The Canadian Pandemic Influenza Plan for the Health Sector

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Annex E
The Use of Aniviral Drugs During a Pandemic

At the time of an outbreak with a novel virus or a pandemic, these recommendations need to be considered in the context of this situation and changes made to strategies on the basis of the emerging epidemiology or other data (e.g. antiviral resistance, optimal treatment course).

Table of Contents

Pandemic H1N1 Updates
1.0 Introduction
2.0 Role of Antivirals
3.0 Classes of Antiviral (Anti-Influenza) Drugs
3.1 Neuraminidase Inhibitors
3.1.1 Interchangeability of Neuraminidase Inhibitors
3.1.2 Treatment Schedules
3.2 M2 Ion Channel Blockers (Cyclic Amines or Adamantanes)
3.3 Combination Therapy and Other New Approaches

4.0 The National Antiviral Strategy
4.1 Goals of the National Antiviral Strategy
4.2 Antiviral Stockpiles
4.2.1 National Antiviral Stockpile (NAS)
4.2.2 National Emergency Stockpile System (NESS)
4.2.3 Other Government Stockpiles
4.3 Composition of the National Antiviral Stockpile
4.3.1 Early Treatment Strategy
4.3.2 Prophylaxis Recommendations
4.3.3 Rapid Containment Strategy
4.4 Stockpile Management
4.4.1 Recent Recommendations on Composition and Mix
4.4.2 Sustainability Strategy
5.0 Implementation Planning
5.1 Components of an Implementation Plan
5.2 Antiviral Use in the Pandemic Alert Period
5.3 Implementation of the Early Treatment Strategy
5.3.1 Timing of Treatment
5.3.2 Assessment and Treatment Options
5.3.3 Role of Laboratory Testing
5.3.4 Prescribing and Dispensing Antivirals
5.4 Outbreak Control in Health Care and Other Closed Facilities
5.5 Consent and Off-label Use
5.6 Monitoring Adverse Reactions
5.7 Antiviral Resistance and Effectiveness Monitoring
6.0 Outstanding Issues
7.0 Considerations for Future Research
7.1 Prepandemic
7.2 At the Time of the Pandemic/Postpandemic
Acknowledgements
References
Appendix – Definition of Critical Infrastructure

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Pandemic H1N1 Updates

With the emergence of the pandemic (H1N1) 2009 influenza virus, the following guidance documents were created that contain different advice to that offered in this Annex. Here is a list of H1N1 guidance documents and how they differ from Annex E:

Interim Guidance for Ambulatory Care of Influenza–like–illness in the context of H1N1 influenza virus
Annex E recommends antivirals for all who need it, based on a moderate pandemic scenario. Due to the mild nature of the pandemic H1N1, antiviral treatment is recommended for those with severe disease, or those who have influenza-like illness and risk factors for complications, including: pregnant women, children 6-23 months and persons with certain chronic health conditions. Antivirals are not recommended to treat mild disease in persons who are otherwise healthy.

Interim guidance for emergency use of oseltamivir (Tamiflu) in children under 1 year of age in the context of 2009 H1N1 pandemic
Annex E does not recommend the use of oseltamivir for infants under 1 year as it is a contraindication in the product monograph (based on limited safety data available at the time of drug approval by Health Canada). Infants have been identified as being at increased risk of morbidity and mortality from pandemic H1N1 influenza. Based on this as well as current scientific evidence and expert opinion, Health Canada released an Interim Order to permit the expanded use of oseltamivir as a treatment or prophylaxis for children less than 1 year of age.

Interim Clinical Guidance for Pregnant and Breastfeeding Women with Influenza-like Illness in the context of pandemic H1N1 virus
In Annex E zanamivir is noted as the treatment of choice for pregnant women. For pandemic H1N1 influenza, oseltamivir is recommended as the treatment of choice; zanamivir may be useful if nausea and vomiting are present.

Interim Guidance for the management of Pandemic H1N1 Influenza outbreaks in closed facilities
This document expands on Annex E’s recommendations for antiviral use in outbreak control in closed facilities. This guidance document includes recommendations for early detection measures; triggers for outbreak investigation; as well as antiviral treatment and prophylaxis strategies depending on the severity of the disease and the risk profile of the resident population.

1.0 Introduction

The purpose of this annex is to provide information and recommendations that will assist pandemic planners with the development and implementation of their antiviral strategies. The recommendations of the Pandemic Influenza Committee are intended to facilitate consistent use of antivirals across Canada at the time of an influenza pandemic and to form the basis for an effective, equitable, flexible and informed national antiviral strategy. It will be necessary for planners to review all recommendations and implementation plans once a pandemic strain has emerged so that appropriate changes can be made in the implemented strategy on the basis of emerging epidemiology or other data (e.g. antiviral resistance, optimal treatment course).

2.0 Role of Antivirals

Antivirals (anti-influenza drugs) will be the only specific medical intervention on hand during the initial pandemic response until pandemic vaccine becomes available, which will take at least 4-6 months. Antiviral drugs can be used to treat cases that are identified early in their illness and can also be used to prevent influenza (prophylaxis). When used for treatment, there is good evidence that antivirals reduce the complications of and mortality from influenza. When antivirals are taken for prophylaxis, their protection is virtually immediate. Taking antivirals does not interfere with the immune response to inactivated influenza vaccines.

To date there has been relatively little practitioner or public experience with antiviral drugs in Canada. During annual influenza seasons, they are used primarily to control outbreaks in health care and long-term care institutions; they are seldom prescribed in the primary care setting. During several recent domestic avian influenza outbreaks in Canada, they have been used for prophylaxis of individuals exposed to avian influenza (e.g. cullers) because of their roles in outbreak control.

3.0 Classes of Antiviral (Anti-Influenza) Drugs

Two classes of antiviral drugs are currently authorized in Canada for prevention and/or treatment of influenza infection: neuraminidase inhibitors and M2 ion channel blockers. There are important differences in the pharmacokinetic characteristics, side effects and rates of drug resistance between these two classes of antivirals. Such performance characteristics and the costs should be considered in selecting the specific drugs to be used for prophylaxis or treatment. Summary information on these drugs is presented in Table 1 and more detailed information follows:

When reviewing Table 1, it is important to note the distinction between:

• Pre-exposure prophylaxis – prolonged and preventive use of antivirals in advance of expected exposure (usually for 4 weeks or more); and
• Post-exposure prophylaxis – preventive use of antivirals following close contact with an infected person (usually for 10 days).

