healthcare provider. Vaccine recipients and guardians should be instructed that annual vaccination is recommended. Vial and Syringe leaflet text
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FLUVIRIN® is a registered trademark of Novartis Vaccines and Diagnostics Limited. Manufactured by: An affiliate of:
Novartis Vaccines and Diagnostics Limited, Speke, Liverpool, UK Novartis Vaccines and Diagnostics, Inc., 350 Massachusetts Avenue, Cambridge, MA 02139 USA 1-800-244-7668
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3111086-87-88 271/371
Page 1 of 4 AHFS Category 80:12
Fluzone®
Flu
Influenza Virus Vaccine
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Fluzone® (Influenza Virus Vaccine) safely and effectively. See full prescribing information for Fluzone.
Each 0.25 mL dose contains a total of 22.5 µg and each 0.5 mL dose contains a total of 45 µg of influenza virus hemaglutinin of each of the following 3 strains: A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (A/Brisbane/10/2007-like strain) (H3N2), and B/Florida/04/2006. (3, 11)
Fluzone® (Influenza Virus Vaccine) Suspension for Intramuscular Injection 2008-2009 Formula
CONTRAINDICATIONS • Severe hypersensitivity to egg proteins or any component of the vaccine or life-threatening reactions after previous administration of any influenza vaccine (4)
Initial US Approval: 1980 INDICATIONS AND USAGE Fluzone is a vaccine indicated for active immunization in persons 6 months of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (1) DOSAGE AND ADMINISTRATION Children • 6 through 35 months of age (0.25 mL dose, intramuscular injection): - Previously unvaccinated children – should receive two 0.25 mL doses, one on day 1 followed by another 0.25 mL dose at least one month later. (2.2) - Previously vaccinated children (ie, received two doses within the same season) should receive only one 0.25 mL dose. (2.2) • 36 months through 8 years of age (0.5 mL dose, intramuscular injection): - Previously unvaccinated children – should receive two 0.5 mL doses, one on day 1 followed by another 0.5 mL dose at least one month later. (2.2) - Previously vaccinated children (ie, received two doses within the same season) should receive only one 0.5 mL dose. (2.2) • 9 years of age and older - A single 0.5 mL dose, intramuscular injection. (2.2) Adults - A single 0.5 mL dose, intramuscular injection. (2.2) DOSAGE FORMS AND STRENGTHS Fluzone, a sterile suspension for intramuscular injection, is supplied in four presentations: • Prefilled syringe, 0.25 mL, no preservative, pediatric dose, distinguished by a pink syringe plunger rod (3) • Prefilled syringe, 0.5 mL, no preservative (3) • Single-dose vial, 0.5 mL, no preservative (3) • Multi-dose vial, 5 mL, contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose contains 25 µg mercury. (3)
FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Recommended Dose and Schedule 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome 5.2 Altered Immunocompetence 5.3 Preventing and Managing Allergic Reaction 5.4 Limitations of Vaccine Effectiveness 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Post-Marketing Experience 6.3 Other Adverse Events Associated with Influenza Vaccines 7 DRUG INTERACTIONS 7.1 Concomitant Administration with other Vaccines 7.2 Immunosuppressive Therapies
WARNINGS AND PRECAUTIONS • If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of previous influenza vaccination, the decision to give Fluzone should be based on careful consideration of the potential benefits and risks. (5.1) • Immunocompromised persons may have a reduced immune response to Fluzone. (5.3) ADVERSE REACTIONS • Most common (≥10%) local reactions were soreness at injection site, tenderness, pain, and swelling. (6) • Most common (≥10%) systemic events were malaise, headache, and myalgia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 at 1-800-822-2463 (1-800VACCINE) or VAERS at 1-800-822-7967 or http://vaers.hhs.gov. DRUG INTERACTIONS • Do not mix with other vaccines in the same syringe or vial. (7.1) • Immunosuppressive therapies may reduce the immune response to Fluzone. (7.2) USE IN SPECIFIC POPULATIONS • Safety and effectiveness of Fluzone have not been established in pregnant women or nursing mothers or children <6 months of age. (8.1, 8.2, 8.3) • Antibody responses were lower in the geriatric population than in younger adults. (8.4)
See 17 PATIENT COUNSELING INFORMATION. Revised: June 2008
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Nursing Mothers 8.3 Pediatric Use 8.4 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Immunogenicity in the Adult and Geriatric Population 14.2 Immunogenicity in Children 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.
