ammi canada guideline

The use of antiviral drugs for influenza:

A foundation document for practitioners
Fred Y Aoki MD1, Upton D Allen MBBS2, H Grant Stiver MD3, Gerald A Evans MD4

INDEX
I. PURPOSE
II. PROCESS STATEMENT
III. GRADING OF RECOMMENDATIONS
IV. THE DISEASE
A. Influenza viruses
B. Clinical aspects
C. Clinical diagnosis of influenza illness
V. TREATMENT OF INFLUENZA ILLNESS
A. Antiviral drugs including off-label use
B. Benefits of antiviral treatment
C. Considerations in selecting treatments
1. Severity of illness
2. Presence of risk factors or co-morbid medical conditions
3. Interval between onset of illness and initiation of antiviral therapy
4. Likely influenza type(s) causing infection
D. Treatment of children
E. Treatment of immunocompromised patients
F. Treatment of patients with renal impairment
G. Treatment of pregnant patients
VI. RECOMMENDATIONS FOR TREATMENT
A. General principles
B. Treatment of non-pregnant adults with mild or uncomplicated influenza
C. Treatment of non-pregnant adults with moderate, progressive, severe or complicated illness with or without risk factors
D. Treatment of infants, children and youth with mild or uncomplicated influenza illness
E. Treatment of infants, children and youth with moderate, progressive, severe or complicated influenza illness with or without risk factors
F. Treatment of immunocompromised patients
G. Treatment of patients with renal impairment
H. Treatment of pregnant women
VII. RECOMMENDATIONS FOR CHEMOPROPHYLAXIS VERSUS EARLY THERAPY
TABLES
1. Grading of recommendations
2. Clinical signs warranting urgent medical attention in infants, children and youth with suspected or proven influenza
3. At-risk groups and co-morbid medical conditions that predispose to severe influenza
4. Oseltamivir and zanamivir regimens
5. Recommended regimens for treatment of patients with renal impairment or failure
6. Selected surrogate indices of immunocompromised states
REFERENCES
APPENDICES
A. Oseltamivir and zanamivir treatments for mild or uncomplicated influenza in non-pregnant adults
B. Oseltamivir and zanamivir treatments for non-pregnant adults with moderate, progressive, severe or complicated illness
C. Oseltamivir and zanamivir treatments for influenza in children (<18 years of age)
D. Oseltamivir and zanamivir for chemoprophylaxis or early therapy in close contacts of infectious patients

1Professorof Medicine, Medical Microbiology and Pharmacology & Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg,
Manitoba; 2Professor, Department of Pediatrics & Institute of Health Policy, Management and Evaluation, Senior Associate Scientist, Research
Institute, Chief, Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario;
3Professor Emeritus of Medicine, Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British

Columbia; 4Professor of Medicine, Biomedical & Molecular Sciences and Pathology & Molecular Medicine, Chair, Division of Infectious
Diseases, Department of Medicine, Kingston General Hospital, Queen’s University, Kingston, Ontario
Correspondence: Dr Gerald A Evans, Division of Infectious Diseases, Department of Medicine, Room 3013, Etherington Hall, 94 Stuart Street,
Queen’s University, Kingston, Ontario K7L 3N6. Telephone 613-533-6619, fax 613-533-6825, e-mail evansg@queensu.ca

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 1C

Aoki et al

I. PURPOSE TABLE 1
The purpose of this document is to provide information for clinicians GRADE Evidence Quality versus Benefit to Harm Ratio and
on the use of antiviral drugs for the prevention and treatment of Recommendation Grading5
seasonal influenza. It is provided as a foundation document which,
with brief supplements published as needed to describe new develop- Preponderance of Balance of
ments, is intended to replace the annual Guidance publications.1,2 Quality of Evidence Benefit or Harm Benefit and Harm
The efficacy and safety of antiviral drugs has been demonstrated in
A. Well-designed, randomized,
controlled trials but the clinical importance of prescribing them for
controlled studies or diagnostic
the treatment of seasonal influenza in largely healthy ambulatory studies on relevant populations
Strong
Recommendation Option
adults and children has been the subject of some ongoing controversy.3
However, in high-risk patients with seasonal or pandemic influenza, B. RCTs or diagnostic studies with

both oral oseltamivir and inhaled zanamivir may reduce hospitaliza- minor limitations; overwhelmingly

tion and oseltamivir may reduce mortality.4 As of August 2013, three consistent evidence from
observational studies
antiviral drugs are licensed in Canada for treatment and prophylaxis of
influenza: amantadine (oral) and two neuraminidase inhibitors (NAI),
C. Observational studies (case Recommendation
oseltamivir (oral) and zanamivir (dry powder for inhalation). Other control or cohort design)
antiviral drugs are available internationally (licensed or investiga-
tional), including intravenous formulations of oseltamivir, zanamivir D. Expert opinion, case reports,
Option No Recommendation
reasoning from first principles
and peramivir. These drugs have been available in Canada in specific
situations for clinical use but are currently not licensed. Another NAI, X. Exceptional situations where Strong
laninamivir, a long-acting orally inhaled powder, has been approved in validating studies cannot be done Recommendation

Japan as a single dose treatment, for the therapy of influenza A and B and there is a clear preponderance
of benefit or harm Recommendation
infection.
Drug or virus-specific recommendations will be published, if
needed, to complement this document. Other aspects of influenza
management, such as laboratory diagnosis, infection control, immun-
ization and non-pharmacological interventions, are beyond the scope Impact of recommendation strength on practicing clinicians
of this article. Strong recommendations should be followed unless a clear and com-
The susceptibility of recently circulating seasonal influenza viruses pelling reason for an alternate approach is present.
to amantadine (AH1N1, AH3N2, influenza B) shows high rates of Recommendations should generally be followed, but clinicians should
resistance, therefore subsequent discussion is limited to the neuramini- remain alert to new information and patient preferences.
dase inhibitor drugs. Option reflects flexibility in decision-making regarding treatment
according to the judgment of the clinician. Patient preference should
II. Process Statement play a substantial influencing role.
The development of this guideline paper arose in early 2013 from two No recommendation reflects no constraints on decision-making, and
sources: a previous guidance authored in 2012 by AMMI Canada clinicians should remain alert to new evidence that clarifies the bal-
members (FA, UA, GS, GE) and following a suggestion from the ance of benefit and harm. Patient preference should play a substantial
Public Health Agency of Canada’s Antiviral Scientific Advisory influencing role.
Group that a generic Canadian guideline be developed for the use of
antivirals for seasonal influenza. The concept was then given the go-
IV. THE DISEASE
ahead by the Guidelines Committee of AMMI Canada. A first draft
A. Influenza viruses
was co-written by all the authors (FA, UA, GS, GE). Subsequently, all
The influenza strains that will predominate in Canada in any given
the authors reviewed, revised and approved the document before sub-
season are unpredictable. Their identification and knowledge of their
mission to PHAC for further review and feedback. The AMMI
antiviral drug susceptibility profiles are fundamental to the rational
Canada Guidelines Committee approved the final document prior to
prescribing of antiviral drugs for the prevention and treatment of influ-
submission to the Journal for publication.
enza because antiviral drug resistance patterns of influenza viruses
III. GRADING OF RECOMMENDATIONS demonstrated in vitro generally correlate with treatment outcomes.
A grading system is used to qualify recommendations based on the Relevant information is usually compiled from different sources each
quality of evidence and the determination of benefit versus harm aris- year. Practitioners can find current information about circulating
ing from the recommendation as defined below.5 In situations where influenza strains from Fluwatch®6, influenza vaccine composition from
high-quality evidence is not available but anticipated benefits strongly NACI7 and antiviral resistance from CDC.8
outweigh the harm, the recommendation could be based on lesser
B. Clinical aspects
evidence. See Table 1 for categories of evidence and their relationship
Seasonal influenza viruses share similar clinical features.
to recommendations. As more data on efficacy are published, the
Virus is transmitted from infected to susceptible persons through res-
grades of recommendation may change.
piratory secretions containing suspensions of virus, especially airborne
Definitions of the strength of evidence for the recommendations droplets generated by coughing and sneezing. The relative contributions of
Strong Recommendation: Benefits of treatment approach clearly small particle aerosols and fomites in transmission are uncertain. The basic
exceed harms; quality of evidence is high (Grade A) or moderate reproductive number [Ro] (mean number of secondary cases transmitted
(Grade B) or exceptional (Grade X). by a single index case to susceptible contacts) ranges from 1.3 to 1.7.
Recommendation: Benefits exceed harms, but quality of evidence is The incubation period of seasonal influenza A illness is one to four
moderate (Grade B), or low (Grade C) or exceptional (Grade X). days with a mean of two days.9
Option: Quality of evidence is very low (Grade D) or well-done stud- In otherwise healthy patients with uncomplicated illness, virus in
ies (Grade A, B or C) show little clear advantage. nasopharyngeal secretions is shed beginning 24 h (1 day) before onset of
No Recommendation: There is a lack of pertinent evidence or quality symptoms, peaks in the first two to three days of illness and declines over
is very low and there is an unclear balance between benefits and five to seven days, although it is commonly accepted that some persons,
harms. particularly young children and immunocompromised persons, may

