Statement on Influenza Vaccination
for the 2005-2006 Season

Canada Communicable Disease Report
Volume 31 • ACS-6
15 June 2005

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

PDF Version
32 Pages - 294 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 (PHAC) 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 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 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 PHAC'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 2005-2006 season. The present statement contains new information on human and avian influenza epidemiology. NACI has added a recommendation for influenza vaccination of individuals with any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration. Changes in the section entitled "Immunization of Health Care Workers" were made to clarify the definitions of health care worker (HCW) and direct patient contact.

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 (amantadine and neuraminidase inhibitors). 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 for 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. Further, 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.

National Influenza Surveillance in the 2004-2005 Season

National influenza surveillance is conducted by the Centre for Infectious Disease Prevention and Control (CIDPC) within the Public Health Agency of Canada (PHAC). Results of surveillance for the 2004-2005 influenza season in this statement are based on data collected as of 12 March, 2005. The season started at the end of November 2004, which is typical for Canada. Surveillance indicators suggest a less severe season compared with 2003-2004. In contrast to the 2003-2004 season in which pediatric cases were predominant, influenza in 2004-2005 had a greater effect on the elderly who reside in long-term care facilities (LTCFs). Most of the influenza A (H3N2) viruses isolated earlier in the season were antigenically similar to A/Fujian/411/2002-like virus. However, since mid-January, an increasing proportion of influenza A (H3N2) viruses have been reported to be similar to A/California/7/2004, a recent reference strain that is related to A/Fujian/411/2002 but is antigenically distinguishable.

Laboratory-confirmed influenza was at low levels until week 50-51 (18 December, 2004) when there was a clear and marked increase in the percentage of laboratory-confirmed influenza. This increase was first reported by the prairie provinces, British Columbia, and Quebec. Ontario and the Atlantic provinces followed, showing a gradual increase in laboratory-confirmed influenza over the month of January 2005.

Between 22 August, 2004 and 12 March, 2005, a total of 68,849 laboratory tests for influenza were reported, of which 10,319 (14.9%) were positive. The weekly percentages of specimens testing positive for influenza increased from 0.2% at the start of this period to a peak of 24.4% at week 5, ending 5 February, 2005.

Influenza A has predominated across the country this past season. Of the 10,319 positive influenza identifications, 9,630 (93.3%) were influenza A viruses, and 689 (6.7%) were influenza B viruses. Influenza B identifications was first seen in early February 2005 and continued to increase in March 2005. Most of the influenza B identifications have occurred in Ontario and Quebec.

Of the laboratory confirmed influenza infections reported, 24.5 % have been reported in children < 15 years. Last season, 45.6% of laboratory confirmed influenza infections were reported in children under age 15 years.

The National Microbiology Laboratory (NML) has antigenically characterized 775 influenza viruses that were received from Canadian provincial and hospital laboratories: 688 (88.7%) were influenza A (H3N2) strains, and 87 (11.3%) were influenza B strains. Of the 688 influenza A (H3N2) strains, 503 (73%) were A/Fujian/411/2002(H3N2)-like (similar to the influenza A (H3N2) component (A/Wyoming/3/2003) recommended for the 2004-2005 influenza vaccine) and 185 (27%) were a recently identified reference strain, A/California/7/2004-like virus. Since mid-February 70% of influenza A viruses have been characterized as A/California/7/2004.

Antibodies produced against A/Fujian/411/2002-like viruses cross-react with A/California7/2004-like viruses but at a lower level. It is expected that the 2004-2005 vaccine provided some cross-protection for the A/California/7/ strain. However, given the antigenic difference, effectiveness of the 2004-2005 vaccine could be reduced. A select number of isolates reported to be A/Fujian/ 411/2002-like prior to February 2005 await further classification using the new reference reagents for A/California/7/04.

Of the 87 influenza B strains which have been characterized, 73 were B/Shanghai/361/2002-like, similar to the influenza B component recommended for the 2004-2005 influenza vaccine, and 14 were B/Hong Kong/330/2001-like virus. The B/Hong Kong/330/ 2001-like virus, belonging to the B Victoria lineage, was the influenza B component recommended for the 2003-2004 influenza vaccine.

The weekly incidence of patient visits to approximately 200 sentinel providers nationwide for influenza-like illness (ILI) has ranged from six to a peak of 51 per 1,000 patient visits (week 9, ending 5 March, 2005). ILI activity remained at low levels until week 53 (week ending 1 January, 2005). The average weekly incidence of patient visits for ILI during the 2004-2005 season was less than the weekly average for the preceding seven influenza seasons.