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FULL PRESCRIBING INFORMATION: 1. INDICATIONS AND USAGE Fluzone® is an inactivated influenza virus vaccine indicated for active immunization in persons 6 months of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. 2.
DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration Inspect Fluzone vaccine syringes and vials visually for particulate matter and/or discoloration prior to administration. If either of those conditions exists, the vaccine should not be administered. Shake the syringe and single-dose vials well before administering the vaccine and shake the multi-dose vial each time before withdrawing a dose of vaccine. 2.2 Recommended Dose and Schedule Children Children 6 through 35 months of age who have not previously been vaccinated with an influenza vaccine should receive two 0.25 mL doses, one on day 1 followed by another 0.25 mL dose at least 1 month later.1 Children 6 through 35 months of age who have been previously vaccinated with two doses of any influenza vaccine should receive only one 0.25 mL dose.1 Children 36 months through 8 years of age who have not previously been vaccinated with influenza vaccine should receive two 0.5 mL doses, one on day 1 followed by another 0.5 mL dose at least 1 month later. Children 36 months through 8 years of age who have been previously vaccinated with two doses of any influenza vaccine should receive only one 0.5 mL dose.1 Children 9 years of age and older should receive a single 0.5 mL intramuscular dose.1 There are recommendations available for needle length in different age groups. For needle length, refer to the Advisory Committee on Immunization Practices (ACIP) recommendations.2 For children over 36 months, the deltoid muscle should be used; for children 36 months and younger, the anterolateral aspect of the thigh should be used. Adults Fluzone vaccine should be administered as a single 0.5 mL intramuscular dose preferably in the deltoid muscle. The vaccine should not be injected into the gluteal region or into areas where there may be a major nerve trunk. 3.
DOSAGE FORMS AND STRENGTHS Fluzone vaccine is a sterile suspension for intramuscular injection. Each 0.25 mL dose of Fluzone vaccine contains a total of 22.5 micrograms (µg) of influenza virus hemagglutinin and each 0.5 mL dose contains a total of 45 µg of influenza virus hemagglutinin from the 3 influenza virus strains in the vaccine. [See Description (11).] Fluzone vaccine is supplied in 4 presentations: 1) Prefilled syringe, 0.25 mL, no preservative, pediatric dose, for 6 through 35 months of age, distinguished by a pink syringe plunger rod; 2) Prefilled syringe, 0.5 mL, no preservative, for 36 months of age and older; 3) Single-dose vial, 0.5 mL, no preservative, for 36 months of age and older; 4) Multi-dose vial, 5 mL, for 6 months of age and older, contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose contains 25 µg mercury. 4.
CONTRAINDICATIONS Do not administer Fluzone vaccine to anyone with a known severe hypersensitivity to egg proteins or any component of the vaccine or life-threatening reactions after previous administration of any influenza vaccine. [See Warnings and Precautions (5) and Description (11)]. 5.
WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome Recurrence of Guillain-Barré syndrome (GBS) has been temporally associated with the administration of influenza vaccine. Fluzone vaccine should be administered to individuals who have a prior history of Guillain-Barré syndrome only based on careful consideration of the potential benefits and risks. 5.2 Altered Immunocompetence If Fluzone vaccine is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the immune response may be diminished. 5.3 Preventing and Managing Allergic Reaction Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. 5.4 Limitations of Vaccine Effectiveness Vaccination with Fluzone vaccine may not protect all recipients. 6.
