Statement on Influenza Vaccination for the 2006-2007 Season

Canada Communicable Disease Report
Volume 32 • ACS-7 15 June 2006

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)*†

PDF Version 28 Pages - 368 KB

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of 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. People administering the vaccine should also be aware of the contents of the relevant product leaflet(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s)/leaflet(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Introduction

The antigenic components of the influenza vaccine have been updated for the 2006-2007 season. This statement contains new information on human and avian influenza epidemiology. NACI has grouped the various subgroups of persons at increased risk of the complications associated with influenza into a single grouping of those with chronic conditions. Neuraminidase inhibitors are recommended as the first-line antiviral agents for the prevention of influenza rather than amantadine.

In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis or therapy with influenza-specific antiviral drugs. Immunization is the most effective means to reduce the impact of influenza. Programs should focus on those at high risk of influenza-related complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services.

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.

Person-to-person transmission of influenza virus occurs through droplets from the respiratory tract that are spread by direct contact, through coughing or sneezing, or by hands contaminated with respiratory secretions. Adults spread influenza to others during a period from 1 day before symptom onset to up to 7 days afterwards. Children may have more prolonged viral excretion.

National influenza surveillance in the 2005-2006 season

National influenza surveillance is conducted by the Public Health Agency of Canada (PHAC). The results of surveillance for the 2005-2006 season given in this statement are based on data reported up to 8 April, 2006. The 2005-2006 season started later than usual in Canada with activity first increasing towards the end of December in the west (Alberta and British Columbia). FluWatch data indicate that overall the 2005-2006 influenza season was relatively mild. Also, when compared with the previous two seasons, 2005-2006 was a milder season in terms of a lower proportion of positive laboratory tests for influenza, fewer long-term care facility (LTCF) outbreaks, and fewer influenza surveillance regions reporting widespread and localized activity. In contrast to the 2004-2005 season, which heavily affected the elderly residing in LTCFs(^1,2, influenza in the 2005-2006 season had a greater impact on children. Since the start of the season, a mix of influenza A and B viruses have been detected across Canada. The majority of the influenza A detections were A/H3N2 viruses (A/California/7/2004(H3N2)-like), and the majority of influenza B detections belonged to the B/Victoria/02/1987 lineage, which was not covered by the 2005-2006 vaccine.

Slightly more influenza A than influenza B viruses have been isolated across the country to date during the 2005-2006 season. Of the 5,696 positive influenza identifications, 3,246 (57.0%) were influenza A viruses, and 2,450 (43.0%) were influenza B viruses. Both influenza A and B identifications were first seen in mid-September, 2005, and continued to increase during the season. Widespread influenza activity (due to influenza B) was first observed in Alberta during the week of 24 December, 2005. To date, in this season a mix of influenza A and B viruses have been identified in British Columbia, the Prairies, and Ontario. Mostly influenza A viruses were identified in Quebec, whereas mostly influenza B viruses were identified in the Atlantic provinces.

Of the laboratory-confirmed influenza infections reported, 44.6% were in children < 15 years of age and 17.0% were in adults ≥ 65 years of age. This is in contrast to the previous season, when 45.9% of laboratory-confirmed influenza infections were reported in adults aged ≥ 65 and only 27.7% were reported in children < 15 years of age^1,2.

Influenza activity this season has had a lesser impact on elderly residents of LTCFs, as demonstrated by much fewer outbreaks within LTCFs than in the previous season. As of the week of 8 April, 2006, a total of 134 LTCF outbreaks were reported compared with 835 LTCF outbreaks reported during the same period last season. The number of outbreaks reported in LTCFs this season increased gradually from 1 to 5 outbreaks reported per week in late December to early February, to 15 to 18 outbreaks per week from mid-February onwards.

Surveillance of influenza-associated hospitalizations of children admitted to pediatric centres, reported through the Immunization Monitoring Program, Active (IMPACT), is part of the national influenza surveillance program. Aggregate reports of laboratory- confirmed influenza hospitalizations in children < 16 years of age are reported to PHAC on a weekly basis. Since 27 November, 2005, 296 hospitalizations have been reported in children aged < 16 years from the 12 IMPACT centres. This is somewhat less, yet comparable to, the 381 hospitalizations reported during the same time last season^3,4. Of the hospitalizations occurring in the 2005-2006 season, 40% were of children < 2 years of age. While influenza A and B infections were reported in similar proportions this season, influenza A was responsible for the majority (61%) of the hospitalizations reported by the IMPACT centres. Three influenza-associated deaths in children have been reported to PHAC so far this season. This is within the expected annual range for influenza-associated pediatric mortality in Canada and comparable to the two deaths reported last season^5,6.

To date, the National Microbiology Laboratory (NML) has antigenically characterized 806 influenza viruses received from sentinel public health and hospital laboratories across Canada: 364 (45.2%) were identified as influenza A (H3N2) strains, 52 (6.4%) were influenza A (H1N1) strains, and 390 (48.4%) were influenza B strains. All of the influenza A strains identified so far this season were characterized as being A/California/7/2004 (H3N2)-like and A/New Caledonia/20/1999(H1N1)-like viruses, which are similar to the influenza A/H3N2 and A/H1N1 components of the 2005-2006 influenza vaccine. The A/New Caledonia/20/1999(H1N1)-like virus is also the recommended A/H1N1 component for the 2006-2007 northern hemisphere vaccine. A/California/7/2004(H3N2)-like viruses were antigenically characterized by the NML very early in the season (late-September 2005), whereas A/New Caledonia/20/1999 (H1N1)-like viruses were characterized later (mid-January 2006).

So far this season, the A/Wisconsin/67/2005-like virus, a new A/H3N2 antigenic variant seen elsewhere in the world, has not been identified in Canada. However, isolates recently received by the NML will be tested against the new reagent for A/Wisconsin/ 67/2005-like viruses for further classification. On the basis of current information it is expected that the 2005-2006 vaccine will provide some protection against the A/Wisconsin/67/2005 (H3N2)-like strain, but the degree of protection is not known. It is also expected that the A/H3N2 component recommended for the 2006-2007 northern hemisphere vaccine (A/Wisconsin/67/ 2005(H3N2)-like) would provide some protection against the currently circulating A/California/7/2004(H3N2)-like strains, but again the degree of protection is currently not known.