2C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013

 The use of antiviral drugs for influenza

Table 2 myocarditis or pericarditis, toxic shock-like picture (due to secondary

Clinical signs warranting urgent medical attention in bacterial infection) and neurologic complications. The latter include
infants, children and youth with suspected or proved febrile seizures, status epilepticus, encephalitis/encephalopathy, Reye’s
influenza syndrome and Guillain-Barré syndrome.11
Infants and toddlers (<1 year and 1–3 years, respectively) Conditions that place individuals (including infants, children and
Rapid breathing and difficulty breathing youth) at risk of severe outcomes from influenza illness are shown in
Bluish skin colour or change in skin colour
Table 3, which is adapted from the Canadian National Advisory Committee
on Immunization12 and incorporates recently published data.13
Not drinking enough fluids
Not waking up or not interacting C. Clinical diagnosis of influenza illness
Being so irritable that child does not want to be held The accuracy of clinical diagnosis varies substantially. However, when
Flu-like symptoms improve but then return with fever and a worse cough influenza is circulating in the community, the presence of cough and a
Fever with a rash fever of 37.8°C or higher in otherwise healthy adults has a positive
Seizures predictive value of 86.8% for a laboratory-confirmed diagnosis of influ-
Children and youth (>3 to <12 years and 12–18 years, respectively) enza, although the negative predictive value is poor at 39.3%.14
Rapid breathing, difficulty breathing or shortness of breath Among non-immunized young healthy adults, the combination of a
Bluish skin colour, bloody or coloured sputum fever of 37.8°C or higher plus at least one respiratory symptom (sore
Flu-like symptoms improve but then return with fever and a worse cough
throat, cough or nasal symptoms) and one constitutional symptom
(myalgia, headache, sweats, chills or fatigue) are predictive of influ-
Confusion, listlessness, altered consciousness
enza confirmed by laboratory testing in 60% to 71% of cases.14,15,16
Severe or persistent vomiting
Among immunized patients 60 years of age and older, the combination
Fever with a rash
of fever, coughing and acute onset have a predictive value of 44% for
Severe chest pain or abdominal pain laboratory-confirmed diagnosis of influenza.17
Seizures Diagnosing influenza illness by clinical criteria in infants and
young children is more problematic than in adults because they cannot
articulate their symptoms as readily and the signs and symptoms of
influenza illness are often non-specific. Studies evaluating the sensitiv-
shed virus for longer periods.9 For purposes of post-exposure prophylaxis,
ity and specificity of a clinical diagnosis of influenza in children com-
the infectious period is considered to extend from one day before onset
pared with a laboratory gold standard are limited.18 The common
of symptoms until 24 h after fever ends.
presenting findings of fever, cough and rhinorrhea do not distinguish
Illness caused by influenza virus can range from asymptomatic to
influenza illness from that due to other respiratory viruses. Thus, in
mild, uncomplicated, self-limited upper respiratory tract infection to
diagnosing influenza in a patient and arriving at a treatment decision,
serious complicated illness dominated by exacerbation of a co-morbid,
practitioners should be guided by knowledge of whether influenza
underlying medical condition or severe viral lower respiratory tract
virus is circulating in their community as well as their clinical assess-
infection (pneumonia) with or without multiorgan failure.9
ment of the individual patient, taking into account factors that may
In adults, influenza typically begins with fever, respiratory symp-
influence the presentation such as extremes of age, co-morbid condi-
toms such as cough or sore throat and systemic symptoms, such as
tions and immunocompetence.
myalgia, arthralgia and headache. Gastrointestinal symptoms, notably
diarrhea, have been described uncommonly as manifestations of sea-
sonal influenza A. V. TREATMENT OF INFLUENZA ILLNESS
While the typical clinical features of influenza illness appear in A. Antiviral drugs
older children and youth, among those younger than 10 years of age, For both zanamivir and oseltamivir, this document describes some uses
the clinical features may be atypical. Indeed, among children younger that are outside of the authorizations provided by Health Canada, as
than five years of age, influenza illness is often non-specific and may be outlined in the Canadian Product Monographs, as of August 2013.
indistinguishable from illness due to other respiratory viruses. Young 1. Oseltamivir – The NAI drug oseltamivir (Tamiflu®) is authorized by
infants may present with a sepsis-like picture. Infants younger than six Health Canada for the treatment of uncomplicated influenza A and B in
months of age are more likely to present with rhinorrhea and dehydra- patients one year of age or older who have been symptomatic for no
tion than cough and pneumonia and among those younger than three more than two days. Oseltamivir is also authorized in Canada for pre-
months of age, fever alone or fever with dehydration are common vention of influenza A and B in adults and children one year of age and
presenting features.9 Diarrheal illness may be observed. Some clinical older who are close contacts of an individual with characteristic symp-
signs in infants, children and youth warrant urgent medical attention. toms of influenza. In the United States, oseltamivir is also approved for
Familiarity with these signs is advised (Table 2). the treatment of influenza in infants two weeks of age or older.19
Severe lower respiratory tract disease encompasses diffuse primary Oseltamivir is formulated as oseltamivir phosphate in capsules
viral pneumonia, which often develops directly from progression of containing 30 mg, 45 mg or 75 mg per capsule or as a suspension con-
initial symptoms, and secondary bacterial pneumonia, which may arise taining 6  mg/mL or 12 mg/mL. Intravenous oseltamivir may be
after a period of initial improvement. Acute respiratory distress syn- obtained either through clinical trials (if available) or in specific cir-
drome (ARDS) may develop several days after illness onset. The cumstances through the Special Access Program of Health Canada
importance of secondary bacterial infections in influenza is further (http://www.hc-sc.gc.ca/dhp-mps/acces/drugs-drogues/index-eng.php).
illustrated by the fact that among fatal cases of A(H1N1)pdm09, con- Oseltamivir phosphate is well absorbed and extensively converted
comitant bacterial pneumonia was demonstrated in 26% to 38% of by hepatic and intestinal epithelial cells to oseltamivir carboxylate,
cases.10 These bacteria included Streptococcus pneumoniae, methicillin- which is the active antiviral molecule. It is eliminated almost com-
susceptible and methicillin-resistant Staphylococcus aureus (MRSA). pletely as unchanged drug in the urine by glomerular filtration and
Influenza-related complications in infants, children and youth renal tubular secretion.20
include severe hemorrhagic viral pneumonia, secondary bacterial pneu- In part due to lack of further metabolic transformation, oseltamivir
monia (due to S. pneumoniae, S. aureus, or group A Streptococcus), carboxylate has little potential for drug-drug interactions and this
mixed viral and bacterial pneumonia, localized viral pneumonia, severe expectation has been borne out by limited clinical studies.
laryngotracheobronchitis (croup) and exacerbation of chronic pul- Influenza B viruses are approximately 10- to 20-fold less susceptible
monary disease. Non-pulmonary complications include acute myositis, to oseltamivir carboxylate than are influenza A viruses20 and this in

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 3C

Aoki et al

vitro difference may explain differences in clinical efficacy of oseltamivir associated encephalopathy, increased access to oseltamivir in that
for treatment of influenza A and B virus infections in children21,22 and population, and a coincident period of intensive monitoring of adverse
adults.23 events.38 They were not able to establish a causal relationship between
Treatment and prophylaxis regimens of oseltamivir and zanamivir for oseltamivir and the reports of pediatric deaths. Of note, deaths
adults and for children by age and weight are detailed in Table 4.24 Doses occurred in children two years of age and older but the ages of those
do not need to be adjusted in obese adults.25 Dose reduction is advised with neuropsychiatric manifestations were not reported.39
for pharmacokinetic reasons in persons with creatinine clearance Drug Interactions: Interactions during co-administration of
<10 mL/min although the drug has a wide margin of safety and causes no oseltamivir with other drugs are unlikely as it is eliminated largely
serious, dose-related adverse effects. Dose reduction is advised for unchanged into urine by glomerular filtration and renal tubular secre-
patients with impaired renal function, as detailed in Table 5.26-29 tion by an anionic transporter and does not cause dose-related adverse
In adults, oral oseltamivir is generally well tolerated. Mild, rapidly effects even at high doses.20
reversible nausea and/or vomiting have been observed in approxi- 2. Zanamivir – Zanamivir (Relenza®) is authorized by Health Canada
mately 5% to 10% more persons taking oseltamivir versus placebo. for the treatment of uncomplicated influenza A and B in patients
Nausea and/or vomiting are more common in young adults taking seven years of age or older who have been symptomatic for no more
150 mg twice daily (12% to 15%) than 75 mg twice daily (8% to 11%) than two days. It is also authorized for the prevention of influenza A
compared to placebo (3% to 7%).20 No other side effects occurred and B in patients seven years of age or older.
significantly more frequently in oseltamivir than placebo recipients. In vitro, influenza A and B viruses exhibit similar susceptibility to
Influenza A and B viruses rarely cause central nervous system symp- zanamivir.40 In observational studies of children and young adults with
toms including convulsions and coma.30 A causal relationship between influenza A or B virus infection treated with either oseltamivir or
oseltamivir and such adverse effects or a wider spectrum including zanamivir, there was no difference in duration of fever between treat-
delirium with hallucinations has been suspected but not definitively ments in young children four to 16 years of age.22 However, in older
established.31,32 Close monitoring of treated patients is advised. children and adults (mean [± SD] age 15±12 years) with influenza B
For adults with seasonal influenza of less than 36 h duration, there virus infection, the duration of fever was significantly less in individ-
appears to be no advantage of combining oseltamivir and zanamivir.33 uals treated with zanamivir versus oseltamivir.23 In a small, observa-
Administering higher doses of oseltamivir to critically ill patients with tional study in persons of unspecified age directly comparing the
influenza is not warranted. Preliminary analysis from a randomized efficacy of zanamivir in ill persons with influenza A or influenza B
comparison of 150 mg BID and 75 mg BID oseltamivir for treatment of virus infection, no differences in duration of fever were observed.41
patients seriously ill with influenza, including A(H1N1)pdm09 No data are available on the comparative effects of oseltamivir and
viruses, suggested that the higher dose was safe but offered no benefit zanamivir on influenza B virus infection in older adults and those in
over the standard dose regimen, as evaluated by reductions in viral high-risk groups.
shedding at day 5 of treatment.34 Oseltamivir was used to treat critic- Zanamivir is marketed as a powder in a proprietary inhalational
ally ill patients during the 2009 H1N1 pandemic. Such use included device that delivers 5 mg of zanamivir per inhalation.40 Approximately
treatment with higher doses administered for longer periods than the 80% of an inhaled dose is deposited onto the upper respiratory tract
approved five-day regimen of 75 mg BID. In critically ill ventilated lining and 13% in the bronchi and lungs, where it exerts its antiviral
patients with A(H1N1)pdm09, oseltamivir administered via a gastric effect. Ten per cent to 20% of inhaled drug is absorbed and eliminated
tube was well absorbed, yielding plasma concentrations that exceed unchanged into the urine.
the inhibitory concentration of influenza A virus.35 No dose reductions are recommended for any patient population.
In children, data on the safety and efficacy of oseltamivir exist for There have been case reports of mechanically ventilated patients with
those one year of age and older.36 Pharmacokinetic data show that A(H1N1)pdm09 influenza who had been treated with zanamivir
2 mg/kg twice daily resulted in drug exposures within the range associ- diskhaler powder in water administered by nebulizer, resulting in bron-
ated with tolerability and efficacy in adults who were administered chospasm and obstruction of ventilator filters.42
approximately 1 mg/kg twice daily. A liquid formulation was shown in Intravenous formulations of zanamivir are under clinical investiga-
a randomized placebo controlled trial to be safe and well accepted by tion but are not authorized for use in Canada. Intravenous zanamivir
healthy children one to 12 years of age and children with asthma six may be obtained either through clinical trials (if available) or in specific
to 12 years of age.36 Emesis occurred in 14.3% of children receiving circumstances through the Special Access Program of Health Canada
oseltamivir 2 mg/kg/dose BID for 10 doses (maximum 100 mg/dose) (http://www.hc-sc.gc.ca/dhp-mps/acces/drugs-drogues/index-eng.php).
and 8.5% receiving placebo. Discontinuation rates due to adverse Zanamivir is safe and well tolerated as evidenced by studies reveal-
events were not different, being 1.8% and 1.1%, respectively.36 ing no adverse effects after intravenous injection of 1200 mg/day to
The safety and efficacy of oseltamivir in infants younger than adult volunteers for five days.43 Although practitioners are advised to
one year of age have not been established. This is clearly an area where beware of bronchospasm in zanamivir-treated patients, in one study of
additional research is needed. A caution was issued due to deaths zanamivir inhaled once daily as prophylaxis of family members of
observed in seven-day old mice receiving extremely high doses of the index cases there was no increase in asthma exacerbations in asth-
drug.37 These animals were fed a dose that was about 250 times the matic contacts receiving zanamivir (6%) versus placebo (11%).44
dose recommended for children. The concentrations of the pro-drug in Another double-blind placebo-controlled trial of zanamivir treatment
the brain were 1500 times those of the adult animals exposed to the of influenza in patients 12 to 88 years of age (median 38 years of age)
same dose. Thus, it was felt that an immature blood-brain barrier may with asthma or chronic obstructive pulmonary disease did not find an
have caused the toxicity in these animals. Based on the ages of the increased incidence of bronchospasm in the zanamivir group.45 In fact
animals and the stage of the development of their blood-brain barrier, the morning and evening peak expiratory flow rates were significantly
the human equivalent was felt to be infants younger than one year of increased in the zanamivir group.46 Despite these data there have been
age. However, recent reports from Japan did not show CNS toxicity in reports of acute bronchospasm in patients taking zanamivir, so that the
infants younger than one year of age who were treated with Advisory Committee on Immunization Practices of the US Centers for
oseltamivir. Diseases Control and Prevention advised caution in using zanamivir
In November 2005, there were reports of neuropsychiatric events for asthmatic and COPD patients and advised that the patient should
and deaths in Japanese children receiving oseltamivir. The United have a short acting bronchodilator available during treatment.
States FDA reviewed the available information and concluded that Drug Interactions: Interactions between zanamivir and other drugs
the increased reports of neuropsychiatric events in Japanese children co-administered systemically are neither likely nor expected due to the
are most likely related to an increased awareness of influenza- minimal absorption of zanamivir after oral inhalation.40