ADVERSE REACTIONS Adverse event information from clinical trials provides the 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, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trial of another vaccine, and may not reflect the rates observed in practice. 6.1 Clinical Trial Experience Adults and Geriatrics In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts <2 days, local pain and swelling. These local reactions typically are mild. Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no prior exposure to the influenza virus antigens in the vaccine (eg, young children). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (eg, fever, malaise, myalgia, and headache) when compared with placebo injections.1 Children The 2003-2004 formulation of Fluzone vaccine was studied in 19 children 6 to 23 months of age and in 12 children 24 to 36 months of age, given in 2 doses one month apart. Local reactions and systemic events were solicited for 3 days after each dose. Most local and systemic reactions were mild. The proportions of local and systemic reactions in children were similar to the proportions in adults. No reported local or systemic reaction required a therapeutic intervention other than analgesics.3 6.2 Post-Marketing Experience The following additional events have been reported during post-approval use of Fluzone vaccine. 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: Thrombocytopenia, lymphadenopathy
Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema)
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Nervous System Disorders: GBS, convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paresthesia Vascular Disorders: Vasculitis, vasodilation/flushing Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome General Disorders and Administration Site Conditions: Fever, pain, pruritis, asthenia/fatigue, pain in extremities, chest pain 6.3 Other Adverse Events Associated with Influenza Vaccines Anaphylaxis has been reported after administration of influenza vaccines. Although Fluzone vaccine 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 polyangitis (vasculitis) has been reported temporally associated with influenza vaccination. 7.
DRUG INTERACTIONS 7.1 Concomitant Administration with Other Vaccines Fluzone vaccine should not be mixed with any other vaccine in the same syringe or vial. If Fluzone vaccine is to be given at the same time as another injectable vaccine(s), the vaccine(s) should always be administered at different injection sites.
7.2 Immunosuppressive Therapies If Fluzone vaccine is administered to immunosuppressed persons or persons receiving immunosuppressive therapy, immunologic response may be diminished. 8.
USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with Fluzone vaccine. It is also not known whether Fluzone vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fluzone vaccine should be given to a pregnant woman only if clearly needed. 8.2 Nursing Mothers It is not known whether Fluzone vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fluzone vaccine is administered to a nursing woman. 8.3 Pediatric Use Safety and effectiveness of Fluzone vaccine in children below the age of 6 months have not been established. The immune response and safety of Fluzone vaccine was evaluated in 31 children between the ages of 6-26 months. [See Adverse Reactions (6.1), Clinical Studies (14).] 8.4 Geriatric Use Immune response to Fluzone vaccine in subjects older than 65 years of age may be lower when compared to immune responses in younger subjects. [See Clinical Studies (14).] 11. DESCRIPTION Fluzone vaccine (Influenza Virus Vaccine), an inactivated influenza virus vaccine, for intramuscular use, is prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, polyethylene glycol p-isooctylphenyl ether, (Triton® X-100) producing a “split virus”. The split virus is further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. Fluzone vaccine has been standardized according to the US Public Health Service (USPHS) requirements for the 2008-2009 influenza season and is formulated to contain 45 micrograms (µg) hemagglutinin per 0.5 mL dose in the recommended ratio of 15 µg HA of each of the following 3 strains: A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (A/Brisbane/10/2007-like strain) (H3N2), and B/Florida/04/2006. Gelatin 0.05% is added as a stabilizer. Each 0.5 mL dose may contain residual amounts of formaldehyde (not more than 100 µg), polyethylene glycol p-isooctylphenyl ether (not more than 0.02%), and sucrose (not more than 2.0%). There is no thimerosal used in the manufacturing process of the No Preservative single-dose presentations of Fluzone vaccine. The multi-dose presentation of Fluzone vaccine contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose contains 25 µg mercury. Fluzone vaccine is a clear to a slightly opalescent suspension. Antibiotics are not used in the manufacture of Fluzone vaccine. All presentations of Fluzone vaccine are latex-free. 12. CLINICAL PHARMACOLOGY 12.1 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 hemagglutinin inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titer of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.4,5 Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies 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, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (ie, typically two type A and one type B), representing the influenza viruses likely to be circulating in the US in the upcoming winter. Annual vaccination with the current vaccine is recommended because immunity during the year after vaccination declines, and because circulating strains of influenza virus change from year to year.1 13. NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fluzone vaccine has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.