Of the 390 influenza B strains antigenically characterized by the NML, six (1.5%) were B/Shanghai/361/2002-like viruses (belonging to the B/Yamagata/16/1988 lineage) covered by the influenza B component of the 2005-2006 vaccine. Of the remaining 384 influenza B strains (98.5%), 136 (35.4%) were B/Hong Kong/330/ 2001-like viruses and 248 (64.6%) were B/Malaysia/2506/2004- like viruses (belonging to the B/Victoria/02/1987 lineage), which were not covered by the 2005-2006 vaccine. B/Shanghai/361/ 2002-like viruses were identified as early as late September 2005; however, from the end of November 2005 to the end of February 2006, the majority of influenza B characterizations identified were B/Hong Kong/330/2001-like viruses. Since March 2006, over 99% of the influenza B viruses characterized have been similar to B/Malaysia/2506/2004-like viruses, which is the recommended B component for the 2006-2007 northern hemisphere vaccine.

Ongoing surveillance of antiviral resistance patterns of circulating influenza strains is an important activity for informing appropriate use of antiviral medications to reduce the impact of influenza. By 13 April, 2006, the NML had tested 414 influenza A isolates received from provincial and territorial laboratories since October 2005. Results indicated that 341 influenza A isolates (82%) were resistant to amantadine. Viral resistance to amantadine can emerge rapidly during treatment because of a single point mutation at amino acid position 26, 27, 30, 31, or 34 of the M2 protein. Genetic sequencing of influenza A isolates obtained in the 2005-2006 season revealed that the majority of influenza A (H3N2) isolates contained an amino acid change at position 31 of the M2 protein from serine to asparagine (S31N). The data also indicated that drug-resistant viruses were distributed across Canada. On the basis of this finding, PHAC recommended discontinuation of amantadine for the treatment and prevention of influenza for the remainder of the 2005-2006 influenza season^7,8. Instead, neuraminidase inhibitors were recommended temporarily. Testing of influenza isolates for the 2005-2006 season will continue, and recommendations will be updated according to the results.

International influenza surveillance

Seasonal influenza activity started later than expected for most regions of the world. Globally, a mix of influenza A (H1N1 and H3N2) and influenza B viruses co-circulated during the 2005-2006 season⁹. The overall levels of influenza activity have remained moderate to low in intensity throughout most parts of the world^9,10. In the United States, influenza A (H3N2) predominated this season, most isolates being characterized as similar to A/California/07/2004-like viruses. Since mid-February 2006, an increasing proportion of isolates have been similar to the A/Wisconsin/67/ 2005-like virus, which is the A (H3N2) component recommended for the 2006-2007 northern hemisphere vaccine¹¹. In Europe, influenza B predominated, the majority of influenza B detections being reported in two-thirds of the European countries. Earlier in the season, most of the influenza B isolates were identified as B/Jiangsu/10/2003-like viruses (similar to the B/Shanghai/361/ 2002-like virus currently in the 2005-2006 vaccine) belonging to the B/Yamagata/16/1988 lineage. However, more recently, the majority of isolates have been identified as B/Malaysia/2506/2004- like viruses belonging to the B/Victoria/2/1987 lineage, which is the recommended influenza B component for the 2006-2007 northern hemisphere vaccine¹².

The now extensive outbreaks of avian influenza (H5N1), which began in poultry flocks in South East Asia in 2003 and have since spread to over 50 countries throughout Asia, Africa, and Europe, have been associated with a total of 194 human cases and 109 deaths (overall case fatality rate 56%) in nine countries (Thailand, Vietnam, Cambodia, Azerbaijan, China, Egypt, Indonesia, Iraq, and Turkey) between 1 December, 2003, and 13 April, 2006.

Analysis of World Health Organization (WHO)-confirmed cases for which epidemiologic information is available indicates that the median age of confirmed cases is 17 years (range: 4 months to 73 years, n = 178). Almost half of these (48%) have been male.

The human cases have occurred in three waves: wave 1 (December 2003 to March 2004) consisted of 36 cases and 24 deaths; wave 2 (June 2004 to November 2004) consisted of nine cases and eight deaths; and wave 3, which began in December 2004 and is ongoing, has resulted in 149 WHO-confirmed cases and 77 deaths13.

Although human-to-human transmission among close contacts cannot be excluded in some instances, no evidence of efficient or sustained human-to-human transmission exists to date. Genetic and antigenic analyses reported by theWHO have shown that the influenza A/H5N1 virus (Asian strain) has undergone some changes since 1997 when the first human infections were reported^9,14 . More investigation, both virologic and epidemiologic, is needed to better understand the effects of these mutations on the transmissibility of the virus from birds to human as well as from human to human. However, at this time, these changes do not appear to have altered the epidemiology of the disease in humans, and the mutations have not become fixed in the circulating viruses. The virus continues to be a zoonotic virus, not a human-adapted one, and human infections remain a rare event.

Recommendations for the 2006-2007 influenza vaccine

General considerations

The national goal of influenza immunization programs is to prevent serious illness caused by influenza and its complications, including death. NACI therefore recommends that immunization programs target vaccine delivery, as a priority, to those persons at high risk of influenza-related complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services; however, NACI encourages annual vaccine for all Canadians.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year's vaccine. NACI recommends that the trivalent vaccine for the 2006-2007 season in Canada contain A/New Caledonia/ 20/99 (H1N1)-like, an A/Wisconsin/67/2005 (H3N2)-like and a B/Malaysia/2506/2004-like virus strains. Vaccine producers may use antigenically equivalent strains because of their growth properties. The influenza strain A/Hiroshima/52/2005 is antigenically equivalent to influenza A/Wisconsin/67/2005 virus strain. The vaccine to be marketed in Canada for the 2006-2007 influenza season contains A/New Caledonia /20/99 (H1N1), either A/Hiroshima/52/2005 (H3N2) or A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 virus antigens.