4C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013

 The use of antiviral drugs for influenza

3. Combination therapy – The clinical utility of combination therapy Table 3

for treating influenza remains uncertain. A retrospective cohort study At-risk groups and co-morbid medical conditions that
compared a triple combination of drugs (oseltamivir, amantadine & predispose to severe influenza (adapted from references
ribavirin) with oral oseltamivir in adults with serious influenza illness 12 and 13)
requiring ventilator support.47 Both regimens were similarly effective
• Asthma and other chronic pulmonary disease, including bronchopulmonary
in reducing mortality. A modeling study using three antiviral drugs
dysplasia, cystic fibrosis, chronic bronchitis and emphysema
with different mechanisms of action suggested that this therapeutic
• Cardiovascular disease (excluding isolated hypertension; including
strategy could delay the emergence of resistance better than treatment
congenital and acquired heart disease such as congestive heart failure
with a single influenza inhibitor.48
and symptomatic coronary artery disease)
B. Benefits of antiviral treatment • Malignancy
NAI therapy of patients ill with infection due to seasonal influenza • Chronic renal insufficiency
viruses has been demonstrated in controlled trials to reduce the dur- • Diabetes mellitus and other metabolic diseases
ation and severity of uncomplicated, self-limited laboratory-confirmed • Hemoglobinopathies such as sickle cell disease
influenza, largely due to influenza A viruses, in otherwise healthy chil- • Immunosuppression or immunodeficiency due to disease (e.g. HIV infection,
dren older than one year of age and adults.3,49 A meta-analysis con- especially if CD4 is <200×106/L), or iatrogenic, due to medication
cluded that these drugs seemed to reduce total influenza-related • Neurologic disease and neurodevelopmental disorders that compromise
complications but could not distinguish between mild and serious handling of respiratory secretions (cognitive dysfunction, spinal cord injury,
complications.50 NAIs have been shown to reduce the frequency of seizure disorders, neuromuscular disorders, cerebral palsy, metabolic
otitis media as a complication of influenza in pediatric patients.49 NAI disorders)
treatment of hospitalized patients with seasonal influenza may reduce • Children younger than 5 years of age*
the duration of hospitalization and mortality.51 • Individuals 65 years of age or older
In a number of observational studies of patients with A(H1N1) • People of any age who are residents of nursing homes or other chronic
pdm09 infection, it was reported that treatment with NAIs, chiefly care facilities
oseltamivir, reduced the progression and severity of illness in the gen-
• Pregnant women and women up to 4 weeks post partum regardless of
eral population as well as in vulnerable groups. These groups include
how the pregnancy ended
pregnant women and solid organ transplant recipients.52
• Individuals <18 years of age who are on chronic aspirin therapy
As noted above, in vitro and available clinical data from observa-
• Obesity with a BMI >40 or a BMI >3 z-scores above the mean for age and
tional studies,21-23 but not randomized, controlled trials, suggest that
gender
inhaled zanamivir may be more efficacious than oral oseltamivir for the
treatment of influenza B virus infection in older, but not younger • Aboriginal peoples
children. * Children who are two through four years of age also have a higher rate of
Investigational intravenous zanamivir 600 mg BID has been complications compared to older children; however, the risk for these children
reported to be efficacious for preventing experimental human influ- is lower than the risk for children younger than two years of age
enza A virus infection53 and treating oseltamivir-resistant A(H1N1)
pdm09 pneumonitis54,55 as well as critically ill patients with A(H1N1)
pdm09 influenza.56 Based on these data, intravenous zanamivir is rec-
ommended for antiviral therapy of patients severely ill with suspected • Moderate or progressive illness is characterized by typical
or confirmed oseltamivir-resistant influenza who are unable to use the symptoms plus signs or symptoms suggesting more than mild
inhalational device. illness: chest pain, poor oxygenation (e.g. tachypnea, hypoxia,
Inasmuch that a number of respiratory tract viral pathogens can labored breathing), cardiopulmonary insufficiency (e.g. low blood
cause an influenza-like illness, anti-influenza drug therapy will pressure), CNS impairment (e.g. confusion, altered mental
invariably result in treatment of some persons whose influenza-like status), severe dehydration, or exacerbations of chronic
illness is not due to influenza virus. At present, there are no data to conditions (e.g. asthma, chronic obstructive pulmonary disease,
suggest that such treatment is ecologically harmful. Since NAIs are chronic renal failure, diabetes or cardiovascular disease).
specific inhibitors of only influenza virus neuraminidase, such treat- • Severe or complicated illness is characterized by signs of lower
ments are unlikely to engender resistance in other microorganisms. respiratory tract disease (e.g., hypoxia requiring supplemental
Moreover, influenza viruses are not constituents of the normal flora oxygen, abnormal chest radiograph, mechanical ventilation),
of humans. CNS abnormalities (encephalitis, encephalopathy), complications
of low blood pressure (shock, organ failure), myocarditis or
C. Considerations in selecting treatments rhabdomyolysis, or invasive secondary bacterial infection based
The indications for treatment may be structured around the following on laboratory testing or clinical signs (e.g. persistent high fever
considerations: and other symptoms beyond three days).
1. Severity of illness;
2. Presence of risk factors or co-morbid conditions; 2. Presence of risk factors or co-morbid medical conditions:
3. Interval between onset of illness and diagnosis; • Patients with risk factors such as age, ethnicity or co-morbid
4. Likely influenza type(s) causing infection (see Section III). medical conditions have been identified as being at greater risk
for complications of influenza based on extensive experience
1. Severity of illness: during seasonal influenza outbreaks and the recent experience
Useful definitions of the range of clinical illness caused by influenza during the A(H1N1)pdm09 pandemic (see Table 3).
viruses have been adapted from those published by the CDC57: Notwithstanding the above association of the aforementioned
• Mild or uncomplicated illness is characterized by typical medical conditions as risk factors for severe influenza, 20% to 40% of
symptoms like fever (although not everyone with influenza, patients with severe A(H1N1)pdm09 influenza admitted to intensive
especially at the extremes of age, will have a fever), cough, sore care units were previously healthy persons not belonging to any known
throat, rhinorrhea, muscle pain, headache, chills, malaise, high-risk group. The corollary is that practitioners must be vigilant in
sometimes diarrhea and vomiting, but no shortness of breath and their evaluation of otherwise healthy individuals in whom seasonal
little change in chronic health conditions. influenza illness appears to be mild but may be progressing.

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 5C

Aoki et al

Table 4
Oseltamivir and zanamivir treatment of influenza (treatment regimens adapted from reference 24).
The Use of Antiviral Drugs for Influenza: A Foundation Document for Practitioners
Medication Treatment (5 days) Chemoprophylaxis (10 days)
Oseltamivir1
Adults
75 mg twice daily 75 mg once daily
Children ≥12 months
Body Weight (kg) Body Weight (lbs)
≤15 kg ≤33lbs 30 mg twice daily 30 mg once daily
>15 kg to 23 kg >33 lbs to 51 lbs 45 mg twice daily 45 mg once daily
>23 kg to 40 kg >51 lbs to 88 lbs 60 mg twice daily 60 mg once daily
>40 kg >88 lbs 75 mg twice daily 75 mg once daily
Children 3 months to <12 months2*
3 mg/kg/dose twice daily 3 mg/kg/dose once per day
Children <3 months3*
3 mg/kg/dose twice daily Not recommended unless situation judged critical due to
limited data on use in this age group
*Please note that antivirals are not authorized in Canada for the routine treatment of seasonal influenza illness in infants younger than one year of age. Such use
may be considered on a case-by-case basis.
Zanamivir4
Adults
10 mg (two 5 mg inhalations) twice daily 10 mg (two 5 mg inhalations) once daily
Children (≥7 years or older)
10 mg (two 5 mg inhalations) twice daily  10 mg (two 5 mg inhalations) once daily
1. Oseltamivir is administered orally without regard to meals, although administration with meals may improve gastrointestinal tolerability. Oseltamivir is available in
30 mg, 45 mg, and 75 mg capsules, and as a powder for oral suspension that is reconstituted to provide a final concentration of either 6 mg/mL or 12 mg/mL. If the
commercially manufactured oral suspension is not available, the capsules may be opened and the contents mixed with a sweetened liquid to mask the bitter taste
or a suspension can be compounded by retail pharmacies.
When dispensing commercially manufactured Oseltamivir (TAMIFLU) Powder for Oral Suspension (6 mg/mL or 12 mg/mL), pharmacists should ensure the units of
measure on the prescription instructions match the dosing device.
2. Weight-based dosing is preferred. However, if weight is not known, dosing by age for treatment of influenza (give two doses per day) or prophylaxis (give one dose
per day) in full-term infants younger than one year of age may be necessary: 0 to 3 months = 12 mg per dose for treatment (not for prophylaxis); 3 to 5 months =
20 mg per dose; 6 to 11 months = 25 mg per dose.
3. Current weight-based dosing recommendations are not intended for premature infants. Premature infants may have slower clearance of oseltamivir due to imma-
ture renal function, and doses recommended for full term infants may lead to very high drug concentrations in this age group. Very limited data from a cohort of
premature infants demonstrated that oseltamivir concentrations among premature infants given 1 mg/kg body weight twice daily were similar to those observed with
the recommended treatment doses in term infants (3 mg/kg body weight twice daily). Observed drug concentrations were highly variable among premature infants.
The IDSA 2011 recommendations for pediatric pneumonia suggest 2 mg/kg/day divided twice daily. Currently available data are insufficient to recommend a specific
dose of oseltamivir for premature infants; it is strongly suggested that an infectious disease physician or clinical pharmacist be consulted.
4. Zanamivir is administered by inhalation using a proprietary “Diskhaler” device distributed together with the medication. Zanamivir is a dry powder, not an aerosol,
and should not be administered using nebulizers, ventilators, or other devices typically used for administering medications in aerosolized solutions. Zanamivir is not
recommended for persons with chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease that increase the risk of bronchospasm.

