| FLUZONE® |
|Influenza Virus Vaccine Trivalent Types A and B (Zonal Purified, Subvirion) |
|Active Immunizing Agent |
|Action And Clinical Pharmacology: The inoculation of antigen prepared from inactivated influenza virus stimulates the production of specific antibodies. Protection is afforded only against those strains of virus from which the vaccine is prepared or closely related strains.
Influenza A viruses are classified into subtypes on the basis of 2 surface antigens: hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, H3) and 2 subtypes of neuraminidase (N1, N2) are recognized among influenza A viruses that have caused widespread human disease. Immunity to these antigens - especially to the hemagglutinin - reduces the likelihood of infection and lessens the severity of disease if infection occurs. Infection with a virus of one subtype confers little or no protection against viruses of other subtypes. Furthermore, over time, antigenic variation (antigenic drift) within a subtype may be so marked that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype. Although influenza B viruses have shown more antigenic stability than influenza A viruses, antigenic variation does occur. For these reasons, major epidemics of respiratory disease caused by new variants of influenza continue to occur. The antigenic characteristics of circulating strains provide the basis for selecting the virus strains included in each year's vaccine.
Each year's influenza vaccine contains 3 virus strains (usually 2 type A and 1 type B) representing the influenza viruses that are likely to circulate in Canada in the coming winter.
Most vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titres. These antibody titres are protective against illness caused by strains similar to those in the vaccine or the related variants that may emerge during outbreak periods. Elderly persons and persons with certain chronic diseases may develop lower postvaccination antibody titres than healthy young adults and thus may remain susceptible to influenza-related upper-respiratory-tract infection.
However, even if such persons develop influenza illness despite vaccination, the vaccine can be effective in preventing lower-respiratory-tract involvement or other secondary complications, thereby reducing the risk for hospitalization and death.
The effectiveness of influenza vaccine in preventing or attenuating illness varies, depending primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains included in the vaccine and those that circulate during the influenza season. When a good match exists between vaccine and circulating viruses, influenza vaccine has been shown to prevent illness in approximately 70 to 90% of healthy persons less than 65 years of age. In these circumstances, studies also have indicated that the effectiveness of influenza vaccine in preventing hospitalization for pneumonia and influenza among elderly persons living in settings other than nursing homes or similar chronic-care facilities ranges from 30 to 70%.
Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and death. Studies of this population have indicated that the vaccine can be 50 to 60% effective in preventing hospitalization and pneumonia and 80% effective in preventing death, even though efficacy in preventing influenza illness may often be in the range of 30 to 40% among the frail elderly. Achieving a high rate of vaccination among nursing home residents and staff can reduce the spread of infection in a facility, thus preventing disease through herd immunity. Vaccination of health care workers in nursing homes also has been demonstrated to reduce the impact of influenza among residents.
Although the current influenza vaccine can contain 1 or more of the antigens administered in previous years, annual vaccination using the current vaccine is necessary because immunity declines in the year following vaccination.
Indications And Clinical Uses: For adults and children 6 months of age and older when influenza vaccine is recommended.
The National Advisory Committee on Immunization recommends annual vaccination for individuals in the following categories: People at High Risk: Vaccination of people at high risk is the single most important measure for reducing the impact of influenza. Priority should be given to ensure annual vaccination of people in the following groups: Adults and children with chronic cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis, and asthma) severe enough to require regular medical follow-up or hospital care: Chronic cardiac and pulmonary disorders are by far the most important risk factors for influenza-related death.
People of any age who are residents of nursing homes and other chronic care facilities: Such residents often have one or more of the medical conditions outlined in the first group. In addition, their institutional environment may promote spread of the disease. Studies have shown that the use of vaccine in this setting will decrease occurrence of illness and has an even greater impact in reducing the rates of hospitalization, pneumonia and death.
People 65 years of age and over: The risk of severe illness and death related to influenza is moderately increased in healthy people in this age group, but is not as great as in people with chronic underlying disease. Vaccination is effective in preventing hospitalization and death.
Adults and children with chronic conditions such as diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression, renal disease, anemia and hemoglobinopathy: The degree of risk associated with chronic renal and metabolic diseases in children is uncertain but this uncertainty should not preclude consideration of vaccination.
Children and adolescents (age 6 months to 18 years) with conditions treated for long periods with ASA: ASA might increase the risk of Reye's syndrome after influenza.