Annual immunization against influenza must be given in order to provide optimal protection. Continual antigenic drift of the influenza virus means that a new vaccine, updated yearly with the most current circulating strains, is needed to protect against new infections. The antigenic match between the WHO recommended vaccine strains and epidemic strains was appropriate during 12 of the 15 influenza seasons (80%) between 1982-1983 and 1996-1997¹⁵.With a good match, influenza vaccination has been shown to prevent laboratory-confirmed influenza illness in approximately 70% or more of healthy individuals^16,17 In older persons living in residential facilities influenza vaccine prevents pneumonia, hospital admission, death from pneumonia (vaccine effectiveness 42% to 46%), and all-cause mortality (vaccine effectiveness 60%)¹⁸.

The recommended time for influenza immunization is the period from October to mid-November. However, decisions regarding the exact timing of vaccination of ambulatory and institutionalized individuals must be made according to local epidemiology, recognition of the need to use patient contact 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 (HCWs) 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.

Recommended recipients (see Table 1)

Current influenza vaccines approved for use in Canada are immunogenic, safe, and associated with minimal side effects (see Adverse Reactions and Contraindications and Precautions). Influenza vaccine may be administered to any child ≥ 6 months of age, 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 of influenza-related complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services. These groups remain the priority for influenza vaccination programs. However, significant morbidity and societal costs are also associated with seasonal influenza illness and its complications occurring in people who are not considered at high risk of complications (i.e. healthy children ≥ 2 years of age and healthy adults). For this reason, healthy children ≥ 2 years of age and adults should be encouraged to receive the vaccine.

Table 1. Recommended recipients of influenza vaccine

People at high risk of influenza-related complications

• Adults and children with selected chronic health conditions. A number of chronic health conditions, if significant enough to require regular medical follow-up or hospital care, are associated with increased risk of influenza-related complications and/or lead to exacerbation of the chronic disease. These include cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis, and asthma), diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), renal disease, anemia or hemoglobinopathy, and conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration. This category includes children and adolescents (age 6 months to 18 years) with conditions treated for long periods with acetylsalicylic acid (because of the potential increased risk of Reye syndrome associated with influenza). Pregnant women with any of these co-morbidities are also at increased risk of the complications of influenza and should be immunized.

• People of any age who are residents of nursing homes and other chronic care facilities. Such residents often have one or more chronic medical conditions and live in institutional environments that may facilitate spread of the disease. Studies have shown that the use of vaccine in this setting will decrease the occurrence of illness, hospital admission, pneumonia, and death.

• People ≥ 65 years of age. The risk of severe illness and death related to influenza is increased in healthy people in this age group. Vaccination is effective in preventing hospital admission and death, and results in direct health care cost savings. In a study of US national hospital discharge data, Simonsen et al. reported influenza-associated hospitalization rates of 125 to 228 per 100,000 healthy persons > 65 years of age¹⁹.

• Healthy children aged 6 to 23 months. Children in this age group are at increased risk of influenza-associated hospitalization compared with healthy older children and young adults. Hospitalization rates in this age group have been estimated in a variety of studies to be from 90 to 1,000 admissions per 100,000 healthy children^20,21. NACI recognizes that both the number of studies and participants in the randomized controlled trials of influenza vaccine in children in this age group are limited, that there are unanswered questions, including the unknown efficacy of vaccine in children who have not had experience with the vaccine or infection (unprimed), and that routine immunization programs in this age group may not be considered cost-effective^{22, 24}.NACI strongly encourages research regarding these issues. However, on the basis of existing data regarding the high incidence of influenza-associated hospitalization in healthy children < 24 months, NACI recommends the inclusion of this age group among high-priority recipients of influenza vaccine.

People capable of transmitting influenza to those at high risk of influenza-related complications

People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk person(s) has been immunized. These individuals include the following:

• Health care and other care providers in facilities and community settings who, through their activities, are potentially capable of transmitting influenza to those at high risk of influenza complications. This group includes regular visitors, emergency response workers, those who have contact with residents of continuing care facilities or residences, and those who provide home care for persons in high-risk groups.

• Household contacts (adults and children) of people at high risk of influenza complications, whether or not they have been immunized. This group includes household contacts of children < 6 months of age (who are at high risk of complications from influenza but for whom there is no available effective vaccine) and of children aged 6 to 23 months. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn.

• Those providing regular child care to children < 24 months of age whether in or out of the home.

• Those who provide services within closed or relatively closed settings to persons at high risk (e.g. crew on ships).

People who provide essential community services

Vaccination for these individuals should be encouraged in order to minimize the disruption of routine activities during annual epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults, as this has been shown to decrease work absenteeism due to respiratory and other illnesses.

People in direct contact with avian-influenza-infected poultry during culling operations

These individuals may be at increased risk of avian influenza infection because of exposure during the culling operation^25,26. Influenza immunization on a yearly basis for these workers is increasingly being recommended in many countries¹¹ with the theoretical rationale that it may prevent the infection of these individuals with human influenza strains and thus reduce the potential for human-avian reassortment of genes should such workers become coinfected with avian influenza. Direct involvement may be defined as sufficient contact with infected poultry to allow transmission of avian virus to the exposed person. The relevant individuals include those performing the cull as well as others (such as supervising veterinarians and inspectors) who may be directly exposed to the avian virus. Note that those who are immunized with influenza vaccine just before exposure to avian influenza will not produce protective antibodies against the human vaccine strains for approximately 10 to 14 days. Antiviral prophylaxis should be used during that interval in order to prevent infection with human influenza and avian influenza during the culling operation. For further information on human health issues related to domestic avian influenza outbreaks see the PHAC guidance at http://www.phac-aspc.gc.ca/publicat/daioenia/index.html (see also the section entitled Prophylactic use of Antivirals, NACI Statement on influenza vaccination for the 2005-2006 season).