3. Interval between onset of illness and initiation of antiviral The attack rates for seasonal influenza in healthy children range
therapy. from 3% to 30% with 1% requiring hospitalization.59,60 During com-
Initiation of treatment of uncomplicated seasonal influenza in healthy munity outbreaks of seasonal influenza, the highest attack rates occur
adults and children with NAI within 36 h to 48 h of illness onset is in school-age children. Children are a common source from which
efficacious. Optimal benefits are obtained if treatment is initiated as infection is spread to other household members. The shedding of virus
early as possible after the onset of symptoms.49,58 Thus, starting treat- usually starts 24 h prior to the onset of overt symptoms and generally
ment within 12 h of illness onset should be a practice goal. ceases at seven days.
Influenza illness may be indistinguishable from illness due to other
4. Likely influenza type(s) causing infection: respiratory viruses. The atypical and non-specific nature of influenza
Practitioners should be mindful of reports in the Public Health Agency illness in young children is evidenced by Canadian surveillance data
of Canada’s FluWatch <http://www.phac-aspc.gc.ca/fluwatch/> and that suggest that among hospitalized children, fever and cough are the
reports from their provincial or territorial public health departments. most common presenting features.61
Since 2009-10, the predominant influenza viruses have been sensitive The pulmonary and non-pulmonary influenza-related complica-
to NAIs; however it remains important to maintain awareness in case tions in infants, children and youth are generally similar to those in
oseltamivir-resistant seasonal influenza viruses reappear. adults with the exception that some conditions are more likely to be
seen in children (sepsis-like illness, diarrhea, otitis media, severe
D. Treatment of children laryngotracheobronchitis (croup), febrile seizures, Reye’s syndrome,
While some aspects of influenza prevention and treatment in adults and refusal to walk due to myositis.59
can be extrapolated to children, there are several areas where special In general, children with pre-existing high-risk medical conditions
pediatric considerations are necessary. In general, when compared to are more likely to have adverse outcomes. However, previously healthy
adults, there are fewer data to guide the management of children, children may also experience adverse consequences. In this regard, in
notably young infants. some influenza seasons previously healthy children may account for up

6C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013

 The use of antiviral drugs for influenza

Table 5
Recommended oseltamivir regimens for prevention and treatment of adult patients with renal impairment (26-29, TamifluR
Canadian Product Monograph, 2012)
Creatinine clearance Treatment for 5 days Prophylaxis until outbreak is over
>60 mL/min 75 mg twice daily 75 mg once daily
>30–60 mL/min 75 mg once daily OR 30 mg suspension twice daily OR 30 mg capsule twice daily 75 mg on alternate days or 30 mg once daily
10-30 mL/min 30 mg once daily 30 mg on alternate days
<10 mL/min (renal failure)* Single 75 mg dose for the duration of illness No data
Dialysis patients* Low-flux HD: 30 mg after each dialysis session 30 mg after alternate dialysis sessions
High-flux HD: 75mg after each dialysis session No data
CAPD dialysis: 30 mg once weekly 30 mg once weekly
CRRT high-flux dialysis: 30 mg daily or 75 mg every second day No data
The following dosing regimen has been suggested for children based on limited data (29):
In children older than one year of age, after alternate HD sessions as follows:
• 7.5 mg for children weighing >15 kg
• 10 mg for children weighing 16–23 kg
• 15 mg for children weighing 24–40 kg
• 30 mg for children weighing >40 kg
While this may provide a framework for guidance, it is strongly suggested that an infectious disease physician or clinical pharmacist should be consulted.
*Experience with the use of oseltamivir in patients with renal failure is limited. These regimens have been suggested based on the limited available data27,28,29
Consultation with an infectious physician or clinical pharmacist is recommended

to 50% of reported influenza-related deaths.62 Influenza B has been than two days. (Tamiflu USA Product Monograph Revised December
identified in a disproportionate number of pediatric influenza- 2012). Oseltamivir was temporarily approved for use in infants less
associated deaths (38%).62 than one year of age on the basis of a favourable risk-to-benefit ratio
Children at the highest risk of adverse outcomes from influenza during the 2009 H1N1 pandemic. However, antivirals are not cur-
illness include those younger than five years of age.63 Hospitalizations rently authorized in Canada for the treatment of seasonal influenza in
occur more frequently among those younger than two years of age infants younger than one year of age and their use in infants should be
compared with older children, with the highest hospitalization rates handled on a case-by-case basis, based on severity of illness.
being among those younger than six months of age.61 This does not Recommendations for oseltamivir dosing for infants less than one year
necessarily translate into a recommendation to use antiviral therapy in of age varied within a reasonably narrow range and have been updated
those younger than two years of age; such children with mild influenza for seasonal influenza.74-76 Current dosing recommendations are
illness and in the absence of risk factors other than age do not usually shown in Table 4, but clinicians should be aware of possible dose chan-
need treatment. ges as more information becomes available for young infants.
Among the currently available antiviral agents, three are approved
for use for children in Canada: amantadine (which is not currently E. Treatment of immunocompromised patients
useful because of resistance) for influenza A; oseltamivir and zanamivir This group includes individuals with a wide range of congenital and
for influenza A and B. Clinical trials supporting the role of the NAIs acquired immunodeficiencies. The heterogeneity of populations of
in children were previously summarized and have been the subject of immunocompromised hosts is well recognized, resulting in varying
recent meta-analyses. 49,64 One meta-analysis suggested that NAIs degrees of risk for adverse outcomes from influenza illness. In this con-
shorten the duration of illness in children with seasonal influenza and text, Table 6 summarizes selected clinical, laboratory and other mark-
reduce household transmission, but that they have little effect on ers that help to categorize various immunodeficiency states and
asthma exacerbations or the use of antibiotics.64 identify patients who might be at the greatest risk of adverse outcomes
Data from the only double-blind, randomized, controlled trial of from influenza illness.77 The presence of these markers suggest
oseltamivir for the treatment of influenza in previously healthy children, increased risk for acquisition of infection, progression to more severe
indicated significant reductions in physician-diagnosed complications and potentially life-threatening consequences of infection, and for an
requiring antibiotic therapy (relative risk-reduction 40%) and in the impaired ability to develop immunity to infection following subse-
likelihood of developing otitis media (relative risk reduction 44%).65 quent exposure to influenza virus.77
Another randomized trial among children aged one to three years, indi- In addition to the well-recognized variability in the clinical mani-
cated an 85% reduction in acute otitis media when oseltamivir was festations of influenza illness, atypical clinical features may be present in
started within 12 h after the onset of influenza illness, but no reduction immunocompromised individuals. For example, immunocompromised
when treatment was started at >24 h after the onset of symptoms.66 A individuals may present with fever as the sole manifestation of influenza
benefit on asthma exacerbations among oseltamivir-treated children has illness78 or may present with respiratory symptoms without fever.79
also been demonstrated in a randomized controlled trial.67 The complications seen among persons with normal immune sys-
Since the earlier studies on NAIs, additional studies have been tems may also be seen in immunocompromised hosts. Invasive second-
reported or are in progress and experience with their use has ary bacterial infections caused by S. pneumoniae, S. aureus, S. pyogenes
increased.68-71 However, there exists a relative paucity of new data and other bacterial pathogens may occur and can be devastating for the
from randomized trials in infants and young children. Recent studies immunocompromised host. For example, asplenic individuals are known
have provided valuable safety data72 as well as data on the use of to be at increased risk of severe invasive pneumococcal disease.
oseltamivir in premature newborns.73 In the United States, oseltamivir Prolonged illness and viral shedding are features of infection in
is approved for the prevention of influenza in patients one year and immunocompromised individuals. Indeed, in some of the more immuno-
older and the treatment of acute uncomplicated influenza in patients compromised individuals, the virus may be persistently present in the res-
two weeks of age and older who have been symptomatic for no more piratory tract for several weeks or months.80,81 This persistent shedding

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 7C

Aoki et al

Table 6
Selected surrogate indices of immunocompromised states
Laboratory-based Indices Clinical States Treatment-related Indices
Significant risk Significant but variable risk due to heterogeneity in clinical states Significant but variable risk due to
heterogeneity in nature and intensity of
treatments
• Severe neutropenia • Individuals with malignancies receiving active cytotoxic chemotherapy A history of ongoing myelosuppressive and/
(ANC <0.5×109/L), • Acute leukemia patients or immunosuppressive therapies such as:
and/or, • HSCT recipients • Corticosteroid therapy71 (i.e., among adult
• Severe lymphopenia • SOT recipients (e.g. lung, heart, kidney) patients >700 mg cumulative dose of
(ALC <0.5×109/L) • Individuals with congenital immunodeficiency states prednisone equivalent on an ongoing basis
and at the time of clinical evaluation;
• Individuals with acquired immunodeficiency states (e.g. Human Immunodeficiency
among pediatric patients,72 >2 mg/kg per
Virus infection, plasma cell dyscrasias, B-lymphocyte malignancies)
day of prednisone or its equivalent, or
• Individuals with rheumatic diseases or autoimmune disorders (e.g. RA or SLE)
>20 mg/day if they weigh more than 10 kg
• Individuals with GI diseases receiving immunosuppressive drugs (e.g. IBD),
administered for 14 days or more)
• Individuals on renal dialysis
• Cytotoxic therapy*
• Individuals with asthma or COPD receiving corticosteroid therapy.
• Immunomodulator therapies**
*Examples of cytotoxic therapy include, but are not limited to: **Examples of immunomodulator therapy include, but are not limited to:
(e.g., anthracyclines such as doxorubicin or epirubicin; purine analogues such Calcineurin inhibitors (e.g., cyclosporine, tacrolimus, sirolimus),
as azathioprine, thioguanine, mercaptopurine, fludarabine, pentostatin, or Guanine synthesis inhibitors (e.g., Mycophenolate mofetil),
cladribine; pyrimidine analogues such as flurorouracil, cytarabine, Anti-B lymphocyte therapy (e.g., rituximab),
capecitabine, or gemcitabine; anti-folate agents such as methotrexate or Anti-T lymphocyte therapy (e.g., anti-thymocyte globulin or anti-CD3),
pemetrexed; alkylating agents such as the nitrogen mustards
Anti-B and T cell therapy (e.g., alemtuzumab, basiliximab, daclizumab),
(cyclophosphamide or ifosphamide), nitrosoureas (carmustine, lomustine,
Anti-TNF therapy (e.g., infliximab or etanercept),
semustine, streptozotocin), and platinum analogues (cis-platin, carboplatin, or
Alpha-interferon therapy
oxaliplatin); taxanes (e.g., docetaxel, paclitaxel); topoisomerase I inhibitors
(e.g., irinotecan).
Adapted from: Allen et al (reference 77). Abbreviations: ANC, absolute neutrophil count; ALC, absolute lymphocyte count; HSCT, haematopoietic stem cell transplant;
SOT, solid organ transplant; RA, rheumatoid arthritis; SLE, systemic lupus erythematosis; GI, gastrointestinal; IBD, inflammatory bowel disease; COPD, chronic
obstructive airways disease; TNF, tissue necrosis factor