Antiviral (Anti-Influenza) Drugs Currently Approved for Use in Canada

Drug	Trade name and Manufacturer	Class	Authorized Indications (as per product monograph)	Formulation(s)	Shelf Life/Stability	Proposed Use(s) During Pandemic
Oseltamivir	Tamiflu®, Hoffmann-La RocheInc.	Neuraminidase Inhibitor	Treatment of influenza A and B in persons 1 year of age and older who have been symptomatic for no more than 2 days Prevention of influenza A and B in persons 1 year of age and older after close contact with an infected individual for post-exposure prophylaxis (10 days)	Capsules (30 mg, 45 mg and 75 mg): 10 capsules per blister pack Powder for oral suspension (12 mg/ mL when reconstituted): 900 mg per bottle (volume of 75 mL in a 100-mL glass bottle)	Shelf life of capsules: 7 years for new government stockpile orders (previously 5 years) Shelf life of powder for suspension: 2 years Stability: Once reconstituted, 10 days in refrigerator (at 2º-8º C)	Capsules (adult and paediatric) for early treatment of ill persons and for outbreak control (treatment and post-exposure prophylaxis) in health care and other closed facilities where high-risk persons reside Oral suspension not included in the national stockpile
Zanamivir	Relenza®, GlaxoSmithKline	Neuraminidase Inhibitor	Treatment of influenza A and B in persons 7 years of age and older who have been symptomatic for no more than 2 days Prevention of influenza A and B in persons 7 years of age and older (post-exposure prophylaxis and up to 28 days’ pre-exposure prophylaxis)	ROTADISK® consisting of a circular foil disk with four blisters each containing 5 mg of zanamivir. A DISKHALER® inhalation device is provided to administer the medication (through inhalation). One box contains 5 disks, which is equivalent to one treatment course	Shelf life: 5 years	Early treatment of ill persons and outbreak control (treatment and prophylaxis) in health care and other closed facilities where high-risk persons reside Preferred treatment for pregnant and nursing women
Amantadine	Symmetrel® syrup, Bristol-Myers Squibb Generic amantadine manufacturers: Dominion Pharmacal, GenPharm, Medican Pharma, Pharmel, Pharmascience	M2 ion Channel blocker (cyclic amines or adamantanes)	Treatment of influenza A in persons 1 year of age and older Prevention of influenza A in persons 1 year of age and older	Capsules (100 mg/capsule): bottles of 100 capsules Syrup (10 mg/mL): bottles of 500 mL	Shelf life of capsules: 3.5 to 4 years depending on manufacturer* Shelf Life of syrup: 2 years	For use as combination therapy (with a neuraminidase inhibitor) for the treatment of severe disease Prophylaxis if strain is known to be susceptible to amantadine
* Note: In one study amantadine was found to be stable after 25 years of uncontrolled storage on the shelf.1 The stability of other antiviral drugs may also extend beyond the currently stated expiry date. If the currently stockpiled antivirals are not used by their respective expiry dates, stability testing could be used to determine whether the drugs are still potent.

3.1 Neuraminidase Inhibitors

Oseltamivir (Tamiflu®) and zanamivir (Relenza®) are the two neuraminidase inhibitors that are currently approved for use in Canada for the treatment of influenza A or B. Both are also approved for post-exposure prophylaxis, i.e. 10 days of daily treatment after close contact with an infected individual. Zanamivir, but not oseltamivir, is also approved for pre-exposure (or seasonal) prophylaxis during community outbreaks, but for up to 28 days only. Oseltamivir and zanamivir are currently the only neuraminidase inhibitors in the global market; however, other agents such as peramivir, an injectable neuraminidase inhibitor, are under development.

Oseltamivir and zanamivir inhibit the neuraminidase enzyme of influenza A and B viruses. This action interferes with virus replication by causing aggregation and clumping of budding virions, impeding their release and thereby limiting spread of virus to contiguous uninfected cells in the respiratory epithelium. The drugs are well tolerated and have been used effectively for the treatment and prophylaxis of seasonal influenza A and B infections. Although there can be no certainty, neuraminidase inhibitors are expected to be effective against pandemic viruses. Data from uncontrolled clinical trials of oseltamivir treatment of H5N1- infected persons suggest improved survival, although the optimal dosage and duration of therapy are uncertain.²

Neuraminidase inhibitors are effective as treatment when administered within 48 hours of onset of illness, but for optimal benefit treatment should begin as early as possible.³ Current estimates of the benefits of early oseltamivir therapy include a 25%-30% reduction in symptom duration plus a reduction in illness severity, a 59% reduction in hospitalizations (range: 30% to 70%), a 63% reduction in antimicrobial drug use (range: 40% to 80%) and a 1-day reduction in work days lost under treatment (range: 0.5 to 1.5 days).⁴ In a prospective cohort study of patients hospitalized with influenza in southern Ontario, treatment with antiviral drugs was associated with a significant reduction in mortality (odds ratio, 0.21; p = 0.03).⁵

Evidence is limited on the effects of neuraminidase inhibitors in reducing influenza complications in individuals with high-risk conditions. The available evidence supporting such a benefit derives from analyses of pooled data from multiple independent studies.⁶

Both oseltamivir and zanamivir have similar effectiveness, of 70%-90%, compared with placebo in preventing laboratory-confirmed influenza illness.⁷ A detailed review of the effectiveness of neuraminidase inhibitors for the prevention of influenza was conducted by the Canadian Agency for Drugs and Technologies in Health.⁸ This report reviewed studies of pre-exposure (seasonal) prophylaxis, post-exposure prophylaxis (e.g. in family settings) and outbreak control in closed settings (e.g. nursing homes). Data are limited or absent for prophylaxis among very young children, pregnant women, immunocompromised persons and for specific occupational groups such as health care workers. There are no randomized controlled trial data on oseltamivir and only two trials on zanamivir for control of outbreaks in long-term care facilities. Of the two trials on zanamivir one showed a significant difference between the placebo and treatment groups, and one did not. Observational studies support the use of oseltamivir for outbreak control in these settings.

Data on whether viral shedding is reduced by early treatment with neuraminidase inhibitors are inconsistent. The duration of viral shedding was reduced in one study that employed experimental infection; however, other studies have not demonstrated any reduction in the duration of viral shedding.⁹ A re-analysis of four household-based, randomized clinical trials (two oseltamivir and two zanamivir) showed that the efficacy of oseltamivir against the infectiousness of treated cases was significant, whereas the efficacy of zanamivir was not.¹⁰ The authors caution against over-interpreting these results because of the small samples.

In most cases neuraminidase inhibitor prophylaxis does not suppress the antibody response to influenza infection if an individual acquires infection during prophylaxis.¹¹ This is felt to be an advantage, as this acquired protection will persist after prophylaxis has been stopped.

Oseltamivir and zanamivir are generally well tolerated, and experience to date suggests that serious side effects are very rare. Relatively common side effects with oseltamivir are nausea and vomiting, but this seldom leads to discontinuation of the drug. Inhalation of zanamivir has been rarely associated with bronchospasm, which may be severe in patients with bronchial asthma and chronic obstructive pulmonary disease. There have been post-marketing reports, mainly from Japan, of delirium and self-injury, in some cases fatal, in patients with influenza who were receiving neuraminidase inhibitors. These events were reported primarily in children. The contribution of the antiviral therapy to these events has not been established, and influenza itself is known to be associated with a variety of neurological and behavioural symptoms. Close monitoring for signs of abnormal behavior during antiviral treatment is advised.

Development of resistance is a risk with any drug. Current evidence suggests that the development of resistance during influenza treatment is less likely with neuraminidase inhibitors (oseltamivir and zanamivir) than with amantadine.¹² Resistance to the neuraminidase inhibitors occurs by different mechanisms, and viruses that are resistant to oseltamivir generally remain sensitive to zanamivir.

Until recently, global surveillance had detected only very low levels of resistance to the neuraminidase inhibitors.⁸ In 2008, however, oseltamivir-resistant influenza A (H1N1) strains were detected in many countries, particularly in Europe and North America, including Canada, and investigation suggested that they were readily transmissible, in contrast to earlier experience with oseltamivir-resistant strains.¹³ This occurrence did not appear to be connected with oseltamivir use either in individuals or in the countries involved. Ongoing, intensified monitoring of antiviral resistance will help clarify the situation over time. The risk of a pandemic virus being resistant from the outset or becoming resistant to oseltamivir is unknown.