Further comments regarding influenza immunization

• Immunization of healthy persons aged 2 to 64 years. Individuals in this age group should be encouraged to receive the vaccine, even if they are not in one of the aforementioned priority groups. Meta-analyses of randomized controlled trials in healthy adults show that inactivated influenza vaccine is about 70% effective in preventing laboratory-confirmed influenza infections¹⁶. Depending on whether infection was defined by serology or culture, trials of inactivated trivalent influenza vaccine in children aged 2 to 5 years estimate vaccine efficacy to be 31% to 83%. Fifteen randomized controlled trials of healthy children aged 6 months to 19 years, conducted over a period during which the recommended vaccine was both well matched and not well matched with circulating viral strains, showed a relative risk reduction in either clinical or laboratory-confirmed illness ranging from 0% to 93%¹⁷.

  Mathematical modelling of influenza transmission in communities suggests that vaccinating schoolchildren would reduce mortality associated with influenza deaths in older adults^27,28. In an open-labelled, non-randomized study of two US communities, vaccination of 20% to 25% of children 1.5 to 18 years of age was associated with indirect protection against medically attended respiratory illness in adults > 35 years of age²⁹. Indirect protection has been demonstrated in other unblinded studies in which school-aged children have been immunized^30-32.

  In the United States, the American Academy of Family Physicians and the Advisory Committee on Immunization Practices recommend that the age of universal influenza vaccination of adults be ≥ 50 years of age. The primary rationale is that many persons aged 50 to 64 years have high-risk conditions such as diabetes mellitus or heart disease, yet the influenza immunization rate among US adults in this age group who have high-risk chronic medical conditions is low. The low immunization rate is a result of persons being unaware that they have a high-risk condition, of lack of health care access, or of failure of HCWs to deliver immunization. Age-based influenza guidelines may be more successful in reaching individuals with medical conditions that put them at higher risk of influenza complications as compared with previous guidelines based on recognition of the specific high-risk conditions, and they have been found to be cost-effective in one analysis³³.

• Influenza vaccine in pregnancy and during lactation. Influenza vaccination is recommended for pregnant and breastfeeding women who are characterized by any of the conditions listed under Recommended Recipients, in particular those who have chronic health conditions or who are close contacts of high-risk persons. Pregnant women with any of the selected chronic conditions putting them at high risk of the complications associated with influenza are a priority for immunization. Influenza vaccine is safe for pregnant women at all stages of pregnancy and for breastfeeding mothers³⁴. Immunization of pregnant women has the advantage of potentially protecting the fetus through transplacental antibody passage or through breast milk. Among healthy pregnant women, morbidity and mortality associated with influenza is increased during pandemics.

  Immunization of all pregnant women is recommended in the United States, where a population-based assessment of maternal and perinatal morbidity in a Tennessee Medicaid population showed a respiratory hospitalization rate of 200 per 100,000 pregnant and perinatal women without risk factors for influenza-associated complications and 100 to 6,000 per 100,000 in women with asthma, diabetes, or other high-risk conditions, but no adverse effects on perinatal outcomes 35. A review of a large, US managed-care organization identified influenza-like illness in 8.3% of pregnant and postpartum women; 5.4% of these were severe enough to require an emergency department visit or hospitalization36. In both studies risk increased in later pregnancy.

  In another large, managed-care setting in which > 49,000 live births were followed, 4.7% of women had at least one outpatient visit for influenza-like illness. There were nine admissions for pneumonia during the influenza seasons (18.2 cases/100,000 population)³⁷. A recent populationbased record linkage study in Nova Scotia for the period 1990-2002 showed that in women with co-morbidities 44.9 respiratory-related hospitalizations during influenza season occurred per 10,000 women-months. Compared with themselves in a non-pregnancy year, this represents a relative risk for hospitalization of 8.5 (95% confidence interval [CI]: 5.1-13.9). Healthy third trimester women had 20 admissions for which a respiratory-related condition was the most responsible diagnosis, representing an admission rate of 1.94/10,000 women-months (adjusted relative risk = 2.4, CI: 1.2-4.9) compared with themselves in a non-influenza season. Healthy third trimester women had an overall respiratory-related admission rate of 7.36/10,000 women-months during influenza season, compared with 3.06/10,000 in a non-influenza season. Immunization rates, even of women with co-morbidities, were low (personal communication: L. Dodds and S. McNeil et al. Faculty of Medicine, Dalhousie University, 2006).

  There are no randomized controlled trials to assess the efficacy of influenza vaccine in pregnancy. A retrospective review of vaccinated and non-vaccinated pregnant women in a large managed-care organization showed no difference in the occurrence of influenza-like illness or hospitalizations with principal diagnoses of influenza or pneumonia, but it was underpowered to do so since only 7% of women had been immunized³⁷.

  Healthy women who will be pregnant during influenza season and who wish to avoid morbidity associated with influenza illness should be encouraged to be vaccinated during any trimester of pregnancy. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn.

• Travellers. People with selected chronic medical conditions should be immunized as previously discussed (Table 1). Healthy persons should be encouraged to receive vaccine. Vaccines prepared specifically against strains that are predicted to circulate in the southern hemisphere are not currently available in Canada. For further information on advising travellers about influenza prevention the Committee to Advise on Tropical Medicine and Travel statement should be consulted³⁸.

NACI suggests that programmatic decisions in Canada regarding how to access and immunize those listed under Recommended Recipients are best made by authorities responsible for the planning and implementation of such programs.

Immunogenicity and efficacy

Intramuscular administration of inactivated influenza vaccine results in the production of circulating IgG antibodies to the viral hemagglutinin as well as a cytotoxic T lymphocyte response. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. Anti-hemagglutinin serum antibody is a predictor of total protection (acquisition of infection) and partial protection (disease after infection). The production and persistence of antibodies after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immunodeficiency states. Humoral antibody levels, which correlate with vaccine protection, are generally achieved 2 weeks after immunization, and immunity usually lasts < 1 year. However, in the elderly, antibody levels may fall below protective levels within 4 months.