may be accompanied by periodic exacerbations of illness.80,81 Cell- were comparable to those observed in individuals with other recognized
mediated immunity is important in mediating protection from influenza co-morbid conditions that increase the risk of influenza-related complica-
illness, viral clearance and recovery from illness.81-85 Thus, reductions in tions.89 As a result of such data, pregnancy is now recognized to be a risk
T-cell number or function as a result of acquired or congenital immuno- factor that warrants annual influenza immunization. During the 2009
deficiency states may result in an increased likelihood of a more severe A(H1N1)pdm09 pandemic, not only were increased rates of hospitaliza-
and prolonged illness and an increased risk of antiviral resistance.81,82 The tion observed in healthy pregnant women, especially in the second and
risk for immunocompromised persons is compounded if they have co- third trimester, but also an increased rate of death compared to that in
morbid states that are themselves risk factors for adverse outcomes from non-pregnant women.90 Such excess mortality had previously been
influenza illness (e.g., underlying chronic lung disease). The risk among observed during the 1918 and 1957 pandemics. A recent meta-analysis
these individuals may be variable due to differences in the nature and demonstrated that women who were less than four weeks post-partum
intensity of their immunosuppressive therapies.86,87 were at greatest risk of death.91 New evidence indicates that there is a
The importance of early treatment of influenza illness in immuno- significant increase in stillbirths, premature deliveries, and infant mortal-
compromised hosts (e.g., organ transplant recipients) is well docu- ity when women have influenza in the third trimester.92
mented. Protracted illness and virus shedding may prompt physicians Oseltamivir pharmacokinetics in pregnant women with influenza
to prolong antiviral therapy with oseltamivir. However, the increased are not different from one trimester to another.93 Oseltamivir is
likelihood of antiviral resistance is a major concern with prolonged excreted in breast milk, but at concentrations below that required to
oseltamivir therapy of influenza in immunocompromised patients.88 inhibit current influenza A and B strains.94 These observations taken
Antiviral resistance should be considered if there is a lack of response together support the recommendation to treat influenza in pregnant
to antiviral therapy, especially in the setting of recent antiviral admin- women in all trimesters with oseltamivir in standard doses as soon as
istration. Accordingly, practitioners should consult with experts and possible after the onset of influenza-like symptoms.95
be vigilant for antiviral resistance when treating such patients. Oseltamivir and zanamivir are listed by the FDA as Pregnancy
Category C drugs, reflecting the fact that no controlled trials have
F. Treatment of patients with renal impairment been done to assess their safety during pregnancy. No adverse effects
Recommended oseltamivir regimens for treatment and prophylaxis of on the pregnant woman or fetus have been observed as a result of
patients with renal impairment or failure are presented in Table 5.26-29 treatment with oseltamivir during pregnancy.96,97
No dosage adjustments are required for inhaled zanamivir treat- Some authorities recommend oseltamivir in preference to zanami-
ment in patients with renal impairment. vir during pregnancy because it is systemically absorbed.98 Systemically
absorbed oseltamivir would likely be delivered to virus-infected res-
G. Treatment of pregnant patients piratory tract tissues more consistently than would inhaled zanamivir,
During seasonal influenza epidemics, healthy pregnant women with influ- especially in the later stages of pregnancy when diaphragmatic excur-
enza, especially those in the third trimester of pregnancy, experienced sion, limited by the gravid uterus, may impair necessary distribution of
rates of hospitalization in excess of those observed in age-matched non- inhaled zanamivir through the respiratory tract. Oseltamivir is now
pregnant women with influenza.89 Moreover, the rates of hospitalization recommended for the treatment of influenza in pregnant women.

8C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013

 The use of antiviral drugs for influenza

VI. RECOMMENDATIONS FOR TREATMENT • Consider hospitalization and admission to ICU.

A. General Principles: (Recommendation, Grade C evidence)
• Treatment should be initiated as rapidly as possible after onset of • Oseltamivir 75 mg BID orally or by nasogastric tube should be
illness as the benefits of treatment are much greater with initiated immediately. (Recommendation, Grade C evidence)
initiation at less than 12 h than at 48 h. (Strong • Oseltamivir should be started even though the window between
recommendation, Grade B evidence) symptom onset and initial administration of antiviral is longer
• Antiviral therapy should be initiated even if the interval between than 48 h. (Recommendation, Grade C evidence)
illness onset and administration of antiviral medication exceeds • Treatment with zanamivir instead of oseltamivir should be
48 h if: considered for
i. The illness is severe enough to require hospitalization (Strong i) Those not responding to oseltamivir therapy,
recommendation, Grade X evidence), (Recommendation, Grade X evidence)
ii. The illness is progressive, severe or complicated, regardless of ii) Those with illness despite oseltamivir prophylaxis,
previous health status (Strong recommendation, Grade X (Recommendation, Grade X evidence)
evidence), or iii) Where influenza B is confirmed or strongly suspected
iii. The individual belongs to a group at high risk for severe (Recommendation, Grade C evidence)
disease (Strong recommendation, Grade X evidence). • In the above circumstances i and ii, virus should be tested for
• Otherwise healthy patients with relatively mild, self-limited oseltamivir resistance, if possible.
influenza are not likely to benefit from NAI therapy initiated
D. Treatment of infants, children and youth with mild or
more than 48 h after illness onset. Clinical judgment should be
uncomplicated influenza illness:
used. (Option, Grade D evidence)
A treatment algorithm is provided as Appendix C.
• Patients for whom antiviral therapy is not initially recommended
• For those with mild disease, no risk factors other than age:
should be advised of symptoms and signs of worsening illness that
i. Younger than one year of age: NAIs are currently not
might warrant reassessment. (Recommendation, Grade X evidence)
approved in Canada for the routine treatment of seasonal
• Treatment duration should routinely be five days (Strong influenza illness ; antiviral use may be considered on a case-
Recommendation, Grade A evidence), but may be continued longer by-case basis. Given that infants less than six months of age
than five days if clinically indicated. (Option, Grade D evidence) are not eligible for influenza vaccination, immunization of
• Intubated patients with influenza illness should receive oseltamivir their household and other close contacts is important in pro-
through a nasogastric tube. (Recommendation, Grade C evidence) tecting them against influenza, thereby potentially leading to
• For patients unable to tolerate or receive oral oseltamivir, inhaled reduced need for antiviral therapy. Influenza immunization of
or intravenous zanamivir (see Zanamivir section V 2 for how to the pregnant woman may also provide protection for her
access) is a suitable option. (Option, Grade D evidence) infant during the first six months of life. (Option, Grade D
• Zanamivir may be preferred to oseltamivir in the following situations: evidence)
i. Patients not responding to oseltamivir therapy (Option, ii. One to less than five years of age: Although children under five
Grade D evidence) years of age are classified as a ‘high risk’ group (with those
ii. Patients with illness despite oseltamivir prophylaxis (Option, younger than two years of age having the highest risk), those who
Grade D evidence) are otherwise healthy and have mild disease not requiring hospi-
iii. Where influenza B is confirmed or strongly suspected talization do not routinely require antiviral therapy. For these
(Recommendation, Grade C evidence) children, treatment is optional. (Option, Grade D evidence).
iii. Five years of age or older: antiviral therapy is not routinely
• For severely ill patients, zanamivir administered intravenously is
recommended for children and youth who are otherwise
preferred to inhaled drug. (Recommendation, Grade X evidence)
healthy and have mild disease not requiring hospitalization.
• In ventilated patients, zanamivir should only be administered (Option, Grade D evidence)
intravenously. (Strong Recommendation, Grade X evidence) • For those with mild disease and risk factors other than age:
• In the above circumstances i and ii, virus should be tested for i. Younger than one year of age: NAIs are currently not approved
oseltamivir resistance, if possible. (Option, Grade D evidence) in Canada for the routine treatment of seasonal influenza ill-
ness. Such use may be considered on a case-by-case basis.
B. Treatment of non-pregnant adults with mild or uncomplicated ii. One year of age and older: illness with onset within 48 h, treat
influenza illness: with oseltamivir or if age appropriate, inhaled zanamivir
A treatment algorithm is provided as Appendix A. (Recommendation, Grade B evidence)
• For individuals with mild disease, no risk factors and: iii. One year of age and older: illness of more than 48 h duration,
illness with onset within 48 h, treatment with oseltamivir or treatment with oseltamivir or if age appropriate, inhaled zana-
inhaled zanamivir may be considered. (Strong recommenda- mivir may be considered on a case-by-case basis. (Option,
tion, Grade A evidence) Grade D evidence)
illness of more than 48 h duration, antiviral treatment is not E. Treatment of infants, children and youth with moderate,
generally recommended. (Recommendation, Grade X evidence) progressive, severe or complicated influenza illness with or without
• For individuals with mild disease, risk factors and: risk factors:
illness with onset within 48 h, initiate oseltamivir or inhaled
• Consider hospitalization and admission to ICU.
zanamivir therapy immediately. (Strong Recommendation,
(Recommendation, Grade C evidence)
Grade X evidence)
illness of more than 48 h duration, treatment with oseltamivir • Start treatment immediately with oseltamivir or zanamivir (if age
or inhaled zanamivir may be considered. (Recommendation, appropriate) in appropriate doses (see Table 4). (Strong
Grade X evidence) recommendation, Grade B evidence)
• Oseltamivir or zanamivir should be started even though the
C. Treatment of non-pregnant adults with moderate, progressive, interval between symptom onset and initial administration of
severe or complicated influenza illness with or without risk factors antiviral is longer than 48 h. (Recommendation, Grade C
A treatment algorithm is provided as Appendix B. evidence)

