Canada Communicable Disease Report
Vol. 25 (ACS-2)
1 June 1999

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*

STATEMENT ON INFLUENZA VACCINATION FOR THE 1999-2000 SEASON

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PREAMBLE

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine(s) should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

INTRODUCTION

The antigenic components of the influenza vaccine have been updated for the 1999-2000 season. The present statement also contains recent observations from global and national influenza surveillance programs, developments in influenza control, and an update concerning the use of amantadine for prophylaxis and therapy.

In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis or therapy with an influenza-specific antiviral drug (amantadine). Vaccination of persons at high risk each year before the influenza season is currently the most effective measure for reducing the impact of influenza.

Influenza A viruses are classified into subtypes on the basis of two surface antigens:  hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and 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 1998-1999 influenza season was characterized by peaks in activity between early to mid-January and early March. From 28 August 1998 to 19 March 1999, the Laboratory Centre for Disease Control (LCDC) received reports on 40,489 laboratory tests for respiratory viruses: 4,449 (11%) were positive for influenza virus; 3,912 (88%) were influenza type A and 537 (12%) were influenza type B. The provincial distribution of the influenza A specimens was as follows: Newfoundland (17), Nova Scotia (28), New Brunswick (57), Quebec (782), Ontario (1,506), Manitoba (179), Saskatchewan (339), Alberta (733), and British Columbia (271). The provincial distribution of the influenza type B specimens was as follows: New Brunswick (2), Quebec (24), Ontario (473), Saskatchewan (14), Alberta (10), and British Columbia (14). These results will, to some extent, reflect local testing policy and resources.

Strain characterization has been completed on 184 influenza isolates submitted to the Bureau of Microbiology, LCDC, from October 1998 to 18 March 1999; 156 (85%) were A/Sydney/5/97-like (H3N2) and 28 (15%) were B/Beijing/184/93-like. The provincial distribution of A/Sydney-like isolates was as follows: Newfoundland (3), New Brunswick (6), Quebec (35), Ontario (57), Manitoba (4), Saskatchewan (20), Alberta (23), and British Columbia (8). The provincial distribution of B/Beijing-like isolates was as follows: Quebec (3), Ontario (18), Saskatchewan (4), and Alberta (3).

Between October 1998 and February 1999, influenza activity was reported from all of the continents. During the first 2 months of this period, influenza occurred sporadically in many countries in the northern hemisphere and continued to be reported in a few countries in the southern hemisphere. Outbreaks were reported in December 1998, and by January 1999 influenza was widespread in some countries in Africa, Asia, Europe, and North America. Both influenza types A and B were common. Influenza A (H3N2) viruses predominated in some countries while influenza B viruses predominated in others. In several countries, both viruses co-circulated. The majority of influenza A (H3N2) isolates from Africa, the Americas, Asia, Europe, and Oceania were antigenically closely related to A/Sydney/5/97.

Influenza B viruses from the Americas and Europe were antigenically related to B/Beijing/184/93.  Influenza B viruses similar to either B/Beijing/184/93 or B/Shangdong/7/97 (a B/Beijing/243/97-like virus) continued to co-circulate in Asia (China, Japan, Singapore, and Thailand). The few laboratory-confirmed cases of influenza A (H1N1) identified and reported in Europe and North America were influenza A/Bayern/7/95-like. The majority of A (H1N1) viruses from Asia were related to A/Beijing/262/95⁽¹⁾.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year's vaccine. As suggested by the World Health Organization (WHO), NACI recommends that the trivalent vaccine for the 1999-2000 season contain an A/Sydney/5/97 (H3N2)-like strain, an A/Beijing/262/95 (H1N1)-like strain, and a B/Yamanashi/166/98-like strain.

Annual immunization is required because there is always a change in the vaccine in response to antigenic drift. As well, immunity declines in the year following vaccination. Each 0.5 mL of vaccine will contain 15 µg of hemagglutinin of each antigen. The vaccine will be available as a split-virus (chemically disrupted) preparation. Protection from the vaccine generally begins about 2 weeks after immunization and may last 6 months or longer. However, in the elderly, antibody levels fall below protective levels in 4 months or less. The recommended time for influenza immunization is from October to mid-November. However, decisions regarding the exact timing of vaccination of ambulatory and institutionalized individuals must be made based on local epidemiology, recognition of the need to use patient contacts with health-care providers as opportune moments for immunization, and programmatic issues. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Health-care workers should use every opportunity to give vaccine to any individual at risk who has not been immunized during the current season, even after influenza activity has been documented in the community.