Repeated annual administration of influenza vaccine has not been demonstrated to impair the immune response of the recipient to influenza virus.

The effectiveness of influenza vaccine varies, depending upon the age and immunocompetence of the vaccine recipient, the endpoint studied, the incidence of infection, and the degree of similarity (“match”) between the vaccine viral strain and the circulating viral strain during influenza season. With a good match, influenza vaccination has been shown to prevent influenza illness in approximately 70% to 90% of healthy children and adults, whereas a vaccine efficacy of 30% to 60% has been demonstrated when there are significant antigenic differences between circulating and vaccine viral strains.

Vaccine efficacy may be lower in certain populations (e.g. the immunocompromised, the elderly) than in healthy adults. However, the possibility of lower efficacy should not prevent immunization in those at high risk of influenza-associated morbidity since protection is still likely to occur. For example, among residents of LTCFs, effectiveness in preventing influenza illness may be relatively low (30% to 40%), but vaccination may be 50% to 60% effective in preventing hospitalization and pneumonia, and up to 85% to 95% in preventing death. Influenza vaccination can induce protective antibody levels in a substantial proportion of immunosuppressed adults and children, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients.

It has been postulated that the routine immunization of healthy pre-school and school-age children may prevent the dissemination of the organism within communities, resulting in an overall decrease in the burden of illness in all age groups. The role of this strategy in controlling disease in those other than the vaccinee is a subject of ongoing research³⁹.

Administration of influenza vaccine

Dosage schedule

The recommended dosage schedule and type of influenza vaccine are presented in Table 2. Influenza vaccines available in Canada are available as split-virus or inactivated subunit preparations. Two products (Vaxigrip®, Fluviral S/F®) are split virus vaccines which are treated with an organic solvent to remove surface glycoproteins, producing a split-virus resulting in reduced vaccine reactogenicity. Influvac™ is a surface antigen, trivalent, inactivated subunit vaccine, which is currently approved for use among persons > 18 years of age. Each 0.5 mL of vaccine contains 15 µg of hemagglutinin of each antigen.

Previously unvaccinated children < 9 years of age require two doses influenza vaccine, with an interval of 4 weeks. The second dose is not needed if the child received one or more doses of vaccine during a previous influenza season.

There are no data suggesting that administration of a second dose of influenza vaccine in elderly individuals or other individuals who may have an altered immune response will boost immunity^40,41.

Immunization with currently available influenza vaccines is not recommended for infants < 6 months of age.

Table 2. Recommended influenza vaccine dosage, by age, for the 2006-2007 season

Influenza vaccine should be administered intramuscularly. The deltoid muscle is the recommended site in adults and children ≥ 12 months of age. The anterolateral thigh is the recommended site in infants < 12 months of age.

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 in adults but rarely interferes with normal activities. Prophylactic acetaminophen may decrease the frequency of pain at the injection site⁴². Healthy adults receiving the split-virus vaccine show no increase in the frequency of fever or other systemic symptoms compared with those receiving placebo.

Split-virus influenza vaccines are safe and well tolerated in healthy children. Mild local reactions, primarily soreness at the vaccination site, occur in 7% or less of healthy children who are < 3 years of age. Post-vaccination fever may be observed in 12% or less of immunized children aged 1 to 5 years.

Several influenza vaccines that are currently marketed in Canada contain minute quantities of thimerosal, which is used as a preservative⁴³. One thimerosal-free vaccine (Influvac™, Solvay Pharma), approved for persons ≥ 18 years of age, is available in Canada¹. Retrospective cohort studies of large health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders. Nevertheless, in response to public concern, influenza vaccine manufacturers in Canada are currently working towards production and marketing of thimerosal-free influenza vaccines.

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

Guillain-Barré syndrome (GBS) occurred in adults in association with the 1976 swine influenza vaccine, and evidence favours the existence of a causal relation between the vaccine and GBS during that season⁴⁴. In an extensive review of studies since 1976, the United States Institute of Medicine concluded that the evidence is inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered after the swine influenza vaccine program in 1976⁴⁵.

In a Canadian study, the background incidence of GBS was estimated at 2.02 per 100,000 person-years in Ontario and 2.30 per 100,000 person-years in Quebec⁴⁶. A variety of infectious agents, including Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae have been associated with GBS⁴⁷. It is not known whether influenza virus infection itself is associated with GBS. A retrospective review of the 1992-1993 and 1993-1994 US influenza vaccine campaigns found a risk of about 1 case per million vaccinees above background incidence⁴⁸. It is 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 8 weeks of a previous influenza vaccination appears prudent at this time.

Influenza vaccine is not known to predispose vaccine recipients to Reye syndrome.

During the 2000-2001 influenza season, PHAC received an increased number of reports of vaccine-associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS)⁴⁹. The case definition is as follows: the onset of bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling occurring within 24 hours of influenza immunization. The pathophysiologic mechanism underlying ORS remains unknown, but it is considered distinct from IgE-mediated allergy.

Since the 2000-2001 influenza season fewer ORS cases have been reported to PHAC. In the province of Quebec the rate of ORS per 100,000 doses distributed declined from 46.6 in 2000 to 34.2 and 20.6 in 2001 and 2002 respectively, to nine per 100,000 in 2003⁵⁰. Surveillance for all adverse events following immunization, including ORS, is ongoing.

Approximately 5% to 34% of patients who have previously experienced ORS may have a recurrence attributable to the vaccine, but these episodes are usually milder than the original one, and vaccinees indicate willingness to be immunized in subsequent years⁵¹. Persons who have a recurrence of ORS upon re-vaccination do not necessarily experience further episodes with future vaccinations. Data on clinically significant adverse events do not support the preference of one vaccine product over another when re-vaccinating those who have previously experienced ORS^52,53.

Please refer to the Canadian Immunization Guide for further details about administration of vaccine and management of adverse events.