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 9C

Aoki et al

• Treatment with zanamivir instead of oseltamivir should be i. Seasonal prophylaxis involves continuous (usually daily) admin-
considered for: istration of antiviral medication for all or part of an influenza sea-
i) Patients not responding to oseltamivir therapy, son to prevent influenza illness. This may include circumstances
(Recommendation, Grade X evidence) in which effective vaccine is not available or vaccine is contra-
ii) Patients with illness despite oseltamivir prophylaxis, indicated. Although efficacious in the setting of clinical trials,
(Recommendation, Grade X evidence) the practicality and effectiveness of such seasonal prophylaxis in
iii) Where influenza B is confirmed or strongly suspected the field have not been established. Two weeks of prophylaxis
(Recommendation, Grade C evidence) initiated at the time of administration of injected, inactivated
• In the above circumstances i and ii, virus should be tested for influenza vaccine during the influenza season may be considered
oseltamivir resistance, if possible. to prevent influenza until vaccine-induced immunity develops, a
strategy referred to as bridging prophylaxis.
• Although oseltamivir was approved temporarily for use in infants
ii. PEP is an efficacious strategy when initiated in the first 48 h
under one year of age on the basis of a favourable risk-to-benefit
after exposure to a contact with suspected or lab-confirmed
ratio during the recent 2009 H1N1 pandemic and is now
influenza. Contacts are considered infectious for the interval
authorized in the U.S., it is not authorized in Canada for the
beginning 24 h before illness onset until the time fever ends.
routine treatment of seasonal influenza illness in infants less than
However, it is recommended that the strategy of early treat-
one year of age. Such use in this population for seasonal influenza
ment be used in place of PEP because of reports of oseltamivir
should be handled on a case-by-case basis, based on severity of
resistance arising during PEP. Early presumptive therapy may
illness. (Option, Grade D evidence)
be appropriate for situations where influenza infection appears
prevalent and persons at very high risk of influenza complica-
F. Treatment of immunocompromised patients:
tions are exposed.74 Early presumptive treatment requires
Recommendations
initiation of therapy with oseltamivir or zanamivir twice daily
1. Immunocompromised individuals who have uncomplicated (versus once daily as recommended for PEP) initiated after
influenza illness are at risk of developing severe or complicated exposure to an infectious contact even before symptoms
illness and thus should be treated with oseltamivir as soon as begin.
possible without regard to the duration of illness. iii. Outbreak control. Chemoprophylaxis combined with antiviral
(Recommendation, Grade C evidence) treatment of ill persons plus other measures is recommended for
2. Immunocompromised patients should be treated with zanamivir, if controlling outbreaks of influenza in closed facilities. Closed
they have recently received or are currently receiving oseltamivir facilities have a fixed residential population with limited turn-
as prophylaxis or therapy. (Recommendation, Grade X evidence) over or units that can be closed.99 Closed facilities include
3. Prolonged antiviral therapy should be avoided in nursing homes and other long-term care facilities that house
immunocompromised individuals if possible due to the potential patients at high risk of influenza complications99 as well as cor-
for antiviral resistance. (Option, Grade D evidence) rectional institutions that pose special other risks and consider-
4. Early initiation of therapy for symptomatic infection in ations with respect to influenza outbreaks due to their unique
immunocompromised patients is preferred over post-exposure environment; these factors mandate consideration of the same
prophylaxis. In the setting of a defined, significant exposure (e.g. measures for outbreak management in both.99 Chief among
household contact or healthcare associated exposure such as shared these additional measures is the concurrent administration of
hospital accommodation) of an immunocompromised patient to a inactivated influenza vaccine parenterally. Zanamivir does not
suspected or lab-confirmed case of influenza, post-exposure interfere with the hemagglutination antibody response to
prophylaxis may be considered. (Option, Grade D evidence) injected vaccine.100 A similar lack of interference with
5. In exposed, susceptible, profoundly immunosuppressed individuals oseltamivir would be expected. Nasal attenuated live influenza
at very high risk of complications, presumptive treatment (as vaccine (FlumistR) should not be used in these situations, as
defined below in VII.ii) may be initiated prior to the onset of oseltamivir and zanamivir would be expected to interfere with
symptomatic illness. (Option, Grade D evidence) its immunogenicity.
6. For early presumptive treatment, oseltamivir is preferred. (Option,
Grade D evidence) Recommendations for Antiviral Prophylaxis
• Early therapy is preferred over routine seasonal pre-exposure
G. Treatment of patients with renal impairment prophylaxis (Recommendation, Grade X evidence).
See the relevant sections above and Table 5 for treatment recommen- • An early treatment strategy should involve counseling together
dations of adults and children with renal impairment as a risk factor. with arrangements for contacts to have medication on hand.
(Option, Grade D evidence)
H. Treatment of pregnant patients • The selective use of pre-exposure prophylaxis can be suggested for
Oseltamivir in standard doses is recommended for treatment of preg- the following scenarios (Option, Grade D evidence) during
nant women with influenza based on the extensive safe use of community outbreaks of influenza illness:
oseltamivir to treat pregnant women during the 2009 H1N1 pan- i. As a bridge to vaccine-induced immunity during the 14-day
demic. (Strong recommendation, Grade C evidence). See also period after immunization of high-risk individuals.
V.G Treatment of pregnant patients. ii. Protection of high-risk persons for whom vaccination is
contraindicated or deemed likely to be ineffective.
VII. recommendations for CHEMOPROPHYLAXIS iii. Protection of patients at high risk and their family members
VERSUS EARLY THERAPY and close contacts when circulating strains of influenza virus
An algorithm for prophylaxis is provided as Appendix D. in the community are not matched with trivalent seasonal
Antiviral prophylaxis with NAIs has been demonstrated to be influenza vaccine strains, based on current data from the local
efficacious and well tolerated. Three chemoprophylactic strategies or national public health laboratories
were first detailed in our previous publications1,2: (i) seasonal prophyl- iv. Protection of family members or health care workers for whom
axis, (ii) post-exposure prophylaxis (PEP) or contact exposure and (iii) influenza immunization is contraindicated (e.g., known anaphyl-
outbreak control. Antiviral chemoprophylaxis is recommended only axis to chicken or egg protein)101 and who are likely to have
in very selected circumstances: ongoing close exposure to unimmunized persons at high risk

10C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013
 The use of antiviral drugs for influenza

including infants and toddlers who are younger than 24 months

of age. http://www.cps.ca/english/statements/ID/ID11-06.htm ACKNOWLEDGEMENTS: The authors thank the Public Health
Agency of Canada, in particular, Dr. Barbara Raymond, Centre for
• Early therapy is preferred over post-exposure prophylaxis due to
Immunization & Respiratory Infectious Diseases, Sharon Smith,
concerns regarding drug resistance. (Option, Grade D evidence)
Pandemic Preparedness Division, Centre for Immunization and
• Post-exposure prophylaxis may be considered in family settings for Respiratory Infectious Disease and Dr. Ken Scott, Federal Co-Chair of
persons who cannot be reliably protected by immunization (e.g., the Antiviral Scientific Advisory Group for their support. We acknowl-
age less than six months, immunocompromised or vaccine edge the critical review of the parent version of this document by the
contraindicated). (Option, Grade D evidence) PHAC Antiviral Scientific Advisory Group and the Infectious Diseases
• To control outbreaks in closed facilities, antiviral drug prophylaxis, and Immunization Committee of the Canadian Paediatric Society and its
combined with treatment and inactivated vaccine administration, review and endorsement by the AMMI Canada Guidelines Committee.
is indicated. (Strong Recommendation, Grade X evidence) The authors also extend appreciation to Ms. Angela Nelson for her
• Neither early treatment nor PEP should be prescribed: excellent secretarial assistance.
For groups of healthy individuals based on possible exposure
in the community CONFLICT OF INTEREST DECLARATION: Dr. Fred Y. Aoki:
If the close contact did not occur during the infectious period Honoraria: Hoffmann La Roche Inc., GlaxoSmithKline and Merck;
of the person with suspected or confirmed influenza which Advisory Board: GlaxoSmithKline, Hoffmann La Roche Inc.; Research:
extends from 1 day before the onset of symptoms until 24 h GlaxoSmithKline, Hoffmann La Roche Inc., Biocryst Inc., Merck;
Dr.  Upton D. Allen: Research: Hoffmann La Roche Inc.; Dr. H. Grant
after fever ends
Stiver: Honoraria: Hoffman La Roche Inc.; Advisory Board: Hoffman La
If >4 days have elapsed since the last infectious contact
Roche Inc.; Dr. Gerald A. Evans: Research: Biocryst Inc.
(Option, Grade D evidence)
References
1. Aoki FY, Allen UD, Stiver HG, Evans GA. The use of antiviral 17. Govaert TM, Dinant GJ, Aretz K, et al. The predictive value of
drugs for influenza: Guidance for practitioners 2011-2012. influenza symptomatology in elderly people. Fam Pract 1998; 15:16-22.
http://www.ammi.ca/guidelines (Accessed October 11, 2013). 18. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B virus
2. Aoki FY, Allen UD, Stiver HG, Evans GA. The use of antiviral infections in children. Clin Infect Dis 2003; 36:299-305.
drugs for influenza: Guidance for practitioners 2012-2013. 19. Tamiflu, US Product Monograph. December 2012.
Can J Inf Dis Med Microbio 2012; 23:e79-i92. 20. Aoki FY. Oseltamivir. In: Kucers’ The Use of Antibiotics. 6th edn.
3. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for Grayson ML, Crowe SM, McCarthy JS, et al, eds. Edward Arnold
preventing and treating influenza in healthy adults: Systematic review Publishers Ltd, London, UK, 2010, pp 3029-42.
and meta-analysis. BMJ 2009;339:b5106. DOI:10.1136/bmj.b5106. 21. Kawai, N, Ikematsu H, Iwaki N, et al. A comparison of the
4. Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of effectiveness of zanamivir and oseltamivir for the treatment of
influenza: A systemic review and meta-analysis of observational influenza A and B. J Infection 2008; 56:1-7.
studies. Ann Int Med 2012; 156:512-526. 22. Sugaya N, Tamara D, Yamazaki M, et al. Comparison of the clinical
5. American Academy of Pediatrics Steering Committee on Quality effectiveness of oseltamivir virus infection in children.
Improvement and Management. Classifying recommendations for Clin Infect Dis 2008; 47:339-45.
clinical practice guidelines. Pediatrics 2004; 114;874-7. 23. Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the
6. FluWatch, August 12-25, 2012. Public Health Agency of Canada. effectiveness of oseltamivir for the treatment of influenza A and
http://www.phac-aspc.gc.ca/fluwatch/11-12/w34_12/pdf/fw2012-34- influenza B: A Japanese multicenter study of the 2003-2004 and
eng.pdf (Accessed October 11, 2013). 2004-2005 influenza seasons. Clin Infect Dis 2006; 43:439-44.
7. National Advisory Committee on Influenza (NACI). Statement on 24. American Academy of Pediatrics. Antiviral Drugs. In: Pickering LR,
seasonal influenza vaccine 2012-2013. July 6, 2012. Available at: Baker CJ, Kimberlin DW, Long SS. Red Book 2012 Report of the
http://resources.cpha.ca/immunize.ca/data/1814e.pdf (Accessed Committee on Infectious Diseases, 29th edn. Elk Grove Village, IL.
October 11, 2013). American Academy of Pediatrics, 2012, pp 845-7.
8. Influenza Antiviral Drug Resistance: Questions and Answers. 25. Thorne-Humphrey LM, Goralski KB, Slayter KC, et al. Oseltamivir
Centers for Disease Control and Prevention (CDC) & National pharmacokinetics in morbid obesity (OPTIMO) trial.
Center for Immunization and Respiratory Diseases (NCIRD), J Antimicrob Chemother 2011; 66:2083-91.
July 23, 2012. Available at: www.cdc.gov/flu/about/qa/ 26. Choo D, Hossain M, Liew P, et al. Side effects of oseltamivir in end-
antiviralresistamce.htm. (Accessed August 2012). stage renal failure patients. Nephrol Dialysis Transpl 2011; 26:2339-44.
9. CDC. Seasonal Influenza. Available at: http://www.cdc.gov/flu/ 27. Smith JR, Ariano RE, Toovey S. The use of antiviral agents for the
about/qa/disease.htm (Accessed October 11, 2013). management of severe influenza. Crit Care Med 2010; 38(4Suppl):43-51.
10. Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus 28. Robson R, Buttimore A, Lynn K, et al. The pharmacokinetics and
Infection Writing Committee of the WHO Consultation on tolerability of oseltamivir suspension in patients on haemodialysis
Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Engl J Med and continuous ambulatory peritoneal dialysis. Nephrol Dial
2010; 362:1708-19. Transplant 2006; 21:2556-62
11. Studahl M. Influenza and CNS manifestations J Clin Virol 2003; 29. Schreuder, MF, van der Flier M, Knops NB, Koster-Kamphuis L,
28:225-32. Brüggemann RJ. Oseltamivir dosing in children undergoing
12. National Advisory Committee on Immunization (NACI). Statement hemodialysis. Clin Infect Dis 2010; 50(10):1427-1428.
on seasonal trivalent inactivated influenza vaccine (TIV) for 2012- 30. Nicholson KG. Human influenza. In: Textbook of Influenza.
2013. http://www.phac-aspc.gc.ca/ccdrw-rmtch/index-eng.php. Nicholson KG, Webster RG & Hay AJ, eds. Blackwell Science,
13. Blanton L, Peacock G, Cox C, et al. Neurologic disorders among London, UK, 1998, pp 219-64.
pediatric deaths associated with the 2009 pandemic influenza. 31. Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir:
Pediatrics 2012; 130:390-6. Case series and overview of causal relationships. Int J Risk Saf Med
14. Boivin G, Hardy J, Tellier G, et al. Predicting influenza infections 2008; 20:5-36.
during epidemics with use of a clinical case definition. 32. Toovey S, Prinssen EP, Rayner CR, et al. Post-marketing assessment
Clin Infect Dis 2000; 31:1166-9. of neuropsychiatric adverse effects in influenza patients treated with
15. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the oseltamivir: An updated review. Drug Safety 2008; 31:1097-114.
neuraminidase inhibitor zanamivir in the treatment of influenza A 33. Duval X, Vander Werf S, Bhanchan T, et al. Efficacy of
and B virus infections. J Infect Dis 1999; 180:254-61. oseltamivir-zanamivir combinations compared to each
16. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of monotherapy for seasonal influenza: A randomized, placebo-
oseltamivir in the treatment of acute influenza: A randomized controlled trial. PLoS Medicine 2010; 7:e1000362.
controlled trial. Neuraminidase Inhibitor Influenza Treatment 34. South East Asia Infectious Disease Clinical Research Network.
Investigator Group. Lancet 2000; 355:1845-50. High-dose versus standard-dose oseltamivir for the treatment of