RECENT OBSERVATIONS FROM GLOBAL AND NATIONAL INFLUENZA SURVEILLANCE, AND DEVELOPMENTS IN INFLUENZA CONTROL

A global influenza surveillance and monitoring system was initiated by WHO in 1948⁽²⁾.  Over 50 years later, the network involves 100 collaborating laboratories located in 82 countries, including Canada. Surveillance system data are used to make recommendations in the spring of that year regarding the three virus strains to be included in the next season's influenza vaccine. WHO is considering the feasibility of recommendations twice a year for vaccine virus strains, allowing production of vaccines that could protect individuals living in and travelling to regions with peak influenza activity between May and September.

• Active surveillance and pandemic planning were instrumental in the timely, orderly, and effective response to the outbreak of avian influenza A (H5N1) virus in humans in Hong Kong (Special Administrative Region of China) in late 1997⁽²⁾. Eighteen cases were detected, of which six died. This virus is the first avian influenza virus isolated from a human with respiratory infection⁽³⁾. No reassortment with a human or porcine influenza virus has been demonstrated in these isolates. Person-to-person transmission was not proven. Further human cases of influenza A (H5N1) have not been detected.  Inefficiency in person-to-person transmission may limit the potential of influenza A (H5N1) to cause a pandemic. However, the possibility of reassortment of this virus with currently circulating human viruses underlines the need for pandemic preparedness^(4,5).

• The Canadian Contingency Plan for Pandemic Influenza was reviewed in 1996. Its purpose is to enhance the capacity of Canada to respond to such an event and to decrease associated mortality, morbidity, and societal disruption. The 1996 draft plan was approved by over 20 health agencies. It designates Health Canada to coordinate implementation of the plan should a pandemic occur, to maintain national influenza surveillance activities, and to secure vaccine supply. Provinces and territories will implement the other features of the plan including the delivery of vaccine to the public, communications management, and provision of acute care. The plan is now undergoing revision by different working groups. It is expected that a memorandum of understanding between federal, provincial, and territorial governments will be developed to address issues such as identified roles and responsibilities, as well as choosing options for vaccine and antiviral drug supply and related funding.

• Morbidity due to influenza is substantial in pre-school and school aged children. In American studies of influenza epidemics occurring from 1972 to 1981, the estimated influenza-associated hospitalization rates for children < 5 years of age (100 per 100,000 for those without high-risk conditions, ranging to 500 per 100,000 for those with high-risk conditions) was second only to the rate observed in those ³ 65 years of age^(6,7).  School-aged children have the highest attack rates during pandemic and interpandemic periods; they predominate among persons presenting for health care early during the influenza season, and are important disseminators of the virus in the community⁽⁷⁾.

• Amantadine is currently available in Canada for the prevention and therapy of influenza A infection. Neuraminidase inhibitors are a new class of influenza antiviral drugs which are presently undergoing testing. They are sialic acid analogues and selectively inhibit both influenza A and B viruses. Recent studies suggest that neuraminidase inhibitors may be effective in preventing infection and reducing the duration of illness when started within 48 hours of symptom onset^(8-10). These agents are not currently licensed in Canada. NACI will continue to publish updates as required on the use of influenza antiviral agents.

Recommendations for the prevention and control of influenza during the 1999-2000 influenza season follow.

RECOMMENDED RECIPIENTS

Current influenza vaccines licensed in Canada are immunogenic, safe, and associated with minimal side effects (see 'Adverse reactions' and 'Contraindications and precautions' below).  Influenza vaccine may be administered to any healthy child, adolescent, or adult for whom contraindications are not present.

To reduce the morbidity and mortality associated with influenza and the impact of illness in our communities, immunization programs should focus on those at high risk for influenza-related complications, those capable of transmitting influenza to individuals at high risk for complications, and those who provide essential community services.  However, those who wish to protect themselves from influenza should be encouraged to receive the vaccine even if they are not in one of these groups^(11,12).

People at high risk

• 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^(13,14).