Contraindications and precautions

Influenza vaccine should not be given to people who have had an anaphylactic reaction to a previous dose.

Persons with know IgE-mediated hypersensitivity to eggs (manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension or shock) should not be routinely vaccinated with influenza vaccine. Egg-allergic individuals who are at risk of complications of influenza should be evaluated by an allergy specialist, as vaccination might be possible after careful evaluation, skin testing, and graded challenge or desensitization.^* If such an evaluation is not possible, the risk of an allergic reaction to the vaccine must be weighed against the risk of influenza disease.

Expert review of the risks and benefits of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent allergic reaction to the vaccine, or any other symptoms (e.g. throat constriction, difficulty swallowing) that raise concern regarding the safety of re-immunization. This advice may be obtained from local medical officers of health or other experts in infectious disease, allergy/immunology, and/or public health. Health care providers who are unsure whether an individual previously experienced ORS versus an IgE-mediated hypersensitivity immune response should seek consultative advice. In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation (which may involve skin testing) from an allergy/immunology expert.

Individuals who have experienced ORS symptoms, including severe ORS consisting of non-lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling), may be safely re-immunized with influenza vaccine.

Adults with serious acute febrile illness usually should not be vaccinated until their symptoms have abated. Those with mild non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine. Opportunities for immunization should not be lost because of inappropriate deferral of 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.

Therapy with beta-blocker medication is not a contraindication to influenza vaccination. Individuals who have an allergy to substances that are not components of the influenza vaccine, are not at increased risk of allergy to influenza vaccine.

Simultaneous administration of other vaccines

Influenza vaccine may be given at the same time as other vaccines. The same limb may be used if necessary, but different sites on the limb should be chosen. Different administration sets (needle and syringe) must be used.

The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Health care providers should take the opportunity to vaccinate eligible persons against pneumococcal disease when influenza vaccine is given.

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

Vaccination is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death from influenza infection and related complications. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% to 91% of LTCF residents and 20% to 40% of adults and children with chronic medical conditions receive vaccine annually. Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%.

Low rates of utilization are due to failure of the health care system to offer the vaccine and refusal by persons who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary. HCWs 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 for which they care⁵⁴. Educational efforts aimed at HCWs and the public should address common concerns about vaccine effectiveness and adverse reactions. These include the beliefs of patients at risk, the belief that HCWs and other service providers 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 a very important factor affecting whether a person accepts immunization. Most people at high risk are already under medical care and should be vaccinated during regular fall visits. Strategies to improve coverage include the following:

• Vaccinating people at high risk who are being discharged from hospital or visiting the emergency department in the autumn

• Promoting influenza vaccination in clinics in which high-risk groups are seen (e.g. cancer clinics, cardiac clinics, and pulmonary clinics)

• Using community newspapers, radio, television, and “flu information lines”, and collaborating with pharmacists and specialist physicians to distribute positively framed information about the benefits and risks of influenza immunization

• Issuing computer-generated reminders to HCWs, mailing reminder letters to patients, or using other recall methods to identify outpatients at high risk

• Issuing patient-carried reminder cards

• Increasing accessibility of immunization clinics to staff in institutions and community-based elderly by, for example, implementing mobile programs

• Organizing activities such as vaccination fairs and competitions between institutions

• Working with multicultural groups to plan and implement effective programs

• Incorporating influenza vaccination within the provision of home health care.

Immunization of Health Care Workers (HCW)

Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality. Studies have demonstrated that HCWs who are ill with influenza frequently continue to work, thereby potentially transmitting the virus to both patients and co-workers. In a British study, 59% of HCWs with serologic evidence of recent influenza infection could not recall having influenza, suggesting that many HCWs experience subclinical infection. These individuals continued to work, potentially transmitting infection to their patients. In addition, absenteeism of HCWs who are sick with influenza results in excess economic costs and, in some cases, potential endangerment of health care delivery due to scarcity of replacement workers.

For the purposes of this document we define a HCW as a person who provides direct patient care, as well as one who provides health services in an indirect fashion, such as through administrative activities in a setting where patient care is conducted. The latter group may come into close contact with patients through the sharing of common areas within facilities, such as cafeterias and waiting areas. The term “direct patient contact” is defined as activities that allow opportunities for influenza transmission between HCWs and a patient.

Vaccination of HCWs in health care facilities has been shown to reduce total patient mortality, influenza-like illness, and serologically confirmed influenza. Influenza vaccination programs for HCWs may also result in cost savings and reduced work absenteeism, depending on factors such as disincentives to take sick days, strain virulence, and the match between infecting and vaccine strains.

NACI considers the provision of influenza vaccination for HCWs who have direct patient contact to be an essential component of the standard of care for the protection of their patients. HCWs who have direct patient contact should consider it their responsibility to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, refusal of HCWs who have direct patient contact to be immunized against influenza implies failure in their duty of care to patients.

In order to protect vulnerable patients during an outbreak, it is reasonable to exclude from direct patient contact HCWs who develop confirmed or presumed influenza and unvaccinated HCWs who are not receiving antiviral prophylaxis.

Health care organizations should have policies in place to deal with this issue.

Prophylactic use of antivirals

The prophylactic use of antiviral agents against influenza is discussed in this section. Antiviral treatment of influenza is not covered in this statement.

Antiviral prophylaxis should not replace annual influenza vaccination. Vaccination remains our primary tool for the prevention of influenza infection and illness.

There are two available classes of antiviral drugs that have been used for influenza prevention. Because almost all influenza isolates in the most recent influenza season were resistant to amantadine, this drug is not recommended by NACI for prophylaxis against influenza for the 2006-2007 season. This recommendation will be revisited if new information becomes available. Neuraminidase inhibitors prevent the replication of both type A and B influenza viruses by inhibiting influenza virus neuraminidase. Neuraminidase promotes the release of virus from infected cells by preventing virions from self-aggregating and binding to the surface of infected cells. Oseltamivir is a neuraminidase inhibitor that is licensed for pre- and post-exposure prophylaxis against influenza A and/or B in persons ≥ 1 year of age.