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 11C
Aoki et al

severe influenza. Abstract P-205. Options for the Control of Influenza 57. CDC. Updated Recommendations for the use of Antiviral
VII. Hong Kong, SAR China, 3-7 September 2010. Medications in the Treatment and Prevention of Influenza for the
35. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and 2009-2010 season. Available at: http://www.cdc.gov/h1n1flu/
pharmacokinetics of oseltamivir in critically ill patients with recommendations.htm. (Accessed October 11, 2013)
pandemic (H1N1) influenza. Can Med Assoc J 2010; 182:357-63. 58. Aoki FY, Macleod MD, Paggiaro P, et al; on behalf of the IMPACT
36. Whitley RJ, Young, N, Ipe D, et al. Safety and acceptability of Study Group. Early administration of oral oseltamivir increases the
oseltamivir liquid formulation in the treatment of influenza in benefits of influenza treatment. J Antimicrob Chemother 2003;
children aged one to 12 years. In: 9th International Congress of 51:123-9.
Chemotherapy. Buenos Aires, 2000. 59. American Academy of Pediatrics. Influenza. In: Pickering LR,
37. Wooltorton E. Oseltamivir (Tamiflu) unsafe in infants under 1 year Baker CJ, Kimberlin DW, Long SS. Red Book 2012 Report of the
old. Can Med Assoc J 2004; 170:336. Committee on Infectious Diseases, 29th edn. Elk Grove Village, IL.
38. U.S. Food and Drug Administration. Tamiflu Pediatric Adverse Events: American Academy of Pediatrics 2012, pp 439-53.
Questions and Answers. Available at: http://www.fda.gov/cder/drug/ 60. World Health Organization. Vaccines against influenza WHO
infopage/tamiflu/QA20051117.htm (Accessed October 11, 2013). position paper. Wkly Epidemiol Rec 2012; 87:461-76.
39. Truffa MM. One-Year Post Exclusivity Adverse Event Review for 61. Moore DL, Vaudry W, Scheifele DW, et al. Surveillance for
Tamiflu® (oseltamivir). Available at: http://www.fda.gov/ohrms/dockets/ influenza admissions among children hospitalized in Canadian
ac/05/slides/2005-4180s_03_truffa.ppt (Accessed October 11, 2013). Immunization Monitoring Program ACTive centers, 2003-2004.
40. Aoki FY. Zanamivir. In Kucer’s The Use of Antibiotics, 6th edn. Pediatrics 2006; 118:e610-9.
Grayson ML, Crowe SM, McCarthy JS, et al, eds. Edward Arnold 62. Centers for Disease Control and Prevention. Influenza-associated
Publishers Ltd, London, UK, 2010, pp 3013-3127. pediatric deaths – United States, September 2010–August 2011.
41. Kawai N, Ikematsu , Iwaki N, et al. Zanamivir treatment is equally MMWR Morb Mort Wkly Rep 2011; 60:1233-8.
effective for both influenza A and influenza B (letter). Clin Infect 63. Neuzil KM, Zhu Y, Griffin MR, et al. Burden of interpandemic
Dis 2007; 44:1666. influenza in children younger than 5 years: A 25-year prospective
42. FDA. Safety: Relenza (zanamivir) inhalation powder. 2009. study. J Infect Dis 2002; 185:147-52.
Available at: http//:www.fda.gov/Safety/MedWatch/ 64. Shun-Shin M, Thompson M, Heneghan C, et al. Neuraminidase
SafetyInformation/SafetyAlertsforHumanMedicalProducts/ inhibitors for treatment and prophylaxis of influenza in children:
ucm186081 (Accessed October 11, 2013). Systematic review and meta-analysis of randomized controlled trials.
43. Cass LMR, Efthymiopoulas C, Bye A. Pharmacokinetics of zanamivir BMJ 2009; 3339:b3172. doi:10.1136/BMJ.b3172.
after intravenous, oral, inhaled or intranasal administration in 65. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir
healthy volunteers. Clin Pharmacokinet 1999; 36(Suppl 1):1-11. treatment of influenza in children. Pediatr Infect Dis 2001; 20:127-33.
44. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for 66. Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir
the prevention of influenza in families. Zanamivir Family Study treatment of influenza in children 1-3 years of age. A randomized
Group. N Engl J Med 2000; 343:1282-9. controlled trial. Clin Infect Dis 2010; 51:887-94.
45. Murphy KR, Eivindson A, Pauksens K, et al. Efficacy and safety of 67. Johnston SL, Ferrero F, Garcia ML, et al. Oral oseltamivir improves
inhaled zanamivir for the treatment of influenza with asthma or chronic pulmonary function and reduces exacerbation frequency for influenza-
obstructive pulmonary disease. Clin Drug Invest 2000; 20:337-49. infected children with asthma. Pediatr Infect Dis 2005; 24:225-32.
46. Cass LM, Gunawardena KA, Macmahon MM, Bye A. Pulmonary 68. Kitching A, Roche A, Balasegaram S, et al. Oseltamivir adherence
function and airway responsiveness in mild to moderate asthmatics and side effects among children in three London schools affected by
given repeated inhaled doses of zanamivir. Respir Med 2000; 94:166-73. influenza A (H1N1)v, May 2009 – an internet-based cross-sectional
47. Kim aW-Y, Suh GY, Huh JW, et al. Triple-combination antiviral survey. Euro Surveill 2009; 14:19287.
drug for pandemic H1N1 influenza virus infection in critically ill 69. Barr CE, Schulman K, Iacuzio D, et al. Effect of oseltamivir on the
patients on mechanical ventilation. Antimicrob Ag Chemother 2011; risk of pneumonia and use of health care services in children with
55:5703-5709. clinically diagnosed influenza. Curr Med Res Opin 2007; 23:523-31.
48. Perelson AS, Rong L, Hayden FG. Combination antiviral therapy 70. Piedra PA, Schulman KL, Blumentals WA. Effects of oseltamivir on
for influenza: Predictions from modeling of human infections. influenza-related complications in children with chronic medical
J Infect Dis 2012; 205:1642-5. conditions. Pediatrics 2009; 124:170-8.
49. Matheson NJ, Harnden AR, Perera R, et al. Neuraminidase 71. Gums JG, Pelletier EM, Blumentals WA. Oseltamivir and influenza-
inhibitors for preventing and treating influenza in children. related complications, hospitalization and healthcare expenditure in
Cochrane Database of Systematic Reviews 2007(1):CD002744. healthy adults and children. Expert Opin Pharmacother
DO1.10.1002/14651858.CD002744.pub2. 2008; 9:151-61.
50. Falagas ME, Koletsi PK, Vouloumanon EK, et al. Effectiveness and 72. Kimberlin DW, Shalabi M, Abzug MJ, et al. Safety of oseltamivir
safety of neuraminidase inhibitors in reducing influenza compared with the adamantanes in children less than 12 months of
complications: A meta-analysis of randomized, controlled trials. age. Pediatr Infect Dis J 2010; 29:195-8
J Antimicrob Chemother 2010; 65:1330-46. 73. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza
51. McGeer A, Green KA, Plevneski A, et al. Antiviral therapy and infection in premature neonates. J Infect Dis 2010; 202:563-6.
outcomes of influenza requiring hospitalization in Ontario, Canada. 74. WHO. Guidelines for pharmacological management of pandemic
Clin Infect Dis 2007; 45:1568-75. influenza A (H1N1) 2009 and other influenza viruses. Revised
52. Hayden FG. Influenza antivirals: Challenges and future directions. February 2010. Part I. Recommendations Available at: http://www.
Plenary presentation. Options for the Control of Influenza VII. who.int/csr/resources/publications/swineflu/h1n1_guidelines_
Hong Kong, SAR China, 3-7 September 2010. Available at: pharmaceutical_mngt.pdf (Accessed October 11, 2013).
www.controlinfluenza.com/webcasts/optionsvii (Accessed October 75. Centers for Disease Control and Prevention. Antiviral agents for the
11, 2013). treatment and chemoprophylaxis of influenza – recommendations of
53. Calfee DP, Peng AW, Cass LM, et al. Safety and efficacy of the Advisory Committee on Immunization Practices (ACIP).
intravenous zanamivir in preventing experimental human MMWR Mork Mort Wkly Rep 2011: 60(RR01);1-24
influenza A infection. Antimicrob Ag Chemother 1999; 43:1616-20. 76. Hackett S, Hill L, Patel J, et al. Clinical characteristics of pediatric
54. Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for H1N1 admissions in Birmingham, UK. Lancet 2009; 374:605.
oseltamivir-resistant 2009 H1N1 influenza (letter). N Engl J Med 77. Allen U, Doucette K, Bow E. Guidance on the management of
2010; 362:88-9. pandemic H1N1 infection in immunocompromised individuals.
55. Dulak DE, Williams JV, Creech CB, et al. Use of intravenous Available at: http://www.ammi.ca/pdf/guidelineh1N1.pdf (Accessed
zanamivir after development of oseltamivir resistance in a critically October 11, 2013).
ill immunosuppressed child with 2009 pandemic influenza A 78. Khanna N, Steffen I, Studt JD, et al. Outcome of influenza
(H1N1) virus. Clin Infect Dis 2010; 50:1493-6. infections in outpatients after allogeneic hematopoietic stem cell
56. Fraay PLA, van der Vries E, Beersma MFC, et al. Evaluation of the transplantation. Transpl Infect Dis 2009; 11:100-5.
antiviral response to zanamivir administered intravenously for 79. O’Riordan S, Barton M, Yau Y, et al. Risk factors and outcomes
treatment of critically ill patients with pandemic influenza A among children admitted to hospital with pandemic H1N1
(H1N1) infection. J Infect Dis 2011; 204:777-82. influenza. Can Med Assoc J 2010; 182:33-44.