Persons infected with Human Immunodeficiency Virus (HIV): Limited information exists regarding the frequency and severity of influenza illness among HIV-infected persons, but reports suggest that symptoms may be prolonged and the risk for complications increased for some HIV-infected persons. Because influenza can result in serious illness and complications, vaccination is a prudent precaution and will result in protective antibody levels in many recipients. However, the antibody response to vaccine may be low in persons with advanced HIV-related illnesses; giving a second dose of vaccine 4 or more weeks after the first does not improve the immune response for these persons.
HIV load does not increase with influenza immunization according to a randomized, placebo-controlled trial.
Because influenza can result in serious illness and complications and because influenza vaccination may result in protective antibody titres, vaccination will benefit many HIV-infected patients.
People capable of transmitting influenza to those at high risk: People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination.
Health care and other personnel who have significant contact with people in the high risk groups previously described: The potential for infecting people at high risk outlined above, particularly those in institutions, may be reduced through vaccination programs for health care personnel. Such personnel include: physicians, nurses and other personnel in both hospital and outpatient-care settings; employees of nursing homes and chronic-care facilities who have contact with patients or residents; providers of home care to persons at high risk (e.g., visiting nurses and volunteer workers).
Household contacts (including children) of people at high risk who either cannot be vaccinated or may respond inadequately to vaccination: Because low antibody responses to influenza vaccine may occur in some people at high risk (e.g., the elderly, people with immunodeficiency), annual vaccination of their household contacts may reduce the risk of influenza exposure.
Other People: People who provide essential community services should be considered for vaccination to minimize disruption of routine activities in epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults as this has been shown to decrease work absenteeism because of respiratory and other illnesses.
Pregnant Women: Vaccination is recommended for pregnant women in high-risk groups (see above), regardless of their stage of pregnancy (see Precautions, Pregnancy).
Foreign Travellers: Predeparture influenza immunization for prevention of the disease in travellers should be considered for anyone leaving Canada during the local influenza transmission season and should be offered to anyone leaving Canada who will be exposed during the influenza transmission season at the destination.
General Population: Health care providers should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza.
Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize disruption of routine activities during epidemics.
Vaccine should be offered to both children and adults up to and even after influenza virus activity is documented in a community.
Contra-Indications: General: The influenza virus for Fluzone is propagated in eggs, therefore, this vaccine should not be administered to anyone with a history of hypersensitivity (allergy) and especially anaphylactic reactions, to eggs or egg products. It is also a contraindication to administer this vaccine to individuals known to be sensitive to thimerosal. In any case, epinephrine HCl solution (1:1 000) must be immediately available should an acute anaphylactic reaction occur due to any component of the vaccine.
Absolute Contraindication: Allergy to any component of Fluzone (see Supplied) or an allergic or anaphylactic reaction to a previous dose of influenza vaccine are contraindications to vaccination.
Children: The use of Fluzone in infants less than 6 months of age is not recommended.
Immunization with Fluzone should be deferred in the presence of any acute illness, including febrile illness, or active infection to avoid superimposing adverse effects from the vaccine on the underlying illness or mistakenly identifying a manifestation of the underlying illness as a complication of vaccine use. A minor afebrile illness such as mild upper respiratory infection is not usually reason to defer immunization.
Immunization should be delayed in a patient with an active neurologic disorder, but should be considered when the disease process has been stabilized.
Manufacturers' Warnings In Clinical States: I.M. injections should be given with care in persons suffering from coagulation disorders or on anticoagulant therapy because of the risk of hemorrhage.
During recent decades, data on influenza vaccine immunogenicity and side effects have been obtained for i.m. administered vaccine. Because recent influenza vaccines have not been adequately evaluated when administered by other routes, the i.m. route is recommended.
This product contains dry natural rubber as follows: The stopper to the vial contains dry natural rubber. In the case of the syringe, the needle cover contains dry natural rubber, but the plunger for the syringe contains no rubber of any kind.
If Fluzone is used in persons with malignancies, persons receiving immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, or who are otherwise immunocompromised (including HIV-infected individuals, transplant recipients, persons suffering from autoimmune disorders), the expected immune response may not be obtained.
Corticosteroid therapy can result in immunosuppression although the exact dose and duration of therapy required to suppress the immune system is not well defined. Persons treated with high doses of systemic steroids, e.g., ³2 mg/kg/day of prednisone orally for more than 2 weeks, should be considered to have a compromised immune system.
Although influenza vaccination can inhibit the clearance of warfarin, theophylline, and phenytoin, clinical studies have consistently failed to show any adverse effects attributable to these drugs in people receiving influenza virus vaccine.