3.1.1 Interchangeability of Neuraminidase Inhibitors

Use of oseltamivir and zanamivir for treatment or prophylaxis is expected to be interchangeable
in most cases. They cannot, however, be used interchangeably in the following circumstances:

• Zanamivir is preferred for pregnant and nursing women as it is administered by inhalation and
  is poorly absorbed systemically;
• Zanamivir is not suitable for:
  • Children under the age of 7;
  • Persons with reactive airways disease;
  • Persons who cannot use the inhaler, e.g. some elderly and nursing home patients and
    small children;
  • Persons with severe respiratory disease, because absorption would be impeded; and
  • Treatment of seriously ill persons if there is evidence that the pandemic virus replicates
    outside of the respiratory system.

3.1.2 Treatment Schedules

The standard dosages for treatment and prophylaxis with oseltamivir and zanamivir are shown in
Table 2. It is possible that the dosage and/or duration of treatment might need to be modified for
a novel or pandemic virus; this will be monitored closely during the pandemic.

Table 2 - Standard dosages for neuraminidase inhibitor treatment and prophylaxis

		Oseltamivir (Tamiflu®)	Zanamivir (Relenza®)
Treatment	Adults	75 mg twice daily for 5 days	2 inhalations (10 mg) twice daily for 5 days
	Children	15 kg or less: 30 mg twice daily for 5 days >15-23 kg: 45 mg twice daily for 5 days >23-40 kg: 60 mg twice daily for 5 days (given as two 30 mg capsules) >40 kg: 75 mg twice daily for 5 days Adolescents 13 years and older: 75 mg twice daily for 5 days	Age 7 and above: 2 inhalations (10 mg) twice daily for 5 days
Prophylaxis*	Adults	75 mg daily	2 inhalations (10 mg) once daily
	Children	15 kg or less: 30 mg once daily >15-23 kg: 45 mg once daily >23-40 kg: 60 mg once daily (given as two 30 mg capsules) >40 kg: 75 mg once daily	Age 7 and above: 2 inhalations (10 mg) once daily
Renal impairment: adult	Creatinine clearance of 10-30 mL/min	Treatment: 75 mg once daily for 5 days Prophylaxis: 75 mg every other day or 30 mg once daily	No dosage adjustment necessary
	Renal dialysis (treatment or prophylaxis)	Low flux hemodialysis: 30 mg orally every second hemodialysis session Continuous ambulatory peritoneal dialysis: 30 mg orally once a week	No dosage adjustment necessary
* Duration of prophylaxis is determined by the circumstances. Standard post-exposure prophylaxis is given for 10 days. For outbreak control, prophylaxis is continued until the outbreak is over, usually 10-14 days. Pre-exposure prophylaxis generally continues for the duration of exposure. Note: Pre-exposure use for oseltamivir and use beyond 28 days for zanamivir are not approved indications.

3.2 M2 Ion Channel Blockers (Cyclic Amines or Adamantanes)

M2 ion channel blockers (amantadine and rimantadine) interfere with the replication cycle of influenza A but are not effective against influenza B. Rimantadine has fewer side effects than amantadine but is not currently approved for use in Canada.

Amantadine is approximately 70% to 90% effective in preventing illness from influenza A infection, providing the strain is amantadine susceptible. When administered within 2 days of onset of illness, it can reduce the duration of uncomplicated influenza A illness by approximately 1 day, but its ability to reduce the complications of influenza has not been studied. Amantadine resistance has been shown to develop rapidly (in up to 30% of recipients) when this drug is used for treatment purposes, and these resistant viruses are readily transmissible.¹⁴ In recent years, the majority of circulating H3N2 viruses in many parts of the world have been resistant to M2 blockers. Resistance of the H5N1 viruses to the M2 blockers is common but varies by geographical origin and viral clade. Fortunately, amantadine resistance to H1N1 virus remains relatively rare.

Amantadine should not be used as the sole agent for treatment because of the frequency with which resistance develops. However, in light of its proposed role in combination therapy, as described in the following section, standard dosages for amantadine treatment and prophylaxis are provided in Table 3.

Table 3* - Standard dosages for amantadine to be considered in the context of combination therapy

Age	Dosage†
No renal impairment
1-9 years or < 40 kg	5 mg/kg once daily, or divided twice daily, total daily dose not to exceed 150 mg
10-64 years	200 mg once daily, or divided twice daily Reduce to 100 mg daily for persons with seizure disorder
≥ 65 years	100 mg once daily
Renal impairment
Creatinine clearance (mL/min/1.73 m²)	Dosage for those 10-64 years	Dosage for those ≥65 years
≥ 80 mL/min	100 mg twice daily	100 mg once daily
60-79 mL/min	Alternating daily doses of 200 mg and 100 mg	Alternating daily doses of 100 mg and 50 mg
40-59 mL/min	100 mg daily	100 mg every 2 days
30-39 mL/min	200 mg twice weekly	100 mg twice weekly
20-29 mL/min	100 mg three times weekly	50 mg three times weekly
10-19 mL/min	Alternating weekly doses of 200 mg and 100 mg	Alternating weekly doses of 100 mg and 50 mg
* Adapted from: National Advisory Committee on Immunization. Statement on influenza for the 2006-07 season. CCDR 2006;32(ACS 7). † Duration of treatment is 5 days or until 48 hours after recovery, whichever is shorter. Duration of prophylaxis is determined by the circumstances. Standard post-exposure prophylaxis is given for 10 days. For outbreak control, prophylaxis is continued until the outbreak is over, usually 10-14 days. Pre-exposure prophylaxis generally continues for the duration of exposure.

These dosages are based on a 2006 statement by the National Advisory Committee on Immunization related to monotherapy for seasonal influenza outbreaks (see Table 3 footnote reference). It is possible, on the basis of additional studies and experience, that the dosages used in combination may need to be adjusted to reduce adverse reactions and achieve better therapeutic effects. For outbreaks in long-term care facilities, once-daily dosing and the use of amantadine syrup may make this regimen easier to administer.

3.3 Combination Therapy and Other New Approaches

The World Health Organization (WHO) recommends the consideration of combination therapy (amantadine and oseltamivir) for persons with avian influenza (H5N1) who are seriously ill in areas of the world where the viruses are likely to be susceptible to amantadine.² Drug combination therapy uses drugs with different mechanisms of action to provide greater benefit than single drugs, reduce the risk of resistance and potentially allow for lowered doses, thus reducing adverse effects. Various combinations of M2 blockers, neuraminidase inhibitors, interferon and ribavirin have been suggested for the treatment of influenza. There have been several preliminary reports of combination therapy with an M2 blocker and neuraminidase inhibitor that are promising;^15,16 however, further studies are indicated. Studies of combination therapy are being monitored, and their applicability to the pandemic stockpile is under assessment.

Because oral medications are not always suitable for seriously ill patients, parenteral products could play an important role, especially in a hospital setting. Intravenous versions of the existing neuraminidase inhibitors are under development. Clinical trials are under way for peramivir, another neuraminidase inhibitor administered by the intramuscular or intravenous route. When available, parenteral products will be assessed for inclusion in the stockpile. Similarly, as other new antivirals become available their potential role will be evaluated.