Influenza this season has had a significant impact on LTCFs. The number of outbreaks in LTCFs this season increased significantly during week 51, ending 18 December, 2004, and has remained high since then. The total number of outbreaks in LTCFs reported to date has exceeded the total number of outbreaks in any of the last three seasons. While some of the increase may be due to increased reporting, it is unlikely to account for all the increase.

Influenza-associated hospitalization surveillance in children, reported through the Immunization Monitoring Program, ACTive (IMPACT) network, is part of the national influenza surveillance program. Aggregate reports of laboratory-confirmed influenza hospitalizations in children age < 16 years are reported to CIDPC on a weekly basis. Since 9 October, 2004, 314 hospitalizations have been reported in children age < 16 years in 12 IMPACT centres. Of these, over 60% of the hospitalizations were in children age <= 23 months. Influenza A is the predominant virus type in these reports; however, in recent weeks the proportion of influenza B detections has been increasing. Two pediatric deaths caused by influenza have been reported so far this season. The overall number of pediatric deaths reported to CIDPC is lower than the seven deaths reported last season.

International Influenza Surveillance

Globally, influenza A (H3N2) viruses predominated during the 2004-2005 season. However, in recent weeks the proportion of influenza B is increasing in several European countries. The overall levels of influenza activity this season have remained at medium-low intensity in most parts of the world. The United States reports a predominance of influenza A (H3N2) with most isolates initially characterized as antigenically similar to A/Wyo-ming/3/2003-like, which is the A/Fujian/411/2002-like (H3N2) component of the 2004-2005 influenza vaccine. Since January, an increasing proportion of isolates have more closely related to A/ California/7/2004. Most countries in Europe have also been experiencing a predominance of influenza A (H3N2). Yet a few are reporting codominance with influenza B. Earlier in the season, most isolates were reported to be similar to A/Wellington/1/2004-like viruses, a strain that is antigenically distinct from the A/ Fujian/411/2002 and A/Wyoming/3/2003 viruses. Recent isolates are now reported to be closely related to A/California/7/2004.

Between 1 December, 2003 and 11 March, 2005, the extensive outbreak of avian influenza (H5N1) in poultry in several Asian countries has been associated with 69 human cases and 46 deaths (overall case fatality rate 67%) in three countries (Thailand, Vietnam and Cambodia). The human cases have occurred in three waves. The latest wave began in December 2004 and has resulted in 25 laboratory-confirmed cases with 14 deaths (56%); one fatal case was from Cambodia, and the remainder were from Viet Nam. Analysis of the initial 60 laboratory-confirmed cases since Decem-ber 2003 indicates that the median age was 17 years (range 1 to 69 years); 51.7% were male, and the overall case fatality rate was 73%. Although sporadic cases of human-to-human transmission among close contacts may have occurred, no evidence of efficient or sustained human-to-human transmission exists. Genetic and antigenic analyses reported by the World Health Organization (WHO) have shown that the influenza A/H5N1 virus has not changed significantly from the previous year. The virus continues to be a zoonotic virus, not a human-adapted one.

Recommendations for the 2005-2006 Influenza Vaccine

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 2005-2006 season in Canada contain A/New Caledonia/20/99 (H1N1)-like, an A/California/7/2004 (H3N2)-like, and a B/Shanghai/361/2002-like virus strains. Vaccine producers may use antigenically equivalent strains because of their growth properties. The A/New York/55/2004 is antigenically equivalent to the A/California/7/2004 (H3N2) virus strain; B/Jiangsu/10/2003 is antigenically equivalent to Influenza B/Shanghai/361/2002 virus strain. The vaccines to be marketed in Canada for the 2005-2006 flu season contains A/New Caledonia/20/99 (H1N1), A/New York/55/2004 (H3N2), and B/Jiangsu/10/2003 virus antigens.

Provide Immunization against Influenza Yearly 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 WHO-recommended vaccine strains and epidemic strains was appropriate during 12 of the 15 (80%) influenza seasons between 1982-1983 and 1996-1997⁽¹⁾. 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. Both humoral and cell-mediated responses are believed to play a role in immunity to influenza. Immunity declines over the year following vaccination. The production and persistence of antibody after vaccination depends on numerous factors, including age, prior and subsequent exposure to antigens, presence of immunodeficiency states, and polymorphisms in HLA class II molecules. Humoral antibody levels, which correlate with vaccine protection, are generally achieved by 2 weeks after immunization. It is postulated that immunity after the inactivated vaccine lasts < 1 year. In the elderly, however, antibody levels may fall below protective levels within 4 months. Data are not available to support a recommendation to administer a second dose of influenza vaccine in elderly individuals to boost immunity⁽²⁾.