12C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013
 The use of antiviral drugs for influenza

80. Couch RB, Englund JA, Whimbey E. Respiratory viral infections in 91. Mertz D, Kim KH, Johnstone J, et al. Populations at risk for severe
immunocompetent and immunocompromised persons. Am J Med or complicated influenza illness: Systematic review and meta-
1997; 102(3A):2-9. analysis. BMJ 2013; 347:f5061. doi:10.1136/bmj.f5061
81. Gooskens J, Jonges M, Claas, EC, et al. Prolonged influenza virus 92. Pierce M, Kurinczuk JJ, Spark P, et al. Perinatal outcomes after
infection during lymphocytopenia and frequent detection of drug- maternal 2009/H1N1 infection: National cohort study. BMJ
resistant viruses. J Infect Dis 2009; 199:1435-41. 2011;342:d3214. doi:10.1136/bmj.d3214.
82. Cohen-Daniel L, Zakay-Rones Z, Resnick IB, et al. Emergence of 93. Greer LG, Leff RD, Laibi-Rogers V, et al. Pharmacokinetics of
oseltamivir-resistant influenza A/H3N2 virus with altered oseltamivir according to trimester of pregnancy. Am J Obstet
hemagglutination pattern in a hematopoietic stem cell transplant Gynecol 2011; 204S89-S93.
recipient. J Clin Virol 2009; 44:138-40. 94. Greer LG, Leff RD, Laibl-Rogers V, et al. Pharmacokinetics of
83. Belshe RB, Gruber WC, Mendelman PM, et al. Correlates of oseltamivir in breast milk and maternal plasma. Am J Obstet
immune protection induced by live, attenuated, cold-adapted, Gynecol 2011; 204:524.e1-4.
trivalent, intranasal influenza virus vaccine. J Infect Dis 2000; 95. Louie JK, Acosta M, Jamieson DJ, et al. Severe 2009 H1N1
181:1133-7. influenza in pregnant and postpartum women in California.
84. McMichael AJ, Gotch FM, Noble GR, et al. Cytotoxic T-cell New Engl J Med 2010; 362:27-35.
immunity to influenza. N Engl J Med 1983; 309:13-17. 96. Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase
85. He X-S, Draghi M, Mahmood K, et al. T cell-dependent production inhibitors against novel influenza A (H1N1) in pregnant and
of IFN-γ by NK cells in response to influenza A virus. J Clin Invest breastfeeding mothers. Can Med Assoc J 2009; 181:55-8.
2004; 114:1812-19. 97. Donner B, Nianjan V, Hoffmann G. Safety of oseltamivir in pregnancy:
86. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in A review of preclinical and clinical data. Drug Safety 2010; 33:631-42.
patients taking glucocorticosteroids. Rev Infect Dis 1989; 11:954-63. 98. Thorner AR. Treatment of pandemic H1N1 influenza (‘swine
87. American Academy of Pediatrics. Immunization in special clinical influenza’). Up To Date. Available at: www.uptodate.com (Accessed
circumstances. In: Pickering LR, Baker CJ, Kimberlin DW, Long SS. October 11, 2013).
Red Book 2012 Report of the Committee on Infectious Diseases, 99. Centers for Disease Control and Prevention. Interim Guidance for
29th edn. Elk Grove Village, IL. American Academy of Pediatrics Correctional and Detention Facilities on Novel Influenza A
2012, p 81. (H1N1) Virus. Available at: http://www.cdc.gov/h1n1flu/guidance/
88. Kumar D, Michaels MG, Morris M, et al. A Multicenter study of correctional_facilities.htm (Accessed October 11, 2013).
outcomes from pandemic influenza A/H1N1 infection in solid organ 100. Webster A, Boyce M, Edmundson S, et al. Coadministration of
transplant recipients. Lancet Infect Dis 2010; 10:521-6. orally inhaled zanamivir with inactivated trivalent influenza
89. Dodds L, McNeil SA, Fell SB, et al. Impact of influenza exposure vaccine does not adversely affect the production of
on rates of hospital admissions and physician visits because of antihemagglutinin antibodies in the serum of healthy volunteers.
respiratory illness among pregnant women. Can Med Assoc J 2007; Clin Pharmacokinet 1999; 36(Suppl 1):51-58.
176:463-8. 101. Hui CPS, McDonald NE; Infectious Diseases and Immunization
90. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 Committee, Canadian Paediatric Society. The use of influenza
influenza A (H1N1) virus illness among pregnant women in the vaccine in children with egg allergies. Paediatr Child Health 2011;
United States. JAMA 2010; 303:1517-25. 16:491-2.

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 13C
Aoki et al

Nonpregnant adult with mild or uncomplicated influenza

No risk factors Risk factors (see Table 3)

• If within 48 hours of • If > 48 hours since • If within 48 hours of If > 48 hours since onset,
symptom onset, onset, anviral symptom onset, iniate oseltamivir or zanamivir
anviral therapy with therapy is not oseltamivir or inhaled therapy may be
oseltamivir or inhaled generally zanamivir therapy considered
zanamivir may be recommended immediately
considered • Provide instrucons
regarding indicaons
for reassessment

Appendix A) Algorithm for oseltamivir and zanamivir treatment of mild or uncomplicated influenza in nonpregnant adults. The Use of Antiviral Drugs for
Influenza:A Foundation Document for Practitioners

Nonpregnant adult with moderate, progressive, severe or

complicated illness

• Consider hospitaliza�on
• Consider admission to intensive care unit

Ini�ate an�viral therapy immediately even if the

interval between symptom onset and ini�a�on of
therapy is longer than 48 hours

• Those not responding to oseltamivir therapy Others

• Those with illness despite oseltamivir
prophylaxis
• Where influenza B is confirmed or strongly
suspected.
Oseltamivir
75 mg BID for 5-10 days

Not responding

Zanamivir
Intravenous zanamivir, if available*, is preferred to inhaled zanamivir
(*through clinical trials or via Health Canada’s Special Access Program)

Test for oseltamivir resistance

Appendix B) Algorithm for oseltamivir and zanamivir treatment of moderate, progressive, severe or complicated influenza in nonpregnant adults. The Use
of Antiviral Drugs for Influenza: A Foundation Document for Practitioners

14C Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013
 The use of antiviral drugs for influenza

Infant, child or youth <18 yrs old with influenza

Mild or uncomplicated illness Moderate, progressive, severe or complicated influenza

No risk factors for severe Risk factors for severe Consider hospitalizaon including ICU admission†
disease other than age disease (Table 3)

< 1 yr 1 to < 5 yrs > 5 yrs Iniate anviral therapy immediately

*Anvirals *No • Those with illness despite No previous oseltamivir

not roune oseltamivir prophylaxis OR exposure
approved; anviral • Those not responding to
use on a therapy oseltamivir therapy
case-by- • Where influenza B is confirmed
case basis or strongly suspected.

*For illness of less than 48 1. Zanamivir (IV Oseltamivir therapy

hours’ duraon, anviral zanamivir‡ is
treatment may be recommended if the
considered, but is not inhalaon device
rounely required. cannot be used)
2. Test for oseltamivir
resistance

Appendix C) Algorithm for oseltamivir and zanamivir treatment of influenza in children and youth (<18 years of age). The Use of Antiviral Drugs for
Influenza: A Foundation Document for Practitioners. *In children of any age with mild or uncomplicated illness, antiviral treatment is not routinely recom-
mended and should not be used if symptoms have been present for >48 h. †Treatment with oseltamivir or, if appropriate zanamivir may be considered on a
case-by-case basis even if symptoms have been present for >48 h. In Canada, antivirals are not authorized for infants <1 year of age but should be considered.
See Table 5, Footnote 2. ‡Accessed through available clinical trials or via Health Canada’s Special Access Program

Close contact of case

Resident of closed facility Others

No risk factors for Risk factors for influenza complicaons (Table 3)

influenza complicaons
especially if influenza
immunizaon is up to date

Not Significant
immunosuppressed Immunosuppression

Presumpve
Oseltamivir or zanamivir outbreak treatment & treatment* with
prophylaxis as per closed facility protocols Early treatment with oseltamivir if symptoms arise oseltamivir or
zanamivir

Appendix D) Algorithm for oseltamivir and zanamivir prophylaxis or early treatment in close contacts of suspected or lab-confirmed case. The Use of
Antiviral Drugs for Influenza: A Foundation Document for Practitioners. *Presumptive treatment is therapy with twice daily doses of oseltamivir or zanamivir
initiated before the onset of influenza symptoms in close contact of individual with suspected or lab-confirmed influenza illness

Can J Infect Dis Med Microbiol Vol 24 Suppl C Autumn 2013 15C