• 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 the occurrence of illness and has an even greater impact on reducing the rates of hospital admission, pneumonia, and death⁽¹⁵⁾.

• People >= 65 years of age. 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 hospital admission and death, and results in direct health-care cost savings⁽¹⁶⁾.

• Adults and children with chronic conditions, such as diabetes mellitus⁽¹⁷⁾ and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), 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 acetylsalicylic acid. This therapy might increase the risk of Reye syndrome after influenza⁽¹⁸⁾.

• Persons infected with 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.  However, the antibody response to vaccine may be low in persons with advanced HIV-related illnesses⁽¹⁹⁾; giving a second dose of vaccine 4 or more weeks after the first dose does not improve the immune response for these persons. A recently published study suggests improved humoral immune response to influenza antigens in HIV-infected individuals treated with highly active antiretroviral therapy, compared to controls⁽²⁰⁾.  Conflicting results have been published regarding whether HIV viral load transiently increases with influenza immunization^(21-23). Influenza immunization of HIV infected persons has not been associated with deterioration in CD4+ T-lymphocyte cell counts or progression of HIV disease.

• People at high risk of influenza complications embarking on travel to destinations where influenza is likely to be circulating.  Immunization with the most current available vaccine may be considered for those who wish to avoid influenza while travelling to areas where influenza is likely to be circulating. In the tropics, influenza can occur throughout the year. In the southern hemisphere, peak activity occurs from April through September. In the northern hemisphere, peak activity occurs from November through March. Travel may expose individuals to situations which facilitate the transmission of influenza^(24-26).  The effectiveness of the influenza immunization for travellers may vary, depending on differences between influenza strains encountered abroad and those included in the current vaccine. There is insufficient evidence at this time to advise in favour of or against routine re-immunization of travellers who were immunized in the fall, and who are subsequently travelling to regions where influenza may be circulating in the late spring and summer months.

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 workers (HCWs) and other personnel who have significant contact with people in the high-risk groups previously described. The following groups should be vaccinated^{(18,24,27,28)}: health-care workers in long-term care facilities, hospitals, and outpatient settings; employees of long-term care facilities who have patient contact; and those who provide services within relatively closed settings to persons at high risk (e.g. providers of home-care services, crew on ships that cater to those at high risk).
• 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)^(19,29), annual vaccination of their household contacts may reduce the risk of influenza exposure.

People who provide essential community services

Vaccination may be considered for these individuals to minimize the 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 from respiratory and other illnesses^(11,12,30).

RECOMMENDED USE

The recommended dosage schedule and type of influenza vaccine are presented in Table 1. Split-virus vaccines are available in Canada. Children < 9 years of age require two doses of the split-virus influenza vaccine, with an interval of 4 weeks; however, the second dose is not needed if the child received one or more doses of vaccine prepared for a previous season.

In infants < 6 months of age, influenza vaccine is less immunogenic than in infants and children aged 6 to 18 months. Therefore, immunization with currently available influenza vaccines is not recommended for infants < 6 months of age⁽³¹⁾.

Table 1 Recommended influenza-vaccine dosage, by age, 1999-2000

Intramuscular administration is preferred. The deltoid muscle is the recommended site in adults and older children, the anterolateral thigh in infants and young children.

Adverse reactions

Influenza vaccination cannot cause influenza because the vaccine does not contain live virus. Soreness at the injection site lasting up to 2 days is common, but rarely interferes with normal activities. Fever, malaise, and myalgia may occur within 6 to 12 hours after vaccination and last 1 to 2 days, especially in young adults who have received the whole-virus vaccine and those receiving vaccine for the first time. Prophylactic acetaminophen may decrease the frequency of some side effects in adults⁽³²⁾. Adults receiving the split-virus vaccine showed no increase in the frequency of fever or other systemic symptoms compared to those receiving placebo⁽³³⁾. In children aged 2 to 12 years, fever and local reactions are no more frequent after administration of split-virus vaccine than after placebo injections. In those < 24 months of age, fever occurs more often but is seldom severe.

Allergic responses are rare and are probably a consequence of hypersensitivity to some vaccine component, most likely residual egg protein, which is present in minute quantities.