4.0 The National Antiviral Strategy

4.1 Goals of the National Antiviral Strategy

The goals of the national antiviral strategy are to support the Canadian pandemic goals of minimizing serious illness and overall deaths and minimizing societal disruption by:

• Reducing the severity and duration of illness (including a decrease in the occurrence of complications, hospitalization and death);
• Mitigating societal disruption by reducing the impact of absenteeism due to illness in the critical infrastructure sectors; and
• Reducing the level and duration of viral shedding, thereby possibly reducing transmission.

4.2 Antiviral Stockpiles

National stockpiles of antiviral drugs help ensure that there is equitable access across Canada to a secure, government-controlled supply of antivirals for pandemic influenza. Without such stockpiling it is unlikely that there would be any antiviral drugs available at the time of a pandemic. The antivirals purchased by the government have largely gone into two stockpile systems in Canada: the National Antiviral Stockpile and the National Emergency Stockpile System.

4.2.1 National Antiviral Stockpile (NAS)

The National Antiviral Stockpile (NAS) was created in the fall of 2004 and contained 16 million doses of oseltamivir. In February 2006, it was decided that the size (and diversity) of the stockpile should be increased to 55.7 million doses to support a national early treatment strategy, namely, to provide antivirals to all Canadians expected to need treatment during a pandemic. The calculations were based on assumptions of a clinical attack rate of 35% over the course of a pandemic of moderate severity, with half of those clinically ill seeking medical care and receiving a standard 5-day course of antiviral treatment. At the time of publication of this annex, the stockpile consists of 48.7 million adult oseltamivir capsules, 2 million paediatric oseltamivir capsules and 5 million doses of zanamivir.

The National Antiviral Stockpile contains enough antivirals to treat 17.5% of the population. It has been distributed on a per capita basis to each of the provinces/territories and is under P/T care and control under the terms of a national agreement for use. Some provinces/territories have chosen to purchase additional quantities of antivirals.

4.2.2 National Emergency Stockpile System (NESS)

The National Emergency Stockpile System (NESS) is a federally owned stockpile of emergency supplies that is managed by the Public Health Agency of Canada (PHAC). It contains a number of emergency supplies for different types of emergencies. At the time of publication of this annex, NESS contains approximately 14.9 million doses of antivirals made up of 8.0 million adult oseltamivir capsules, 2.0 million paediatric oseltamivir capsules, 4.9 million zanamivir doses and 70,000 capsules of amantadine. Additional doses of amantadine, zanamivir and paediatric oseltamivir are being purchased. These NESS antivirals are intended for multiple purposes, including rapid response to an emerging pandemic and provision of surge capacity in support of P/T efforts to manage pandemic/avian influenza.

4.2.3 Other Government Stockpiles

Other federal government departments (e.g. Canadian Forces for active duty personnel, Department of Foreign Affairs and International Trade for mission staff overseas) hold a stockpile of antiviral drugs to meet the anticipated needs of their staff. In addition, some provinces have chosen to augment their portion of the NAS.

4.3 Proposed Uses of Antiviral Drugs

The proposed uses of antivirals from the national stockpiles are summarized in Table 4 and described more fully in the following sections. Note that the prophylaxis indications in the last column of this table are presented for planning purposes and are based on recommendations received by the Public Health Network Council.

For antiviral use in domestic avian influenza outbreaks, see Human Health Issues related to Avian Influenza in Canada: http://www.phac-aspc.gc.ca/publicat/daio-enia/index-eng.php.

Table 4 - Proposed uses of government-stockpiled antiviral drugs in Canada

	Use
Pandemic Phase	Early Treatment	Post-exposure Prophylaxis
Pandemic alert period (Phases 4 and 5)	Cases with novel virus infection	Close contacts of persons with novel virus infection
Pandemic period (Phase 6)	Cases of pandemic influenza	Control of laboratory-confirmed influenza outbreaks in closed health care facilities and other closed facilities where high-risk persons reside

4.3.1 Early Treatment Strategy

The NAS will be used at the time of a pandemic for treatment purposes (indications for use see section 5.3). Modeling suggests that stockpiles that cover 20%-25% of the population (as is the case in Canada when all stockpiles are included) would be sufficient to treat most of the clinical cases and could lead to 50%-77% reduction in hospitalization.¹⁷ A focus on early treatment (in contrast to prophylaxis) is the most efficient way to use antiviral drugs and, according to the estimated impact of a pandemic, antiviral treatment is expected to be cost-saving to the economy.⁴

Indirect benefits of early treatment include the possible reduction of transmission of infection to close contacts and the positive impact on maintaining the critical infrastructure by shortening the duration of illness, thereby reducing absenteeism. The policy recommendations on the use of antivirals for prophylaxis (which are described in detail in the next section) recommend that during the implementation of the early treatment strategy, critical infrastructure workers, including health care workers, have access to rapid assessment and early treatment in order to minimize societal disruption. See Appendix 1 for a list of critical infrastructure sectors.

The principal challenge of a treatment-focused strategy is the ability to deliver drugs in a timely manner to ill individuals. To be effective, neuraminidase inhibitors must be administered as early as possible, ideally within 12-24 hours after the start of illness but definitely within 48 hours. Delivery of the drugs is primarily the responsibility of the respective P/T and local governments and is discussed further in section 5 of this annex.

Antiviral treatment of ill persons infected with a novel virus that has pandemic potential is also recommended during the pandemic alert period (Phases 4 and 5), together with antiviral prophylaxis of their contacts. The Public Health Measures annex (Annex M) provides more detail on control measures during these phases.

While it is anticipated that the NAS will be sufficient to treat all persons who could benefit, on the basis of the assumptions described earlier, there could be developments that will merit reconsideration of this approach. The stockpile could be depleted faster than expected if the attack rate is higher than anticipated or the illness so severe that a higher proportion of ill persons seek care. Treatment could require more than 10 doses, or antiviral resistance could restrict the use of a stockpiled drug. Also, an unknown proportion of antivirals could be “wasted” because some of the patients treated for influenza-like illness will turn out to have other respiratory viruses instead of influenza. Furthermore, should oseltamivir resistance arise, this would reduce our treatment options to zanamivir. Assessment of stockpile adequacy will need to be made as the pandemic progresses and its clinical features become known. If prioritization for treatment is necessary, it is recommended that a national approach be taken using guidelines for the use of antivirals in short supply.

4.3.2 Prophylaxis Recommendations

The Task Group on Antivirals for Prophylaxis was struck in 2006 to conduct a comprehensive review of the provision of antivirals for prophylaxis (prevention) and to advise the Public Health Network Council on whether governments should stockpile antivirals for this purpose for use during an influenza pandemic. In August 2008, after careful analysis and pan-Canadian consultations, the Public Health Network Council published the National Policy Recommendations on the Use of Antivirals for Prevention During an Influenza Pandemic.¹⁸ The recommendations reflect current public health advice, given the scientific evidence available at the time of publication, and will be reviewed periodically to take into account new evidence.

These policy recommendations were received by P/T governments and will be used to inform federal, provincial and territorial policies pertaining to the use of antivirals for prophylaxis. Currently it is assumed that the limited use of antivirals for prophylaxis as described below can be covered by the NAS with back-up from the NESS. Any decision by a province or territory to provide prophylaxis beyond these recommendations will require additional purchases beyond the current NAS/NESS supplies.

The recommendations are as follows:

Pandemic Alert Period (Phases 4 and 5):

• As part of an early response strategy, provide post-exposure prophylaxis of close contacts of cases, together with treatment of cases.