The recommended time for influenza immunization is the period from October to mid-November. Yet 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. 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 licensed 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 healthy child age 6 months, 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. These groups remain the priority for influenza vaccination programs.

However, significant morbidity and societal costs are also associated with seasonal interpandemic influenza illness and its complications occurring in healthy children age >= 2 years and healthy adults. For this reason, healthy children age >= 2 years and adults should be encouraged to receive the vaccine.

People at High Risk of Influenza-Related Complications

• Adults and children with chronic cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis, and asthma) that are severe enough to require regular medical follow-up or hospital care. Chronic cardiac and pulmonary disorders are important risk factors for influenza-related morbidity and mortality.
• 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 group above. 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, hospital admission, pneumonia, and death.
• Adults and children with chronic conditions, such as diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), renal disease, anemia, and hemoglobinopathy. Influenza vaccine is effective in reducing hospital admissions in adults with diabetes. The efficacy of the vaccine in children with chronic metabolic and renal diseases is uncertain, but this uncertainty should not preclude consideration of the vaccine. Immunosuppressed patients are at increased risk for influenza infection, morbidity, and mortality. Although some immunosuppressed individuals may have a suboptimal immune response, influenza vaccination is safe and can induce protective antibody levels in a substantial proportion of adults and children, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and human immuno-deficiency virus (HIV)-infected patients. Influenza may result in significant morbidity and mortality in HIV-infected individuals. Influenza vaccination protects against influenza infection and illness in HIV-infected individuals with a mean CD4+ T-lymphocyte cell count > 100 cells/mm; efficacy varies with degree of immunosuppression. However, influenza vaccine may not induce protective antibody titres in those with very low CD4+ T-lymphocyte cell counts, and there is evidence that a second dose of vaccine does not improve their immune response.
• People age >= 65 years. The risk of severe illness and death related to influenza is moderately increased in healthy people in this age group, but the risk is not as significant as in those with chronic underlying disease. Vaccination is effective in preventing hospital admission and death, ultimately resulting in direct health care cost savings.
• Adults and children with any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration. Such conditions may include cognitive dysfunction, spinal cord injury, seizure disorder, and neuromuscular disorders. NACI makes this recommendation based on expert opinion.
• Healthy children age 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. In a retrospective study of a Tennessee Medicaid population from 1973-1993, Neuzil and colleagues estimated that the influenza-related hospitalization rates for acute cardiac or pulmonary conditions were 496 to 1,038 per 100,000 in healthy children age 0 to 11 months and 186 per 100,000 in those age 1 to 2 years⁽³⁾. Izurieta and colleagues estimated the influenza-associated hospitalization rate as 144 to 187 per 100,000 healthy children age 0 to 23 months⁽⁴⁾. In another Tennessee study, Neuzil and colleagues reported a culture-positive influenza hospitalization rate of 3 to 4 per 1,000 healthy children age < 2 years⁽⁵⁾. In the ongoing New Vaccine Surveillance Network prospective study, the mean annual influenza-associated hospitalization rate from 2000-2004 was 90 per 100,000 for all children age 6 to 23 months; 70% of these children had no identifiable high-risk condition⁽⁶⁾. Conversely, Barker and colleagues noted that influenza-associated hospitalization rates among adults with high-risk medical conditions were 56 to 110 per 100,000 persons age 15 to 44 years⁽⁷⁾. In a study of U.S. national hospital discharge data, Simonsen and colleagues reported influenza-associated hospitalization rates of 125 to 228 per 100,000 healthy persons age >= 65 years⁽⁸⁾.
   