An association between Guillain-Barré syndrome (GBS) and influenza vaccination has not been documented prior to 1976^(34,35).  However, the 1976-1977 A/New Jersey swine influenza vaccine was associated with a relative risk of GBS after vaccination ranging from 4.0 to 7.6 ^(36-39).  In subsequent studies from 1978 to 1988, the relative risk of GBS after influenza vaccine was not statistically significant^(40-42).  During the 1990-1991 season, an elevated relative risk of 3.0 for GBS was demonstrated in vaccinated persons age 18 to 64 years, but not among those age >= 65 years^(39-43). In a recently published retrospective study of the 1992-1993 and 1993-1994 seasons in four American states⁽³⁹⁾, the relative risk of GBS occurring within 6 weeks after influenza vaccination, adjusted for age and sex, was 1.7 (95% confidence interval 1.0 to 2.8; p = 0.04), suggesting slightly more than one additional case of GBS per million persons vaccinated against influenza.  Therefore the available data demonstrate that GBS associated with influenza vaccination has been observed in a minority of influenza seasons over the last two decades.  Apart from the 1976-1977 swine flu season, the risk of GBS associated with influenza vaccination is small. In comparison, the morbidity and mortality associated with influenza are much greater^(6,7).

In Canada, the background incidence of GBS is estimated at just over 20 cases per million population in a study done in Ontario and Quebec⁽⁴⁴⁾. A variety of infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is not known whether influenza virus infection itself is associated with GBS. It is also not known whether influenza vaccination is causally associated with increased risk of recurrent GBS in persons with a previous history of GBS. Avoiding subsequent influenza vaccination of persons known to have developed GBS within 6 to 8 weeks of a previous influenza vaccination appears prudent at this time. Influenza vaccine is not known to predispose to Reye syndrome. Please refer to the Canadian Immunization Guide⁽⁴⁵⁾ for further details about administration of vaccine and management of adverse events.

Contraindications and precautions

Influenza vaccine should not be given to people who had an anaphylactic reaction to a previous dose or with known anaphylactic hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension, and shock.

Individuals with acute febrile illness usually should not be vaccinated until their symptoms have abated.

Influenza vaccine is considered safe for pregnant women at all stages of pregnancy. Vaccination is recommended for pregnant women in high-risk groups (see "Recommended Recipients" above). The routine immunization of otherwise healthy women in the second or third trimester of pregnancy has been recommended, primarily on the basis of case reports and observational studies, by the American Advisory Committee on Immunization^(6,46-50). A recently published retrospective case-control study of a predominantly urban and African American Medicaid population from Tennessee determined the relative risk of hospital admission between 1974 and 1993 for cardiopulmonary conditions and influenza during influenza season⁽⁵¹⁾.  Hospitalization rates were compared in pregnant and non-pregnant women, controlling for chronic disease and demographic factors. The odds ratio increased in pregnant women beyond 20 weeks gestation, from 2.52 for weeks 21 to 26, to 4.67 for weeks 37 to 42. However, applying these results to the Canadian population is questionable. The degree of morbidity due to influenza in Canadian women who are pregnant has not been established, and the preventable fraction of morbidity that could potentially be achieved through the use of the influenza vaccine in this population is unknown. NACI concludes that there is insufficient evidence at this time to recommend the routine immunization of otherwise healthy Canadian women who are pregnant during influenza season.

Influenza immunization does not adversely affect the health of breast feeding mothers or their infants. Breast feeding is not a contraindication for influenza immunization.

Although influenza vaccination can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine.

Simultaneous administration of other vaccines

The target groups for influenza and pneumococcal vaccination overlap considerably. Health-care providers should take the opportunity to vaccinate eligible persons against pneumococcal disease when influenza vaccine is given. The concurrent administration of the two vaccines at different sites does not increase the risk of side effects. Pneumococcal vaccine, however, is usually given only once, whereas influenza vaccine is given annually. Children at high risk may receive influenza vaccine at the same time but at a different site from that used for routine pediatric vaccines.

Storage

Influenza vaccine should be stored at 2^o C to 8^o C and should not be frozen.