Influenza virus is remarkably capricious in that significant antigenic changes may occur from time to time. It is known definitely that Fluzone, as now constituted, is not effective against all possible strains of influenza virus. Protection is afforded most people only against those strains of virus from which the vaccine is prepared or against closely related strains.
As with any vaccine, immunization with influenza vaccine may not protect 100% of susceptible individuals.
Precautions: General: The possibility of allergic reactions in individuals sensitive to the components of the vaccine should be evaluated. Epinephrine HCl solution (1:1 000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Health care providers should be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings including proper airway management.
Before administration of any vaccine, all appropriate precautions should be taken to prevent adverse reactions. This includes a review of the patient's history with respect to possible hypersensitivity to the vaccine or similar vaccine, determination of previous immunization history, and the presence of any contraindications to immunization, current health status, and a current knowledge of the literature concerning the use of the vaccine under consideration.
Special care should be taken to ensure that the product is not injected into a blood vessel.
A separate, sterile needle and syringe, or a sterile disposable unit, must be used for each individual patient to prevent the transmission of infectious agents.
There have been case reports of transmission of HIV and hepatitis by failure to scrupulously observe sterile technique. In particular, the same needle and/or syringe must never be used to re-enter a multidose vial to withdraw vaccine even when it is to be used for inoculation of the same patient. This may lead to contamination of the vial contents and infection of patients who subsequently receive vaccine from the vial.
Needles should not be recapped and should be disposed of properly.
Before administration of Fluzone, health care personnel should inform the parent or guardian or the patient to be immunized of the benefits and risks of immunization, inquire about the recent health status of the patient and comply with any local requirements with respect to information to be provided to the patient before immunization.
Pregnancy: Reproduction studies have not been conducted with Fluzone. Fluzone should be given to a pregnant woman only if clearly needed (see Indications).
Simultaneous Administration of Other Vaccines: Pneumococcal vaccine and influenza vaccine can be given at the same visit at different sites with separate sterile needles and syringes without an increase in side effects, but it should be emphasized that, whereas influenza vaccine is given annually, pneumococcal vaccine should be given only once to adults. Detailed immunization records should be provided to each patient to help ensure that additional doses of pneumococcal vaccine are not given. Children at high risk may receive influenza vaccine at the same time as routine pediatric vaccines but at separate sites with separate sterile needles and syringes.
Adverse Reactions: Split-virus vaccines, produced by chemically disrupting the influenza virus, are generally associated with somewhat fewer side effects in children and young adults than are whole-virus vaccines; consequently, only split-virus vaccines are recommended for persons under 13 years of age.
Because Fluzone contains only noninfectious viruses, it cannot cause influenza. Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination. The most frequent side effect of vaccination is soreness at the vaccination site that lasts for up to 2 days; this is reported by fewer than one-third of vaccinees. In addition, 2 types of systemic reactions have occurred: 1. Fever, malaise, myalgia, and other systemic symptoms occur infrequently and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6 to 12 hours after vaccination and can persist for 1 to 2 days. Recent placebo-controlled trials suggest that in elderly persons and healthy young adults, split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections.
2. Immediate - presumably allergic - reactions (such as hives, angioedema, allergic asthma, or systemic anaphylaxis), occur rarely after influenza vaccination. These reactions probably result from hypersensitivity to some vaccine component - the majority are most likely related to residual egg protein. Although current influenza vaccines contain only a small quantity of egg protein, this protein may induce immediate hypersensitivity reactions among persons with severe egg allergy. Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E(IgE)-mediated hypersensitivity to eggs-including those who have had occupational asthma or other allergic responses due to exposure to egg protein-also might be at increased risk for reactions from influenza vaccine, and similar consultation should be considered.
The protocol for influenza vaccination developed by Murphy and Strunk may be considered for patients who have egg allergies and medical conditions that place them at increased risk for influenza-associated complications.
Prophylactic acetaminophen may decrease the frequency of some side effects in adults.
Unlike the 1976 swine influenza vaccine, subsequent vaccines prepared from other virus strains have not been clearly associated with an increased frequency of Guillain-Barré Syndrome (GBS). However, it is difficult to obtain strong evidence for a possible small increase in risk for a rare condition such as GBS, which has an annual background incidence of only 10 to 20 cases per million in the adult population. During 3 of 4 seasons studied between 1977 and 1991 in the USA, the point estimates of the overall relative risks of GBS after influenza vaccination were slightly elevated; but were not statistically significant in any of these studies. However, a recent U.S. study of the 1992-93 and 1993-94 seasons found an elevation in the overall relative risk of 1.83 (95% Confidence Interval 1.12 to 3.00) during the 6 weeks following vaccination, representing an excess of an estimated 1 to 2 cases per million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination. The increase in the relative risks and the increased number of cases in the second week after vaccination may be the result of vaccination but also could be due to other factors (e.g., confounding or diagnostic bias) rather than a true vaccine-related risk.