  Influenza vaccine is safe and well tolerated in healthy children. In a 2-year randomized controlled trial conducted in healthy children, efficacy against culture-positive influenza illness was 64%, 66%, and 69% in those age 6 to 12 months, age 13 to 18 months, and age 19 to 24 months, respectively, during the first year of the study while influenza infection was prevalent⁽⁹⁾. NACI recognizes that the number of studies and of participants in the randomized controlled trials of influenza vaccine in children age 6 to 23 months are limited, and thus unanswered questions remain. These include the efficacy of influenza vaccine in children within this age group who have not had experience with the vaccine or infection (unprimed), the impact of immunization on influenza complications (including hospitalization), and the cost-effectiveness of a routine immunization program in this age group⁽¹⁰⁾. NACI strongly encourages research regarding these issues. However, based on existing data on the high incidence of influenza-associated hospitalization in healthy children age 6 to 23 months, NACI recommends including this age group among high-priority recipients of influenza vaccine.
• 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.
• People at high risk of influenza complications who embark on travel to destinations where influenza is likely to be circulating⁽¹¹⁾. Immunization with the most current available vaccine should be considered for all individuals who wish to avoid influenza while travelling to those 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 infectious persons from other regions of the world and to situations (e.g. cruise ships) that facilitate the transmission of influenza. The effectiveness of influenza immunization for travellers may vary, depending on differences between influenza strains encountered abroad and those included in the current vaccine available in Canada. Vaccines prepared specifically against strains that are predicted to circulate in the southern hemisphere are not currently available in Canada. However, vaccine available in Canada may be useful for protection during southern hemisphere travel in years when there is a good match between North American vaccines and circulating southern hemisphere strains. WHO recommendations for the formulation of southern hemisphere vaccine are available at www.who.int/topics/influenza/en/ .
  
  There is insufficient evidence at this time to recommend routine re-immunization, using the same influenza vaccine, 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.
  
  For travellers to regions experiencing an avian influenza epidemic, prevention of human influenza virus infection through immunization may reduce the theoretical potential for human-avian re-assortment of genes.

Individuals Who Are Capable of Transmitting Influenza to Those at High Risk for 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 service providers in facilities and community settings who, through their activities, are potentially capable of transmitting influenza to those at high risk for influenza complications. This group includes 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.
• Those who provide services within closed or relatively closed settings to persons at high risk (e.g. crew on ships).
• Household contacts (adults and children) of people at high risk for influenza complications. This group includes household contacts of children age < 6 months who are at high risk for complications from influenza but for whom there is no available effective vaccine. It also includes household contacts of children age 6 to 23 months, whether or not they have been immunized. Pregnant women should be immunized if they are expected to deliver during influenza season, because they will become household contacts of their newborn.
• Those providing regular childcare to children age 0 to 23 months, whether in or out of the home.
• People who provide essential community services. Vaccination for these individuals should be encouraged to minimize the disruption of routine activities in epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults; this practice has been shown to decrease work absenteeism from respiratory and other illnesses.
• People in direct contact with avian influenza-infected poultry during culling operations. These individuals may be at increased risk for avian influenza infection due to exposure during the culling operation(12). Influenza immunization on a yearly basis prior to the human influenza season may prevent the infection of these individuals with human influenza strains, thereby reducing the theoretical potential for human-avian re-assortment of genes should they become co-infected 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 to prevent infection with either avian or human influenza during the culling operation. Advice should be sought from the local medical health officer regarding the use of influenza vaccine and antiviral prophylaxis in the control of avian influenza outbreaks. (See the section entitled “Recommendations for the Prophylactic Use of Amantadine and Oseltamivir.")

Further Comments Regarding Influenza Immunization

• Immunization of healthy persons age 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. In an analysis of randomized controlled trials of inactivated influenza vaccine in healthy adults, Demicheli et al. estimated vaccine efficacy to be 24% in preventing ILI and 68% in preventing laboratory-confirmed influenza infections⁽¹³⁾. Depending on whether infection was defined by serology or culture, trials of inactivated trivalent influenza vaccine in children age 2 to 5 years estimate vaccine efficacy to be 31% to 83%^(14-18). Fifteen randomized controlled trials of healthy children age 6 months to 19 years showed a relative risk reduction associated with influenza vaccination ranging from 0% to 93%⁽¹⁹⁾.

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. Between 1962 and 1987, 80% of Japanese school children were immunized against influenza⁽²⁰⁾. However, observations concerning the epidemiology of influenza during the period after the program was stopped are confounded by other determinants of infection and illness^(21-23). Smaller non-randomized community studies have also been subject to bias^(24,25). Studies using computer models of influenza illness in simulated communities that experienced selected immunization rates among children have used assumptions regarding variables (e.g. attack rate and illness severity), which may not apply to real-life situations^(26,27).

The results of cost-effectiveness studies of influenza immunization among adults and children vary according to selected circumstances^{(13,19,27-37)}. The potential benefits of influenza immunization in healthy adults and children depend on numerous factors, including seasonal viral virulence and attack rates, the match between vaccine and circulating viral strains, protective immunity in previously infected individuals, vaccine side effects, and the costs of vaccination and of influenza-associated morbidity.