STRATEGIES FOR REDUCING THE IMPACT OF INFLUENZA

The effectiveness of influenza vaccine varies depending upon the age and immunocompetence of the vaccine recipient, the degree of similarity between the virus strain included, and the strain of circulating virus during the influenza season. With a good match, influenza vaccination has been shown to prevent illness in approximately 70% of healthy children and adults. Under these circumstances, studies have also shown influenza vaccination to be approximately 70% effective in preventing hospitalization for pneumonia, and influenza among elderly persons living in the community. Studies among elderly persons residing in nursing homes have shown influenza vaccination to be 50% to 60% effective in preventing hospitalization and pneumonia and up to 85% 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.

Vaccination is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% of long-term care facility residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually^(52,53). Studies of health-care workers in hospitals and long-term care facilities have shown vaccination rates of 26% to 61%^(54-56).

This low rate of utilization is due both to failure of the health-care system to offer the vaccine, and to refusal by persons who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary^(56-58). Health-care workers and their employers have a duty to actively promote, implement, and comply with influenza immunization recommendations in order to decrease the risk of infection and complications in the vulnerable populations they care for.  Educational efforts aimed at physicians and the public should address common concerns about vaccine effectiveness and adverse reactions. These include the beliefs of patients at risk, health-care workers, and other service providers that they rarely get influenza, the fear of side effects from the vaccine, and doubt about the efficacy of the vaccine.

The advice of a health-care provider is often a very important factor affecting whether a person is immunized or not⁽⁵⁹⁾. Most people at high risk are already under medical care and should be vaccinated during regular fall visits. Strategies to improve coverage include^{(54,58,60-64)}

• standing-order policies in institutions allowing nurses to administer vaccine
• simultaneous immunization of staff and patients in nursing homes and chronic care facilities
• vaccinating people at high risk who are being discharged from hospital or visiting the emergency room in the autumn
• promoting influenza vaccination in clinics which see high-risk groups (e.g. cancer clinics, cardiac clinics, and pulmonary clinics)
• using community newspapers, radio, television, flu-information lines, and collaborating with pharmacists and specialist physicians to distribute positively-framed information about the benefits and risks of immunization
• issuing computer-generated reminders to physicians, mailing reminder letters to patients, or using other recall methods to identify outpatients at high risk
• patient-carried reminder cards
• increased accessibility of immunization clinics to staff in institutions and community-based elderly, including the implementation of mobile programs
• organized activities, such as vaccination fairs and competitions between institutions
• working with multicultural groups to plan and implement effective programs

RECOMMENDATIONS FOR THE USE OF AMANTADINE

Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of type A (but not type B) influenza viruses. Recommendations for its use in prophylaxis and treatment follow.

Prophylaxis

The only drug currently approved in Canada for the specific prophylaxis of influenza virus infections is amantadine hydrochloride. It is 70% to 90% effective in preventing illness caused by type A influenza viruses but is ineffective against type B strains. Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that will protect them when they are exposed to antigenically-related viruses in later years. However, amantadine prophylaxis should not replace annual influenza vaccination in groups for whom vaccine is recommended.

Amantadine prophylaxis may be used as follows:

• For the control of influenza A outbreaks among high-risk residents of institutions.  Consultation with the local medical officer of health to confirm that the circulating influenza strain is type A is essential. Amantadine should be given to all residents, whether previously vaccinated or not, and to unvaccinated staff (see "Precautions" below). Recommended duration of chemoprophylaxis is for a minimum of 2 weeks, or until 1 week after the end of the outbreak.

• As the sole agent for prophylaxis in people at high risk during an outbreak when vaccine is unavailable, contraindicated, or unlikely to be effective due to a shift in the antigenic composition of the outbreak strain. In this case, prophylactic amantadine must be taken each day for the duration of influenza A activity in the community.

• As an adjunct to late vaccination of people at high risk.  Amantadine should be continued for 2 weeks after appropriate vaccination is completed. For those who require two doses of vaccine (e.g. previously unvaccinated children) amantadine should be continued for 2 weeks after the second dose. Amantadine does not interfere with the antibody response to the vaccine.

• As a supplement to vaccination in people at high risk expected to have an impaired immune response to vaccine. This includes persons with HIV infection, especially those with advanced HIV disease. No data are available on possible interactions with other drugs used in the management of patients with HIV infection. Such patients should be monitored closely if amantadine is administered.

• For unvaccinated people who provide care for people at high risk during an outbreak. Amantadine prophylaxis should be continued until 2 weeks after the care provider has been vaccinated.