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14. CLINICAL STUDIES 14.1 Immunogenicity in the Adult and Geriatric Population In an observational study of the immunogenicity of Fluzone vaccine in a geriatric population (median age: 72.0 range: 61 to 86 years of age) compared with younger adults (median age: 38.0 range: 19 to 59 years of age; racial distribution was 2 Asian, 11 Black, 106 Caucasian, and 2 other; no gender data were available), the following results were obtained using a single-dose of the year 1999-2000 formulation of Fluzone vaccine. (See Table 1.) Antibody levels were obtained on the day of and just prior to vaccination and approximately 21 days after vaccination.4 Table 1:
Geometric Mean Titer (GMT) and Percentage (%) Achieving an HI Titer ≥1:40 or Greater (N = 58-62) in Adults and the Elderly PRE-VACCINE GMT
ANTIGEN A (H3N2)
Cohort 1999 Cohort 2000
A (H1N1)
Cohort 1999 Cohort 2000
B
Cohort 1999 Cohort 2000
Young (N = 60) Elderly (N = 61) Young (N = 58) Elderly (N = 62) Young (N = 60) Elderly (N = 61) Young (N = 58) Elderly (N = 62) Young (N = 60) Elderly (N = 61) Young (N = 58) Elderly (N = 62)
POST-VACCINE GMT (% TITER ≥40) 53.1 (72) 58.2 (70) 72.7 (79) 49.7 (68) 35.6 (49) 26.5 (38) 35.9 (54) 16.0 (23) 41.4 (38) 19.4 (10) 21.5 (38) 9.9 (11)
16.6 20.1 18.6 18.1 11.1 12.2 8.9 6.7 14.4 9.9 9.4 7.4
N = Number of participants 14.2 Immunogenicity in Children In a study using 2 doses of Fluzone vaccine (2003-2004) in 31 healthy children 6-36 months of age (3 Black, 23 Caucasian, 2 Hispanic, and 3 other; 15 were male and 16 were female), the following immunogenicity results were obtained on day 0 before vaccination and approximately 14 days after dose number 2. (See Table 2.) Table 2:
Geometric Mean Titer (GMT) and Percentage (%) Achieving an HI Titer of 1:40 in Children ANTIGEN
A (H3N2) A (H1N1) B
PRE-VACCINE GMT 7.7 6.5 5.2
POST-DOSE 2 GMT (% TITER ≥40) 52.9 (77.4) 52.9 (77.4) 27.3 (48.4)
15. REFERENCES 1 Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(RR06):1-54. 2 CDC. General recommendations on immunization: Recommendations of the ACIP and the American Academy of Family Physicians (AAFP). MMWR 2006;55(RR15):1-48. 3 Sanofi Pasteur Inc. Data on file, 071107. 4 Hannoun C, et al. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138. 5 Hobson D, 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. 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Latex-free prefilled syringe, without needle, 0.25 mL, package of 10 prefilled syringes per carton – Product No. NDC 49281-008-25. Latex-free prefilled syringe, without needle, 0.5 mL, package of 10 prefilled syringes per carton – Product No. NDC 49281-008-50. Latex-free single-dose vial, 0.5 mL, package of 10 vials per carton – Product No. NDC 49281-008-10. Latex-free multi-dose vial, 5 mL, one vial per carton. The vial contains ten 0.5 mL doses – Product No. NDC 49281-382-15. 16.2 Storage and Handling Store all Fluzone vaccine presentations refrigerated at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Discard if vaccine has been frozen. Between uses, return the multi-dose vial to the recommended storage conditions at 2° to 8°C (35° to 46°F). Do not use after the expiration date shown on the label. 17. PATIENT COUNSELING INFORMATION • Inform the patient or guardian that Fluzone vaccine contains killed viruses and cannot cause influenza. Fluzone vaccine stimulates the immune system to produce antibodies that protect against influenza, but not against other respiratory diseases. Annual vaccination is recommended. • Vaccine recipients and guardians should be instructed to report any severe or unusual adverse reactions to their health care provider. Fluzone vaccine is a registered trademark of Sanofi Pasteur Inc. Product information as of June 2008. Manufactured by: Sanofi Pasteur Inc. Swiftwater PA 18370 USA
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