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 age 50 years. The primary rationale is that many persons age 50 to 64 years have high-risk conditions, such as diabetes mellitus or heart disease. Yet the influenza immunization rate among U.S. adults in this age group who have high-risk chronic medical conditions is low; they are unaware of their high-risk condition, they lack health care access, or HCWs fail to deliver immunization. Age-based influenza guidelines may be more successful in reaching individuals with medical conditions that put them at a higher risk of influenza complications, compared with previous guidelines based on recognition of the specific high-risk conditions.

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.

Influenza vaccine in pregnancy and during lactation. Evidence indicates that influenza vaccine is safe for pregnant women at all stages of pregnancy and for breastfeeding mothers⁽³⁸⁾.

Influenza vaccination is recommended for pregnant and breast-feeding women who are characterized by any of the conditions listed under “Recommended Recipients." This group includes pregnant and breastfeeding women who have chronic conditions that put them at high risk of complications from influenza, as well as those who are close contacts of high-risk individuals.

Among healthy pregnant women, morbidity and mortality associated with influenza is increased during pandemics. Studies of the burden of illness among healthy pregnant women in non-pandemic years include case reports, observational studies, and a retrospective case-control study of a predominantly young, urban Tennessee population of African-American, socioeconomically disadvantaged women with a high prevalence of chronic disease⁽³⁹⁾. How well the results of these studies can be generalized to Canadian and other populations is unknown. NACI encourages research to determine the degree of morbidity due to influenza in Canadian women who are pregnant and the preventable fraction of morbidity potentially achievable through the use of the influenza vaccine in this population⁽⁴⁰⁾. Pregnant women should be immunized if they are expected to deliver during influenza season, because they will become household contacts of their newborn.

Administration of Influenza Vaccine

Dosage Schedule

Table 2 presents the recommended dosage schedule and type of influenza vaccine. Split-virus vaccines are available in Canada. Previously unvaccinated children age < 9 years require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. The second dose of influenza vaccine is not needed if the child has received one or more doses of vaccine during a previous influenza season.

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

Table 2. Recommended influenza vaccine dosage, by age, for 2005-2006 season

Age	Vaccine Type	Dose (mL)	No. of doses
6-35 months	split-virus	0.25	1 or 2*
3-8 years	split-virus	0.5	1 or 2*
≥ 9 years	split-virus	0.5	1

*Previously unvaccinated children age < 9 years require two doses of the split-virus influenza vaccine, with an interval of 4 weeks.

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

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 site⁽⁴¹⁾. Healthy adults receiving the split-virus vaccine showed 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, occurs in 7% of healthy children who are age < 3 years. Postvaccination fever may be observed in 12% of immunized children age 1 to 5 years.

Several influenza vaccines which are marketed in Canada contain minute quantities of thimerosal, which is used as a preservative⁽⁴²⁾. Retrospective cohort studies of large health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelop-mental outcomes, including autistic-spectrum disorders^(43,44). Nevertheless, in response to public concern, influenza vaccine manufacturers in Canada are working toward 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 season⁽⁴⁵⁾. 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 subsequent to the swine influenza vaccine program in 1976^(45,46).

In Canada the background incidence of GBS is estimated at just over 20 cases per million population in a study from Ontario and Quebec⁽⁴⁷⁾. Various infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is unknown whether influenza virus infection itself is associated with GBS. It is also unknown 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 unknown to predispose to Reye syndrome.

Conjunctivitis and/or respiratory symptoms following influenza immunization were reported sporadically prior to 2000 in Canada, the United States, and Europe^(48,49). However, during the 2000-2001 influenza season, Health Canada received an increased number of reports of vaccine- associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS)(47). The case definition (revised in 2001) 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(50). Assessment of the severity of ORS symptoms is based on the perception of the individual: mild (easily tolerated; present but not problematic), moderate (interferes with activities of daily living; bothersome, requires activity changes and possibly medication) or severe (prevents activities of daily living; unable to work or sleep). The pathophysiologic mechanism underlying ORS remains unknown.

Subsequent to the 2000-2001 influenza season, fewer ORS cases have been reported to Health Canada⁽⁵⁰⁾. Surveillance for all vaccine-associated adverse events, including ORS, is ongoing.

Approximately 5% to 34% of patients who have previously experienced ORS may experience a recurrence that is attributable to the vaccine^(50-56). Most recurrences, however, are less severe than the previous episode. Persons who experience a recurrence of ORS upon revaccination do not necessarily experience further episodes of ORS associated with further vaccination.

Individuals who have experienced mild or moderate ORS symptoms or 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. Data on clinically significant adverse events do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.

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, difficult swallowing) that raise concern about 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.

The Canadian Immunization Guide⁽⁵⁷⁾ provides 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 or who have known IgE-mediated hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension, or shock.