Amantadine may be used in the same dosage for prophylaxis of influenza A infection as is used for treatment (Table 2). However, a prophylactic dose of 100 mg daily in adults age 10 to 64 years and children weighing > 20 kg, who have normal renal function, has been shown to be as effective as the recommended dose of 200 mg daily^(18,65-71). Factors including local epidemiology, potential side effects, compliance, and cost may be considered in decisions regarding the duration of amantadine prophylaxis^(72,73).

Treatment

Amantadine has been shown to reduce the severity and shorten the duration of influenza A in healthy adults. Although there have been no well-controlled studies to demonstrate its efficacy in preventing complications in people at high risk, amantadine may be considered for those at high risk who have suspected influenza A because of the potential benefits.

Amantadine should be administered within 24 to 48 hours after the onset of illness and continued until 2 days after its resolution. Amantadine-resistant influenza viruses may emerge during treatment but there is no evidence that these viruses are more virulent or transmissible than amantadine-sensitive influenza viruses. However, the consequences of widespread therapeutic use of amantadine are not known. Further research is required to assess the clinical importance of amantadine resistant influenza virus strains and strategies to prevent their emergence^(65,74).

Dosage

Dosage recommendations for treatment of influenza A infection with amantadine are presented in Table 2, but the package insert should be read for complete information. Any adjustments for renal function should be made in addition to adjustments for age. While the recommendations made in Table 2 are based on the majority of treatment studies, one published randomized double-blind trial demonstrated equal therapeutic efficacy for 100 mg of amantadine daily, compared to a 200 mg daily dosage, given to healthy young adult volunteers⁽⁷⁵⁾.

Table 2 Recommended amantadine hydrochloride treatment dosage by age and renal status

Precautions

In otherwise healthy young adults given amantadine prophy- lactically, 5% to 10% report difficulty concentrating, insomnia, light-headedness, and irritability. These side effects are usually mild and cease shortly after the prophylaxis is stopped; however, they can be more frequent in the older population unless a reduced dosage is used.

Serious side effects (e.g. marked behavioural changes, delirium, hallucinations, agitation, seizures) have been associated with high plasma drug concentrations. These have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders, and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Lowering the dosage among these persons is effective in reducing the severity of such side effects.

Amantadine is eliminated from plasma wholly by renal tubular secretion and glomerular filtration; it is not metabolized by the liver⁽⁶⁵⁾. Therefore in people with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Recommended treatment dosage by age and renal function is shown in Table 2. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 ± 36 hours⁽⁷⁶⁾. It should be noted that the calculated creatinine clearance is reasonably accurate for those with a creatinine clearance > 40 mL/min, and those with a stable serum creatinine and muscle mass. However, the calculation becomes less accurate when these conditions are not met. In particular, elderly persons with renal impairment and low muscle mass may have a serum creatinine in the normal range and an estimated creatinine clearance that is higher than the true value. Physicians who prescribe amantadine must be familiar with the limitations of formulas to estimate creatinine clearance, and make clinical decisions regarding dosage adjustments based on these considerations.

Amantadine dosage should be reduced in people with a seizure disorder in order to avoid the risk of increased frequency of seizures, and these individuals should be closely observed.

Drug interactions have been noted during concurrent administration of amantadine with triamterene and hydrochlorothiazide, trimethoprim-sulphamethoxazole, quinine, and quinidine⁽⁶⁵⁾.  The patient's age, weight, renal function, comorbid conditions, current medications, as well as the indications for amantadine use should all be considered prior to initiating this medication. Individuals who are given amantadine should be carefully monitored for side effects.

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Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), N. Armstrong (Advisory Committee Secretariat Officer), Dr. G. De Serres, Dr. P. DeWals, Dr. I. Gemmill, Dr. B. Law, Dr. M. Naus, Dr. P. Orr, Dr. W. Schlech III, Dr. B. Ward.

Liaison Members: Dr. J. Carsley (CPHA), Dr. G. Delage (CPS), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. J. Livengood (CDC), Dr. N. MacDonald (CIDS), Dr. A. McCarthy (ND), Dr. J. Salzman (CATMAT), Dr. J. Waters (ACE).

Ex-Officio Members: Dr. L. Palkonyay (LCDC), Dr. R. Pless (LCDC).

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