Pandemic Period (Phases 6):

• Focus on early treatment of people with influenza and no post-exposure prophylaxis of close contacts of cases;
• Provide rapid access to antivirals and early treatment to critical infrastructure workers to minimize societal disruption;
• Use antivirals for outbreak control, including treatment of cases and prophylaxis of close contacts of cases in closed health care facilities and other closed facilities where high-risk people reside; and
• No use of antivirals from government stockpile for pre-exposure prophylaxis.

The widespread use of antivirals for pre-exposure prophylaxis during a pandemic was not recommended because of a number of factors. The relative paucity of clinical trial data was noted. The unknown health and safety risks of administering a drug with known side effects to a large number of healthy people for a prolonged period was a concern, as well as the difficulties of guaranteeing compliance with prolonged use. The risks of resistant strains of the virus developing were identified. It was concluded that the decision to undertake extensive pre-exposure prophylaxis required stronger scientific evidence, such as that obtained from population-based trials.

The use of antivirals from government stockpiles for post-exposure prophylaxis during an influenza pandemic was not recommended. Once a pandemic starts, this measure would require enormous quantities of antivirals and would be very resource intensive to administer. It was noted that during a pandemic, the entire health system would be challenged, and efforts should be focused on the needs of the ill.

The use of antiviral drugs to control outbreaks of influenza in health care settings, such as longterm care facilities and hospitals, is standard practice in Canada. It was recommended that this practice continue in a pandemic along with its consideration for other types of closed facilities, such as correctional facilities, where high-risk persons reside. Effective control of influenza outbreaks in these settings is expected to provide significant benefits in terms of hospitalizations averted and lives saved.

Private stockpiles (individual or corporate) of antivirals for prophylaxis are beyond the scope of this annex, but it is recognized that some organizations have undertaken this as part of their pandemic preparedness or business continuity planning efforts.

4.3.3 Rapid Containment Strategy

The WHO has developed a protocol for a rapid containment strategy to be implemented by national authorities with the assistance of WHO and international partners.¹⁹ Its purpose is to stop the development of pandemic influenza when it is initially detected and before the virus has been able to spread more widely. Mathematical modelling studies suggest that containment of a pandemic might be possible in the early stages if the initial outbreak of human cases is localized and antiviral prophylaxis, movement restrictions and non-pharmaceutical interventions are implemented in the affected area within the first 3 weeks.^20,21 The basic containment strategy uses a geographically based approach in which antiviral medications and non-pharmaceutical measures are used in a defined area surrounding the initial cases (i.e. the Containment Zone) to restrict the virus from spreading beyond that Containment Zone. There is also a surrounding Buffer Zone, where intensive surveillance for possible “break-through” cases would be done to evaluate whether the containment operation is succeeding.

While it is unlikely that the new pandemic will originate in Canada, it is anticipated that PHAC will lead the development of the containment strategy for Canada in the context of commitments under the North American Plan for Avian and Pandemic Influenza and in accordance with the WHO interim protocol on this issue.

4.4 Stockpile Management

Canada’s antiviral stockpiles are constantly being reassessed by F/P/T governments for size, composition (type of antiviral) and relative proportion of the stockpile in line with new science, technologies and formulations; changing resistance rates; disease epidemiology; and changing populations. In addition, all drugs have a shelf-life or an amount of time specified by the manufacturer during which the drug is documented to be stable and potent. This necessitates the development of a stockpile management approach that allows for the regular replacement of stock.

4.4.1 Recent Recommendations on Composition and Mix

The Public Health Network Council has recently approved the following recommendations that will be implemented over time by the provinces and territories:

• diversify the stockpile to 80% oseltamivir and 20% zanamivir (41 million doses of adult oseltamivir and 10.7 million doses of zanamivir for adults and children);
• increase the number of paediatric oseltamivir capsules to 9.2 million; and
• add 5.8 million capsules of amantadine.

More zanamivir will be used as a hedge against resistance. The additional paediatric oseltamivir capsules will provide sufficient quantities for paediatric treatment based on 2005 population data and on the same assumption used for adults (i.e. that 17.5% of the paediatric population will be ill enough that their parents seek medical treatment). Amantadine will be used in combination therapy to treat severe illness targeted for hospitalized patients.

4.4.2 Sustainability Strategy

By 2010, over 50% of the oseltamivir in the current NAS (28.4 million doses of adult oseltamivir) will meet its stated shelf-life of 5 years. An Antiviral Stockpile Management Task Group was established in June 2008 to provide options and recommendations on the management of the NAS with a focus on addressing impending expiring stock and general best practices for stockpile management.

Scientific data indicate that oseltamivir is a very stable drug, and new oseltamivir purchased by the government will have a shelf-life of 7 years. This does not apply to drugs that have already been purchased.

A number of options were considered regarding how to manage the expiring stock, in conjunction with the recent recommendations on composition and mix. Options considered were:

• Participating in a time-limited exchange program with the manufacturer that allows almost expired stock to be exchanged to meet both adult and paediatric targets;
• Replacing some of the expired oseltamivir for zanamivir; and
• Temporarily holding some expiring oseltamivir (with ongoing stability testing).

A final report of the Antiviral Stockpile Management Task Group is planned for release in 2009. Good stockpile management includes careful consideration of storage conditions. All antivirals require storage in a dry place at room temperature (15° to 30° C). Amantadine should be stored in a light-resistant container. A best practice for oseltamivir and zanamivir storage is temperature monitoring and documentation to demonstrate that an average temperature of 20°-25° C has been maintained for the antiviral stockpiles and that there is no variation beyond 15° to 30° C.

5.0 Implementation Planning

The provinces and territories, together with their regional and local partners, are responsible for implementing the antiviral strategy in their own jurisdictions. Since the current antiviral supplies have been allocated on a per capita basis, antivirals should be provided through the local distribution point to all residents, including those who live on First Nations reserves.

While some differences in implementation plans are anticipated, it is expected that the provinces and territories will remain consistent in their uses of antivirals in terms of overall approach, eligibility for drugs, approach to off-label use and communications messages, etc. This will be facilitated by clear national guidelines in these areas. A national forum on implementation of the antiviral strategy was held in October 2007 (summary available from PHAC upon request) and focused specifically on early treatment. Presentations and input from that meeting have informed the guidelines that follow.

5.1 Components of an Implementation Plan

Common elements of a P/T antiviral implementation plan include the following:

• Storage and handling;
• Distribution within the province/territory – secure and efficient delivery system, taking into account the needs of remote and First Nations communities;
• Trigger for release of the antivirals – e.g. release from central depots in advance of anticipated pandemic activity; local use to begin when there is laboratory evidence that the pandemic virus is circulating locally;
• Clinical assessment – service delivery model and accompanying tools;
• Dispensing – who and where, tied to service delivery model;
• Laboratory capacity and guidelines for clinical testing;
• Surveillance and monitoring – uptake/usage, effectiveness, adverse events, antiviral resistance;
• Communications – public, health care professionals and other groups;
• Roles and responsibilities, including potential role of public health in distributing antivirals, promoting or monitoring their use;
• Documentation of distribution, dispensing, etc.;
• Training and exercises; and
• Evaluation of outcomes.

5.2 Antiviral Use in the Pandemic Alert Period

As already outlined, early treatment of cases and post-exposure prophylaxis of close contacts should be offered in Canada during the Pandemic Alert Period (Phase 4 & 5) as part of the rapid response strategy. While these phases could occur as a result of a novel virus originating in Canada, it is more likely that a novel virus would emerge in another country.