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 due to inappropriate deferral of immunization.

Although influenza vaccination can inhibit the clearance of war-farin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in those who receive the 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 pneumo-coccal disease when influenza vaccine is given.

Storage

Influenza vaccine should be stored at 2° C to 8° 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 characteristics of the strain of circulating virus during influenza season. With a good match, influenza vaccination has been shown to prevent laboratory-confirmed influenza illness in approximately 70% or more of healthy individuals. Under these circumstances, studies have also shown influenza vaccination to be 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 be as low as 30%.

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 long-term care facility (LTCF) residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually(58-62). Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%^(59-61,63).

This low rate of utilization is due 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. HCWs and their employers have a duty to actively promote, implement, and comply with influenza immunization recommendations to decrease the risk of infection and complications in vulnerable populations for which they provide care⁽⁶⁴⁾. Educational efforts aimed at HCWs and the general public should address common concerns about vaccine effectiveness and adverse reactions. These include beliefs of patients at risk, HCWs and other service providers - that they rarely get influenza, they fear side effects, and they doubt the efficacy of the vaccine.

The advice of a health care provider is an 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:

• implementing standing-order policies in institutions, allowing nurses to administer vaccine and simultaneous immunization of staff and patients in nursing homes and chronic care facilities. In these settings, increased vaccination rates are associated with a single non-physician staff person who organizes the program, ensuring program aspects are covered by written policies, having a policy for obtaining consent on admission that was durable for future years, and automatically administering vaccine to residents whose guardians could not be contacted for consent
• vaccinating people at high risk who are being discharged from hospital or who are 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 influenza immunization issuing computer-generated reminders to HCWs, mailing reminder letters to patients, or using other recall methods to identify outpatients at high risk having patient-carried reminder cards increased accessibility of immunization clinics to staff in institutions and community-based elderly, including implementation of 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

Person-to-person transmission of influenza virus occurs primarily through respiratory droplets generated by sneezing, coughing, or talking. Adults may spread influenza to others during a period ranging from 1 day before to 7 days after the onset of symptoms. Children may shed virus for 1 day prior to symptoms to 10 to 14 days after illness onset.

Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality⁽⁶⁵⁾. 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⁽⁶⁶⁾. 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⁽⁶⁵⁾. 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 owing to the scarcity of replacement workers.

Vaccination of HCWs in health care facilities has been shown to reduce total patient mortality, influenza-like illness, and serologically confirmed influenza⁽⁶⁶⁾. Influenza vaccination programs for HCWs may also result in cost savings and reduced work absenteeism, depending on factors including disincentives to take sick days, strain virulence, and the match between infecting strain and vaccine^(67-69).

For the purposes of this document, we define HCW as a person who provides direct patient care and as an individual who provides health services in an indirect fashion, such as one who performs administrative activities. The latter may still come into close contact with patients by sharing 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 patient. 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 influenza prevention for the protection of their patients. HCWs who have direct patient contact should consider that their responsibility is to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, HCWs who have direct patient contact and their refusal to be immunized for influenza implies failure in their duty to patient care.

To protect vulnerable patients in an outbreak situation, it is reasonable to exclude from direct patient contact HCWs who develop confirmed or presumed influenza and unvaccinated HCWs who are not taking antiviral prophylaxis. Health care organizations should have policies in place to deal with this issue.

Prophylactic Use of Amantadine and Oseltamivir

This section discusses the prophylactic use of antiviral agents against influenza. Antiviral therapy against influenza is not discussed in this statement.

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

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 adamantanamine antiviral agent that is not licensed in Canada. It will not be discussed in this statement.

Randomized trials in healthy adults suggest that amantadine prevents 23% of clinical influenza cases and 63% of serologically confirmed influenza A illness^(70,71). A non-blind randomized trial of amantadine versus placebo during an influenza outbreak in healthy boys age 13 to 19 years living in a boarding school showed 91% efficacy against culture confirmed influenza illness and 86% efficacy against clinical influenza illness⁽⁷²⁾. A non-randomized trial in boys age 12 to 18 years showed 70% efficacy of amantadine, compared with placebo, in preventing influenza illness⁽⁷³⁾.