Zanamivir is a neuraminidase inhibitor that has not been approved by Health Canada for prophylactic use, although it has been used off-label for this purpose.

A review of randomized placebo-controlled trials among healthy adults reports that neuraminidase inhibitors are 74% effective in preventing naturally occurring cases of clinically defined influenza and 60% effective in preventing laboratory-confirmed influenza. Oseltamivir was 92% effective in preventing laboratoryconfirmed clinical influenza illness in a randomized multicentre controlled trial of prophylaxis among elderly individuals in residential care; however residents with significant renal disease, hepatic dysfunction, cardiac failure, cancer, HIV infection, and history of alcohol/drug abuse were excluded. The efficacy of oseltamivir in preventing influenza in immunocompromised persons has not been established. Oseltamivir has been successfully used as prophylaxis, along with vaccination and infection control measures, to control outbreaks of influenza in nursing homes and LTCFs. In a randomized controlled trial oseltamivir was efficacious in protecting healthy household contacts of index influenza cases who were not treated. Households with pregnant or breastfeeding women, or individuals with cancer, immunosuppression, HIV infection, or chronic liver or renal disease were excluded from this study.

The emergence of oseltamivir-resistant virus during or after prophylactic use of this antiviral has not yet been noted. However, 0.33% to 18% of influenza isolates have been noted to be oseltamivir resistant during follow-up of children and adults in treatment studies.

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, as previously indicated, antiviral prophylaxis should not replace annual influenza vaccination.

Neuraminidase inhibitors are not effective in providing prophylaxis for respiratory infections other than influenza. Therefore it is critically important to base decisions regarding their prophylactic use on appropriate epidemiologic, clinical, and laboratory data regarding the etiology of prevalent infection(s).

NACI recommends that neuraminidase inhibitors may be used prophylactically in the following situations:

• For the control of influenza outbreaks among high-risk residents of institutions. Consultation with laboratories and the local medical health officer is important in order to determine whether the circulating strain is type A or B. Oseltamivir should be given to all residents who are not already ill with influenza, whether previously vaccinated or not, and to unvaccinated staff (see Contraindications and Precautions). Prophylaxis should also be considered for HCWs, regardless of vaccination status, during outbreaks caused by influenza strains that are not well matched by the vaccine. Prophylaxis should be given until the outbreak is declared over. This date may be defined as a minimum of 8 days after the onset of the last case, based on an average 4-day period of infectiousness for the last case plus an average 4-day incubation period for those potentially exposed.

• For prophylaxis in non-institutionalized people at high risk during an outbreak when vaccine is unavailable, contraindicated, or unlikely to be effective because of a poor match between the vaccine and the circulating viral strain. In this case, prophylactic antiviral medication may be taken each day for the duration of influenza activity in the community. The decision as to what constitutes a “poor match” between vaccine and circulating viral strains should be based on any existing data on vaccine protectiveness during that influenza season, if available, and in consultation with the local medical health officer. Unfortunately, data on vaccine protectiveness are often not available until the season is over. NACI encourages the development of methods for the early assessment of vaccine efficacy in years in which the appearance of new circulating strains may result in reduced vaccine efficacy.

  Antiviral prophylaxis may also be given during an outbreak to people at very high risk who have been previously vaccinated but who are expected to have an impaired immune response to the vaccine. This includes persons with advanced HIV disease and the very frail elderly.

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

• For unvaccinated people who provide care for people at high risk during an outbreak. It is reasonable to allow these individuals to work with high-risk patients as soon as they start antiviral prophylaxis. Unless there is a contraindication, they should also be immediately vaccinated against influenza. Antiviral prophylaxis should be continued until 2 weeks after the care provider has been vaccinated. These workers must be alert to the symptoms and signs of influenza, particularly within the first 48 hours after starting antiviral prophylaxis, and should be excluded from the patient care environment if these develop.

• Antiviral post-exposure prophylaxis may be used for non-vaccinated household contacts of index influenza cases. The secondary attack rate among family members of a household in which there is a laboratory-confirmed index case varies from 13% to 25% according to family composition, virus strain, and exposure outside the household, among other variables. Seven days of oseltamivir was 89% effective in preventing laboratory-confirmed influenza A or B among household contacts ≥ 12 years of age when initiated within 48 hours of symptom onset in the index case⁵⁵. However, households containing pregnant or breastfeeding women, individuals with cancer, immunosuppression, HIV or chronic hepatic or renal disease were excluded from this study.

  The diagnosis of influenza in the index case should be based on laboratory confirmation (e.g. by means of a rapid diagnostic test) or clinical parameters that have high positive predictive value in the setting of prevalent infection in the community. Studies suggest that when influenza is circulating in a community, patients with an influenza-like illness who have both cough and fever within 48 hours of symptom onset are likely to have influenza^56,57. The presence of sore throat is suggestive of a diagnosis other than influenza.

  Despite the availability of antiviral agents for post-exposure prophylaxis within households, use of influenza vaccine for pre-exposure prophylaxis at season onset remains the recommended protective strategy of choice. Influenza vaccine provides protection against illness that may result from exposure within the family and community over a more prolonged period of time. Although it is preferred that administration occur in the fall, influenza vaccine may be given through the winter months if the vaccination opportunity was previously missed.

• For prophylaxis among individuals who will be exposed to avian influenza. Consultation with the local medical officer of health is required. Choice of antiviral agent should make use of any available data regarding the susceptibility of the avian virus strain to antiviral agents. At the present time the efficacy of these drugs in preventing avian influenza has not been established. Experience is limited regarding the prophylactic use of neuraminidase inhibitors for periods of time longer than 6 weeks.

When prophylaxis is indicated, the decision regarding which antiviral agent to use should take into account the type of influenza strain circulating and the efficacy, potential toxicity, cost, and ability to administer the agent within a particular population.

Factors including local epidemiology, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost may be considered in decisions regarding the duration of antiviral prophylaxis.