Detailed advice for case and contact management in the pandemic alert period is found in the Public Health Measures annex (Annex M) of the Canadian Pandemic Influenza Plan.

5.3 Implementation of the Early Treatment Strategy

It is intended that the NAS will be used at the time of a pandemic (Phase 6) for early treatment of persons:

• With influenza-like illness;
• Assessed within 48 hours of the onset of symptoms; and
• When there is laboratory evidence that the pandemic influenza virus is known to be circulating in the community.

Putting this policy into operation requires consideration of a number of issues.

5.3.1 Timing of Treatment

Since replication of influenza virus in the respiratory tract peaks between 24 and 72 hours after the onset of the illness, neuraminidase inhibitors (which act at the stage of viral replication) must be administered as early as possible. This is ideally within 12-24 hours of the start of illness. Evidence suggests that there is no benefit in using antivirals to treat community cases of seasonal influenza more than 48 hours from onset of illness. It is important to note that experience with the novel or pandemic virus may differ and result in changes in these recommendations.

It is recognized that adopting a 12-24 hour target to begin treatment puts considerable strain on the health care delivery system and probably means incorporating alternative models for providing clinical assessment and dispensing drugs. However, it is only by optimizing the early treatment strategy that we will achieve the desired results of preventing complications, hospitalizations and deaths.

In the hospital setting however, where more seriously ill persons are seen, clinicians should be allowed clinical latitude on the 48 hour rule, as there is some evidence for the value of delayed treatment in hospitalized patients.⁵ Immunocompromised persons may have prolonged viral replication and might also be expected to benefit from delayed treatment.

5.3.2 Assessment and Treatment Options

P/T planning for early access to antiviral drugs involves a number of considerations and options:

• Can the existing ambulatory care system assess and deliver drugs to the expected number of persons with influenza within the 12-48 hour target? What are the infection control implications?
• Should the existing services be supplemented or replaced by additional services like influenza assessment and treatment centres? Who will provide assessment and treatment services in these centres?
• Will medical directives be used for expansion of prescribing capacity, or could the provinces/ territories consider extending prescribing rights to pharmacists or other health professionals?
• How will vulnerable populations be served?
• Could the response and role of telephone advice lines be expanded?
• What is the role for self-assessment?
• Will distribution of antivirals be under local public health control?

The Clinical Care annex (Annex G, Clinical Care Guidelines and Tools) contains a clinical algorithm for the assessment and management of persons with influenza-like illness. It is anticipated that in ambulatory care settings like influenza centres, nurses and potentially other health professionals will provide assessment using algorithms, and treatment using medical directives. In any triage/assessment setting, the Antiviral Working Group recommends that certain categories of persons be referred to a clinician for assessment and treatment (subject to modification at the time of the pandemic):

• Persons who are seriously ill or appear to be developing complications;
• Persons who are not responding to treatment;
• Persons with serious underlying health conditions, e.g. chronic cardiac or pulmonary disorders (except hypertension); diabetes mellitus and other metabolic diseases; renal disease; cancer; immunodeficiency and immunosuppression (due to underlying disease and/or therapy); anemia or haemoglobinopathy; and conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration;
• Infants and very young children;
• Pregnant women; and
• Any additional high-risk groups identified in the pandemic.

Some of the tools needed to support the early treatment strategy can be found in Annex G. These tools may need modification when the pandemic virus emerges and its characteristics are known. Other national tools to support the early treatment strategy are under development.

5.3.3 Role of Laboratory Testing

The Laboratory annex (Annex C, Pandemic Influenza Laboratory Guidelines) outlines the role that laboratories will play in influenza testing, particularly in surveillance. Once the presence of pandemic influenza has been established in an area, laboratory testing in the ambulatory care setting will decrease in order to conserve laboratory resources for surveillance purposes and monitoring of antiviral resistance and effectiveness. Routine patient diagnosis will be made primarily on clinical grounds, using clinical algorithms that are modified for the pandemic presentation.

The Clinical Care annex (Annex G) contains recommendations for the role of laboratory testing in individual diagnosis and suggests that indications for limited laboratory testing throughout the pandemic include the following:

• Confirmation of an atypical presentation of pandemic influenza, including young children, when it will affect a treatment decision;
• Confirmation of the etiology of an institutional outbreak;
• Non-response to treatment in the hospital setting (for early detection of a resistant strain in a hospital); and
• Admission to the intensive care unit, to enable cohorting of patients.

5.3.4 Prescribing and Dispensing Antivirals

There are several ways to expedite early treatment with antivirals. The use of medical directives is already widely applied in health care settings; these are instructions by physicians to certain health care providers that pertain to any patient meeting the criteria set out in the medical directive. In addition, some provinces/territories have the option of extending prescribing rights to pharmacists or other health professionals.

Dispensing is normally supervised by pharmacists, although P/T legislation may allow others to dispense as well. In the interests of providing widespread access, dispensing antiviral drugs where patients are seen – for example, at influenza centres (if established) or emergency departments – could help to reduce exposure time to infected persons and expedite patient care. An examination of P/T legislation can help planners determine the best avenues to pursue with respect to prescribing and dispensing antivirals.

The option of removing antiviral drugs from prescription drug status during a pandemic is under consideration in several countries. New Zealand currently allows this during the winter season. It is not under consideration in Canada because of the regulatory assessment that identifies antiviral drugs as most appropriate for Schedule “F” (prescription drugs); to date there have been no additional data that would qualify any of the antiviral medications for removal from Schedule F.

5.4 Outbreak Control in Health Care and Other Closed Facilities

Use of antiviral drugs to control outbreaks of influenza in closed health care settings, like long-term care facilities and hospitals, is standard practice in Canada. Outbreak control involves the use of antivirals to treat cases and to provide post-exposure prophylaxis to contacts, that is, to residents, staff, volunteers and others who provide services in these facilities. Guidelines for seasonal outbreak control in institutions recommend antiviral prophylaxis for all susceptible residents, regardless of vaccination status, and for unvaccinated staff.²² Because pandemic vaccine will not be available initially, influenza outbreaks in long-term care facilities may be more severe during a pandemic than during seasonal outbreaks, when most residents are vaccinated.

In long-term care facilities, prophylactic measures generally involve the whole facility, with some exceptions when the outbreak is very small or there is very little mixing of staff or residents between units.²³ In hospitals, antiviral use for outbreak control is restricted to the unit or ward where transmission is occurring.

Early detection and confirmation of institutional outbreaks by laboratory testing will be vital during an influenza pandemic so that antivirals and other outbreak control measures can be started immediately. This should reduce outbreak size, thereby reducing morbidity and mortality in residents and staff illness/absenteeism. Planning should ensure that there is rapid access to laboratory testing to confirm the presence of the novel virus and to antivirals for both treatment of residents and staff and for prophylaxis. Medical directives, dispensing plans and advance consent can facilitate rapid outbreak control.

Many provinces/territories have existing guidelines for managing respiratory outbreaks in health care facilities; Ontario is but one example.²⁴ Such guidelines could be modified if necessary for other types of closed facilities in which high-risk persons reside. Responsibility for guideline development or modification, dissemination and training should be assigned within the province/territory.