In non-randomized controlled trials, amantadine prophylaxis used for periods varying from 9 days to 16 weeks interrupted influenza A outbreaks and reduced mortality in populations at increased risk for influenza complications, including disabled children, hospitalized adults, elderly residents of nursing homes, and prison populations^(74-76). Postexposure prophylaxis with amantadine provides protection (protective efficacy 74%) in families when the index case does not receive antiviral therapy^(74,77). Amantadine does not provide protection from influenza A in household contacts when it is also used to treat the index case, likely owing to the spread of resistant virus within the household^(74,78,79). Amantadine resistance is more likely to occur in populations, such as families and within semi-closed settings, including nursing homes where the drug is used for prophylaxis and treatment, as opposed to prophylaxis alone. Simultaneous use of amantadine for prophylaxis and therapy within a family, facility, or institution is not advised because of the increased risk of the emergence of viral resistance. Failure to adequately isolate institutional patients on amantadine therapy also increases the probability of transmission of any resistant virus that may emerge, which in turn may result in prolongation of an epidemic or a second epidemic wave^(80,81).

Neuraminidase inhibitors prevent the replication of both type A and B influenza viruses by inhibiting influenza virus neuramini-dase. 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, licensed for pre- and post-exposure prophylaxis against influenza A and/or B in persons age 13 years^(82-84).

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. Zanamivir will not be discussed further in this statement.

A review of randomized placebo-controlled trials in 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^(85-87). Sufficient data are not available to assess the efficacy of neuraminidase inhibitors used prophylactically in healthy children age < 13 years, and they are not licensed for prophylactic use in this age group⁽⁸⁸⁾. Oseltamivir was 92% effective in preventing laboratory-confirmed 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⁽⁸²⁾. 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 long-term care facilities^(83,84). In a randomized controlled trial, oseltamivir was efficacious in protecting healthy household contacts of index influenza cases that were not treated⁽⁸⁹⁾. Households with pregnant or breastfeeding women, or individuals with cancer, immunosuppression, HIV infection, chronic liver or renal disease were excluded from this study.

The emergence of oseltamivir-resistant virus during or after pro-phylactic use of this antiviral has not yet been noted⁽⁸⁷⁾. 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^(90-92).

Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that provide protection when they are exposed to antigenically related viruses in later years. However, as previously indicated, antiviral prophy-laxis should not replace annual influenza vaccination.

Amantadine and oseltamivir are ineffective in providing prophylaxis for respiratory infections other than influenza. Therefore, it is critically important to base decisions about their prophylactic use on appropriate epidemiologic, clinical, and laboratory data regarding the etiology of prevalent infection(s).

NACI recommends using influenza antivirals (amantadine or oseltamivir) 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 to determine whether the circulating strain is type A or B. Amantadine is not effective as prophylaxis against influenza B. Amantadine or oseltamivir should be given to all residents who are not already ill with influenza, whether previously vaccinated or not, and to unvaccinated staff (see “Precautions"section). Prophylaxis should also be considered for HCWs, regardless of vaccination status, during outbreaks caused by influenza A strains that are not well matched by the vaccine. Prophy-laxis 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, contraindi-cated, or unlikely to be effective due to a poor match between the vaccine and the circulating viral strain⁽⁹³⁾. In this case, prophylactic antiviral medication may be taken each day for the duration of influenza activity in the community. Deciding 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 unavailable until the season is over. NACI encourages the development of methods for the early assessment of vaccine efficacy in years when the appearance of new circulating strains may result in reduced vaccine efficacy. Antiviral prophylaxis may also be given to individuals who are high risk during an outbreak and 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 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 pro-phylaxis, and should be excluded from the patient care environment if these develop.
• Antiviral postexposure prophylaxis may be used for non-vaccinated household contacts of index influenza cases. The secondary attack rate among family members of a household that has a laboratory-confirmed index case varies from 13% to 25%, according to family composition, virus strain, and exposure outside the household, among other variables(89,94,95). Prophylaxis of household contacts for 10 days with amanta-dine (without amantadine treatment of the index case to avoid emergence of drug-resistant virus) reduced confirmed influenza A illness by 74%(77). A precise time period after onset of illness in the index case during which amantadine should be initiated to be effective has not been defined in clinical studies. Seven days of oseltamivir was 89% effective in preventing laboratory-confirmed influenza A or B among household contacts age 12 years when initiated within 48 hours of symptom onset in the index case(89). However, households that contain pregnant or breastfeeding women and 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. using 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 exhibit cough and fever within 48 hours of symptom onset are likely to have influenza^(96,97). The presence of sore throat suggests a diagnosis other than influenza.

Despite the availability of antiviral agents for postexposure prophylaxis within households, the 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.