Among persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was slightly less than 10 cases per million vaccinations. Even if GBS were a true side effect in subsequent years, the estimated risk for GBS of 1 to 2 cases per million vaccinations is substantially less than that for severe influenza, which could be prevented by vaccination among all age groups, especially for persons 65 years of age or more and those who have medical indications for influenza vaccination. Estimates of excess hospitalization rates during different influenza epidemics have ranged from approximately 200 to 300 hospitalizations per million previously healthy persons age 5 to 44 years to 2 000 to greater than 10 000 hospitalizations per million persons aged 65 and older. Estimates of influenza-associated death rates have ranged from approximately 300 to 1 500 per million persons aged 65 and older, which account for more than 90% of all influenza-associated deaths. The average case-fatality ratio for GBS is approximately 6% and increases with age. There is no indication that the case-fatality ratio for GBS differs by influenza vaccination status. The potential benefits of influenza vaccination clearly outweigh the possible risks for vaccine-associated GBS.
Whereas the incidence of GBS in the general population is very low, persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history. Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination might be causally associated with this risk for recurrence is not known. Avoiding subsequent influenza vaccination of persons known to have developed GBS within 6 weeks of a previous influenza vaccination seems prudent. However, for most persons with a history of GBS who are at high risk for severe complications from influenza, many experts believe the established benefits of influenza vaccination justify yearly vaccination.
Influenza vaccine is not known to predispose to Reye's syndrome.
Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis, facial paralysis, labyrinthitis, and brachial plexus neuropathy have been reported. However, no cause and effect has been established. Almost all persons affected were adults, and the described clinical reactions began as soon as a few hours and as late as 2 weeks after vaccination. Full recovery was almost always reported.
Fatalities from a variety of other causes have been reported in the high-risk population following influenza vaccination without the establishment of a definite causal relationship.
Physicians, nurses and pharmacists should report any adverse occurrences temporally related to the administration of the product in accordance with local requirements and to the Medical Director, Connaught Laboratories Limited, 1755 Steeles Avenue West, Toronto, Ontario, Canada, M2R 3T4.
Dosage And Administration: Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration before administration. If these conditions exist, the product should not be administered.
Shake the vial well to distribute uniformly the suspension before withdrawing each dose. When administering a dose from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose (see Precautions).
Shake the prefilled syringe well before administering dose.
Before injection, the skin over the site to be injected should be cleansed with a suitable germicide.
Administer the vaccine i.m., preferably in the region of the deltoid muscle, in adults and older children. The preferred site for infants and young children (<1 year of age) is the anterolateral aspect of the thigh.
After insertion of the needle, aspirate to insure the needle has not entered a blood vessel.
Do not inject i.v.
Fluzone may be used for all age groups. It is not recommended for infants under 6 months of age. The dosage is as follows: See Table I.
Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.
Availability And Storage: Fluzone Influenza Virus Vaccine Trivalent Types A and B (Zonal Purified, Subvirion) is prepared from the allantoic fluids of chicken embryos infected with a specific type of influenza virus. The virus containing fluids are harvested and the virus 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 glycol p-isooctylphenyl ether (Triton X-100) producing a "split-antigen". The split antigen is then further purified by chemical means and suspended in sodium phosphate buffered, isotonic sodium chloride solution. This product has been standardized according to USPHS requirements.
For the 1998-99 season, the vaccine contains not less than 45 µg hemagglutinin (HA). Each dose (0.5 mL) contains the following 3 strains: A/Beijing/262/95 (H1N1) 15 µg HA, A/Sydney/5/97 (H3N2) 15 µg HA, B/Harbin/07/94 (a B/Beijing/184/93-like strain) 15 µg HA. Gelatin 0.05% is added as a stabilizer and thimerosal 0.01% is added as a preservative. After shaking syringe/vial well, Fluzone is essentially clear and slightly opalescent in color. Antibiotics are not used in the manufacture of this vaccine.
Vials of 5 mL (10 doses), boxes of 1. Prefilled syringes of 0.5 mL (single dose), boxes of 1 and 10. Store between 2 and 8°C. Do not freeze. Product which has been exposed to freezing should not be used. Do not use after expiration.