Pandemic planners may consider using the following criteria in deciding which types of facilities in their jurisdiction might be eligible for antiviral outbreak control:

• The facility is “closed”, i.e. has a fixed residential population with limited turnover, or in the case of a hospital has units or wards that are, or can be, closed;
• The facility has high-risk patients/residents;
• There is ongoing surveillance to detect influenza activity and outbreaks in the facility;
• It would be difficult to manage an outbreak in the setting;
• Outbreak control would reduce the burden on the health care system (e.g. prevent hospitalization or further morbidity and mortality in already-hospitalized patients); and
• The facility is able to manage an antiviral regimen with adequate medical expertise and minimal public health assistance.

A list of potential settings for the use of antivirals for outbreak control and whether they meet the criteria for limited antiviral prophylaxis is shown in Table 5 Provincial and territorial policies may vary.

Table 5 - Potential settings for use of antivirals for the control of influenza outbreaks during an influenza pandemic

Category	Type of Facility	Does it Meet the Criteria for Limited Antiviral Prophylaxis?
Health care facilities	Acute care hospitals	Yes, if the affected unit or ward is closed. Antiviral use for outbreak control would be restricted to the unit or ward where transmission is occurring.
	Long-term care facilities (LTCFs)	Yes. In smaller LTCFs outbreak control measures may involve the entire facility; in large LTCFs only units where transmission is occurring would be included.
	Speciality hospitals, e. g. complex continuing care, rehabilitation, psychiatric	Yes, provided facility is closed and there is adequate medical supervision to support antiviral use; would likely be restricted to the unit or ward where transmission is occurring.
Other closed facilities	Correctional facilities	Yes, on the basis that these are closed facilities with high-risk persons (e.g. immunosuppressed) and have the adequate medical supervision to support antiviral use.
	Retirement homes, lodges	Possibly not, on the basis that they may meet the criterion of high-risk persons but may not meet the criterion of a closed facility or adequate medical supervision to support antiviral use.
	Homes for special care and group homes	Unlikely; may meet the criterion for high-risk persons but may not meet criteria for a closed facility or adequate medical supervision to support antiviral use.

5.5 Consent and Off-label Use

It is recommended that potential recipients of antiviral drugs be given written information about the drugs, including information about potential adverse effects, what to do if adverse events occur and how to report them. Consumer information sheets are attached to the product monographs for both Tamiflu® and Relenza®. Educational materials will need to be translated into multiple languages. Advanced written consent is commonly sought in long-term care facilities to facilitate rapid use of antivirals for outbreak control.

As identified below, some of the proposed pandemic uses for antiviral drugs may be “off-label”. The term “off-label” describes the use of a drug for indications (or intended uses) other than those that have received regulatory authorization. All drugs that are for sale in Canada have received approval by Health Canada before their release on the market. The indications (or intended uses) of each drug are well specified and supported by scientific evidence. An authorized indication generally includes not only the condition to be treated but also for whom the drug is indicated and for how long. However, at the discretion of the clinician, drugs may be prescribed for purposes other than the authorized indications.

Clinicians decide to prescribe drugs off-label for different reasons. In some circumstances, there is good clinical trial evidence to support off-label use. For example, there is good clinical trial evidence to support the use of low-dose aspirin to prevent myocardial infarction. However, this evidence has never been submitted for regulatory review, and thus it is not an authorized indication. In other circumstances, there is no clinical trial evidence to support off-label use, but there is great patient need and a sound medical rationale. For example, anti-seizure medications may need to be prescribed for a pregnant woman with epilepsy even though there no trials for these medications in pregnant women.

It is common practice for physicians to prescribe drugs off-label, but this is informed by evidence, need, a sound clinical rationale and an assessment of the potential risks and benefits of a particular drug for a particular patient. What is important is that there is transparency about what an authorized indication is and what is not. In addition, it is important that patients understand the risks and benefits and consent to taking the prescribed drug.

In summary, this is the recommended approach to off-label use with respect to antiviral medications:

1. It needs to be clear to planners, clinicians and patients alike what an authorized indication of an antiviral drug is and what off-label is.
2. The decision to prescribe an antiviral off-label rests with clinicians after a careful risk/benefit assessment for an individual patient has been undertaken.
3. Transparency is important; guidelines and written patient materials that propose off-label use should include the clinical rationale as well as potential risks and benefits.
4. There should be informed consent.

Some considerations for limited off-label use of oseltamivir and zanamivir during a pandemic are as follows:

Neuraminidase inhibitors for pregnant women: Pregnant women are known to be at increased risk of complications and death from influenza, both for seasonal influenza and during past pandemics. If neuraminidase inhibitors are prescribed, zanamivir is the preferred drug as there is little systemic absorption.

Longer treatment courses: Recent studies on severely ill patients and H5N1 infections suggest potential benefit from longer treatment regimens or the use of combination therapy. More studies are under way to examine this.

Antivirals used beyond their stated shelf life: Oseltamivir and amantadine are known to be stable drugs. A number of countries have extended the functional shelf life of current stockpiles of oseltamivir from 5 to 7 years.

Note: Oseltamivir is currently contraindicated in children less than 1 year of age; however, studies in this age group are under way. The risks and benefits of treating children less than 1 year of age will need to be carefully assessed at the time of a pandemic when more data may be available.

5.6 Monitoring Adverse Reactions

Serious adverse reactions (or side effects) to neuraminidase inhibitors have been very rare. During a pandemic it will be essential to look for, and respond to, the occurrence of known serious adverse reactions and unexpected serious adverse reactions that may be recognized with widespread use of the drugs. Health Canada’s existing adverse reaction surveillance system, known as the Canada Vigilance Program, will be used during a pandemic.

The Canada Vigilance Program collects and assesses reports of adverse reactions to drugs and health products. The Marketed Health Products Directorate (MHPD) of Health Canada is responsible for post-market surveillance, risk management and risk communication for drugs and other health products or medical devices. Adverse reaction reports are submitted by health professionals and consumers on a voluntary basis either directly to Health Canada or through the manufacturer. Manufacturers are required to report serious and unexpected adverse reactions that come to their attention.

The Canada Vigilance Program is supported by seven Canada Vigilance Regional Offices, which provide a regional point-of-contact for health professionals and consumers. Reports are collected by the regional offices before being forwarded to the Canada Vigilance National Office for further analysis. The Canada Vigilance Program provides a variety of tools for health professionals and consumers to report suspected adverse reactions. Reporting is simple and can be done on line, by phone or by submitting the Canada Vigilance Reporting Form by fax or mail.

During a pandemic, MHPD will continue to use the existing system to monitor adverse events to antiviral drugs. The spontaneous reporting system will be “stimulated” as health care professionals, institutions and the public are given information about “what to” and “how to” report adverse reactions to antivirals. Specific pandemic reporting guidelines for health professionals and consumers have been developed and will be posted on Health Canada’s MedEffect web site (http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php).

MHPD will use its Canada Vigilance database to monitor and analyze the reported adverse reactions. In addition, MHPD has been developing plans to enhance its capacity for monitoring adverse reactions and for timely risk management and communication of related safety issues identified for these products. MHPD will work with PHAC to issue regular reports to national bodies and provinces/ territories to provide assurance of continuing drug safety or to flag the possible need to modify recommendations should problems arise.