• For prophylaxis of individuals who will be exposed to avian influenza. Consultation with the local medical office of health is required. When choosing an antiviral agent, make use of any available data on the susceptibility of the avian virus strain to antiviral agents. For example, the current H5N1 avian influenza strain in Asia is resistant to amanta-dine but susceptible to neuraminidase inhibitors in vitro. However, presently the efficacy of these drugs in preventing avian influenza has not been established. There is limited knowledge regarding the prophylactic use of neuraminidase inhibitors for periods longer than 6 weeks.

Note that these recommendations encompass off-label (outside of licensed indications) use of oseltamivir.

When prophylaxis is indicated, deciding which antiviral agent to use should consider the type of influenza strain circulating and

the efficacy, potential toxicity, cost, and ability to administer the agent within a particular population.

Factors such as local epidemiology, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost may be considered when determining the duration of antiviral prophylaxis.

Dosage and Potential Side Effects of Amantadine

Table 3 presents the amantadine dosage recommendations for prophylaxis of influenza A infection, but read the package insert for complete information. Any adjustments for renal function should be made in addition to adjustments for age. Pay particular attention to dosages in those age > 65 years, among whom some degree of renal impairment is common. Dosages may 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^(98,99). Note that, although Table 3 presents the recommended dosage schedule for amantadine prophylaxis, a few studies suggest that a prophylactic dose of 100 mg daily may be as effective as the recommended dose of 200 mg daily in those age 10 to 64 years and in children weighing > 20 kg who have normal renal function⁽⁷⁴⁾.

Although the use of this dosing schedule, when properly adhered to, has been effective in controlling institutional influenza A outbreaks, the intermittent dosages may be confusing. Table 4 shows an alternative - once daily dosage regimen for persons age > 65 years - based on renal function ⁽⁹⁹⁾. This new dosage regimen is based on pharmokinetic modelling, suggesting that it should be as effective and safe as the standard regimen presented in Table 3. HCWs and influenza program planners will need to assess the advantages and disadvantages of the two different schedules when selecting a regimen for their patients.

Amantadine was given for 10 days in studies of postexposure pro-phylaxis among household contacts of index cases with influenza⁽⁷⁷⁾. Amantadine has been given for up to 16 weeks in pre-exposure prophylaxis studies^(74,75).

In otherwise healthy young adults who were given amantadine prophylactically, 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 occur more frequently 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.

(See Table 3)

Amantadine is eliminated from plasma wholly by renal tubular secretion and glomerular filtration; it is not metabolized by the liver. For this reason, for those with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Tables 3 and 4 provide the recommended prophylactic dosages by age and renal function. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 36 hours⁽¹⁰⁰⁾. For patients with a creatinine clearance < 10 ml/min who are not on dialysis, an amantadine dose of 100 mg orally every 3 weeks is recommended [F. Aoki, personal communication, September 14, 2004]⁽¹⁰¹⁾.

(See Table 4)

Note, the calculated creatinine clearance is reasonably accurate for those with a creatinine clearance > 40 ml/min and for those with a stable serum creatinine and muscle mass. The calculation, however, becomes less accurate when these conditions are not met. Specifically, 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 on dosage adjustments based on these considerations.

To avoid the risk of increased frequency of seizures, reduce amantadine dosage in individuals who suffer from seizure disorder, and observe closely.

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, comorbid conditions, and 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.

Dosage and potential side effects of 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. The recommended oral dose of oseltamivir for prevention of influenza in persons age 13 years is 75 mg once daily. For postexposure prophylaxis, oseltamivir should begin within 48 hours of exposure. The duration of household postexposure pro-phylaxis used in a randomized controlled trial was 7 days⁽⁸⁹⁾. 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, because 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. A recent serum creatinine or creatinine clearance result based on a 24-hour urine collection is not required before starting oseltamivir prophylaxis, unless there is reason tosuspect significant renal impairment. For those with a creatinine clearance of 10 to 30 mL/min, reduce the dosage of oseltamivir 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 and for 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 available regarding possible toxic effects on the fetus. It is unknown whether oseltamivir or its active metabolite are excreted in human milk.

Oseltamivir should not be given to children age < 1 year. Oseltamivir is licensed by Health Canada for prophylactic use only for children age ≥ 13 years.

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, as a result of increased active amniotic 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⁽⁹⁰⁾.

Acknowledgements

NACI gratefully acknowledges the assistance of Samina Aziz, Karen Ellison, Theresa Tam, and Jill Sciberras in the preparation of this manuscript.

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*Members: Dr. M. Naus (Chairperson), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. M-N Primeau, Dr. B. Tan, Dr. B. Warshawsky, A. Zierler.

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

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

† This statement was prepared by Dr. P. Orr and approved by NACI and the Public Health Agency of Canada.

[Canada Communicable Disease Report]