Oseltamivir

Oseltamivir is available in 75 mg capsules as well as a powder that can be reconstituted into an oral suspension at 12 mg/mL. Oseltamivir is not approved for use in children < 1 year of age. The recommended oral dose of oseltamivir for prevention of influenza in persons > 13 years of age is 75 mg once daily. The recommended oral dose for prevention of influenza in pediatric patients is based on body weight. For children ≤ 15 kg, 30 mg once a day; for children > 15 to 23 kg, 45 mg once a day; for children > 23 to 40 kg, 60 mg once a day; and for children > 40 kg, 75 mg once a day. For post-exposure prophylaxis, oseltamivir should begin within 48 hours of exposure. The duration of household post-exposure prophylaxis used in a randomized controlled trial was 7 days. Consideration may be given to extending the duration of prophylaxis to up to 14 days if the index influenza case is a child or an elderly individual, as these persons may continue to shed virus for up to 14 days after onset of their illness.

No dose adjustment is necessary with a creatinine clearance above 30 mL/min. Availability of a recent result of a serum creatinine or creatinine clearance based on a 24-hour urine collection is not required before starting oseltamivir prophylaxis, unless there is reason to suspect significant renal impairment. For those with a creatinine clearance of 10 to 30 mL/min, the dosage of oseltamivir should be reduced to 75 mg every other day or 30 mg of suspension every day orally. No dosing recommendation is available for patients with a creatinine clearance < 10 mL/min or those undergoing hemodialysis and peritoneal dialysis.

Oseltamivir is converted to oseltamivir carboxylate by esterases located predominantly in the liver. The safety and efficacy of oseltamivir in those with hepatic impairment has not been established.

Oseltamivir should be used during pregnancy and lactation only if the potential benefit justifies the potential risk to the fetus or nursing infant. Insufficient data are currently available regarding possible toxic effects on the fetus. It is not known whether oseltamivir or its active metabolite is excreted in human milk.

Oseltamivir is contraindicated in persons with known hypersensitivity to any components of the product.

Co-administration of probenecid results in a two-fold increase in exposure to oseltamivir carboxylate, the active metabolite of oseltamivir, because of increased active anionic tubular secretion in the kidney.

The most common adverse events reported in oseltamivir prevention studies using doses of 75 mg once daily are headache, fatigue, nausea, cough, diarrhea, vomiting, abdominal pain, insomnia, and vertigo. However the difference in incidence between oseltamivir and placebo was ≥ 1% only for headache, nausea, vomiting, and abdominal pain.

Amantadine

Although amantadine is not recommended for antiviral prophylaxis this year, information is presented here in the event that susceptibility testing of the 2006-2007 strain indicates susceptibility to this drug. Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of influenza A virus through the blocking of ion channels of the cell membrane. It is not effective against influenza B. Rimantadine is a related adamantane antiviral agent that is not approved for use in Canada. It will not be discussed in this statement.

The dosage recommendations for prophylaxis against influenza A infection with amantadine are presented in Table 3, but the package insert should be read for complete information. Any adjustments for renal function should be made in addition to adjustments for age. Particular caution should be paid to dosages in those > 65 years of age, among whom some degree of renal impairment is common. Dosagesmay be adjusted according to calculated or laboratory-confirmed creatinine clearance. In care facilities for the elderly, serum creatinine levels measured up to 12 months previously can be safely used to estimate creatinine clearance. It should be noted that although Table 3 presents the recommended dosage schedule for amantadine prophylaxis, a few studies suggest that a prophylactic dose of 100 mg daily in those 10 to 64 years of age, as well as in children weighing > 20 kg with normal renal function, may be as effective as the recommended dose of 200 mg daily.

While use of this dosing schedule, when properly adhered to, has been effective in controlling institutional influenza A outbreaks, the intermittent dosages may be confusing. An alternative, once daily dosage regimen for persons > 65 years of age, based on renal function, is shown in Table 4. This new dosage regimen is derived from pharmokinetic modelling, which suggests that it should be as effective and safe as the standard regimen presented in Table 3.

Table 3. Recommended amantadine hydrochloride prophylactic dosage by age and renal status

Table 4. Proposed once daily dosing schedule for amantadine solution
(10 mg/mL) in persons aged > 65 years*

* Table reproduced with permission of McGeer et al. and the Canadian Journal of Infectious Diseases. Daily dosing increments set at 2.5 mL to permit the use of medicine cups marked at 2.5mL.† No daily dose; if outbreak continues, repeat 100 mg dose every 7 days during the outbreak.

Amantadine was given for 10 days in studies of post-exposure prophylaxis among household contacts of index cases with influenza. Amantadine has been given for up to 16 weeks in pre-exposure prophylaxis studies.

In otherwise healthy young adults given amantadine prophylactically, 5% to 10% report difficulty concentrating, insomnia, lightheadedness, 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. Therefore, in people with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Recommended prophylactic dosages by age and renal function are shown in Tables 3 and 4. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 ± 36 hours. For patients with a creatinine clearance of < 10 mL/min who are not receiving dialysis, a dose of amantadine 100 mg orally every 3 weeks is recommended (F. Aoki: personal communication, 14 September, 2004, University of Manitoba).

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. The patient's age, weight, renal function, co-morbid 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.

Acknowledgment

NACI gratefully acknowledges the assistance of Francesca Reyes, Jeannette Macey, Kerri Watkins, and Yan Li, from the Public Health Agency of Canada, in the preparation of this manuscript.

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* Members: Dr. M. Naus (Chair), Dr. S. Deeks (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. K. Laupland, Dr. S. McNeil, Dr. M.N. Primeau, Dr. B. Tan, Dr. B.Warshawsky.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. J. Smith (CDC), Dr. D. Money (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE), Dr. P. Orr (AMMI Canada).

Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB), Dr. M. Tepper (DND).

† This statement was prepared by Dr. Joanne Langley and approved by NACI and by the Public Health Agency of Canada (PHAC).

* Web changes done to the following issue:
http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/06vol32/dr3215-eng.php