Suspicions of counterfeit antiviral drugs will be investigated by the Health Products and Food Branch Inspectorate of Health Canada, in collaboration with partners in the Health Products and Food Branch and other national and international partners. The Inspectorate has developed an anticounterfeit strategy for drugs and medical devices, and has laboratory capacity to test samples that are suspected to be counterfeit or those of unknown origin. To report a problem, call 1-800-267-9675 to be directed to the nearest operational centre.

5.7 Antiviral Resistance and Effectiveness Monitoring

The susceptibility of a novel strain or the pandemic virus to antiviral drugs (both during the Pandemic Alert Period and the Pandemic Period) will be monitored on an ongoing basis. Monitoring for drug resistance is essential to know whether or not antiviral drugs will have the desired effect. This will be carried out at the National Microbiology Laboratory, which is responsible for similar resistance monitoring of seasonal influenza strains. More limited antiviral resistance testing may also be performed in some provincial public health laboratories. Plans call for a proportion of specimens from P/T laboratories to be tested for resistance to amantadine, oseltamivir and zanamivir on an ongoing basis, as well as samples from clinical situations in which drug resistance is suspected, such as outbreaks that antivirals have failed to control. For more details see the Laboratory annex (Annex C).

It will also be important to evaluate the effectiveness of antiviral treatment or prophylaxis so that clinical guidelines can be adjusted as necessary. Methodology and protocols for evaluating effectiveness, in real-time if possible, still need to be developed, and work is ongoing in this regard.

6.0 Outstanding Issues

There are a number of outstanding antiviral issues to be addressed:

• Completion of P/T antiviral implementation plans;
• Advancing a national antiviral prophylaxis strategy and facilitating the development of a national prophylaxis implementation plan;
• Identification of process and triggers for modifying the antiviral strategy during the pandemic: developing clinical guidelines based on new epidemiological data, identifying at what point in a severe pandemic we will need to switch to a prioritized treatment strategy, and creating a rapid response plan in the event of significant adverse events (shared responsibility with surveillance planners);
• Development of protocols for monitoring antiviral drug effectiveness;
• Considerations for stockpiling of antivirals by individuals or private industry for personal use or business continuity purposes;
• Development of tools for the early treatment strategy, including communication materials for health care providers and the public on the appropriate use of antiviral drugs;
• Completion of protocols for monitoring antiviral drug resistance (shared responsibility with laboratory and surveillance planners);
• Guidelines for the use of antivirals in short supply; and
• Ongoing assessment of the size, composition and uses of the NAS based on new scientific evidence, modeling studies, new antiviral agents and formulations, and new international best practices.

7.0 Considerations for Future Research

At a national Influenza Research Priorities Workshop held in 2005, research aimed at the development and use of antivirals for both treatment and prophylaxis was identified as a priority. This included studies of novel approaches with existing antiviral medications as well as research aimed at the development and evaluation of new antiviral agents. Subsequently the Canadian Institutes of Health Research have developed a funded pandemic research program that has sparked considerable Canadian research effort and the development of networks of Canadian researchers. Similar research efforts are under way in other countries. There are now several international networks actively monitoring antiviral resistance, and a Southeast Asian Influenza Clinical Research Network was recently established in response to the H5N1 situation.

Some of the important questions about effective treatment protocols can only be answered when the pandemic strain emerges. Rapid clinical trials will be critical to guide the most appropriate use of antiviral drugs. In Canada, an Emerging Infectious Diseases Research Network is being developed. This would bring government and academic researchers together in advance of a mass emergency like a pandemic to develop research protocols along with advance ethical approvals or mechanisms for rapid ethical approval, so that research studies could be rapidly launched when needed.

Outstanding antiviral research issues include the following.

7.1 Prepandemic

• Protocols for rapid epidemiological studies at the time of the pandemic to identify risk groups, attack rates, presentations, etc. (also need to determine potential researchers and networks, funding mechanisms, ethics reviews, etc).
• Protocols for rapid clinical studies at the time of the pandemic (similar determination of potential researchers and networks, funding mechanisms, ethics reviews, etc).
• Patient assessment and diagnosis:
  • How to improve clinical diagnosis;
  • Improved diagnostic tests; and
  • Predictors of severity or futility of treatment.
• Antiviral treatment:
• Safety and effectiveness of antivirals for the treatment and prophylaxis of infants under the age of 1 year and select high-risk groups, such as pregnant women, immunocompromised persons, the elderly with underlying disease;
• More robust data on the effectiveness of neuraminidase inhibitors in reducing complications, hospitalization and mortality;
• Benefit of delayed treatment; and
• Use of combination therapy in different populations.
• Antiviral prophylaxis – the safety and effectiveness of prolonged prophylaxis.
• Antiviral resistance:
  • Mechanisms for resistance to both classes of antivirals;
  • Assessment of the biological consequences (e.g. infectiousness, virulence) of resistance; and
  • How to prevent or limit resistance.
• Development of new antiviral drugs.
• Effectiveness of antiviral delivery strategies.
• Public and health care worker attitudes to antiviral use, including prioritization scenarios.
• Adverse events – occurrence, predictors, mechanisms.

7.2 At the Time of the Pandemic/Postpandemic

• Rapid epidemiological studies to identify risk groups, attack rates, presentations etc.
• Rapid clinical studies to determine the effectiveness of treatment regimens (including combination therapy) against the pandemic strain and the need for any modifications or benefit of delayed treatment.
• Patient assessment and diagnosis:
  • How to improve clinical diagnosis;
  • Improved diagnostic tests; and
  • Predictors of severity or futility of treatment.
• Investigation of serious adverse reactions.
• Effectiveness of antiviral delivery strategies.

Acknowledgements

This Annex was written by the Antiviral Working Group of the Pandemic Influenza Committee:

• Co-Chair, Patricia Huston, Public Health Agency of Canada
• Co-Chair, Susan Tamblyn, Public Health Consultant
• Fred Aoki, University of Manitoba
• Caroline Alfieri, Hôpital Ste-Justine
• Shiv Brar, Health Canada
• Kun Cao, Health Canada
• Gerald Evans, Queen's University
• Alfred Gin, Health Sciences Centre
• Todd Hatchette, Dalhousie University
• Martin Petric, PAndemic Influenza Laboratory Preparedness Network
• Louise Pelletier, Public Health Agency of Canada
• Barbara Raymond, Public Health Agency of Canada
• Danuta Skowronski, National Advisory Committee on Immunization
• Grant Stiver, University of British Columbia

With the support of:

• Pamela Clarke, Public Health Agency of Canada
• Carolyn Lacaille, Public Health Agency of Canada

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Appendix – Definition of Critical Infrastructure

According to Public Safety Canada, “critical infrastructure” refers to those physical and information technology facilities, networks, services and assets that, if disrupted or destroyed, would have a serious impact on the health, safety, security or economic well-being of Canadians or the effective functioning of governments in Canada. The following is a list of the 10 sectors in the National Critical Infrastructure Assurance Program^*, which provides sample subsectors for each sector.

1. Energy and utilities (e.g. electrical power, natural gas, oil production and transmission systems)
2. Communications and information technology (e.g. telecommunications, broadcasting systems, software, hardware and networks, including the Internet)
3. Finance (e.g. banking, securities and investment)
4. Health care (e.g. hospitals, health care and blood supply facilities, laboratories and pharmaceuticals)
5. Food (e.g. safety, distribution, agriculture and food industry)
6. Water (e.g. drinking water and wastewater management)
7. Transportation (e.g. air, rail, marine, surface)
8. Safety (e.g. chemical, biological, radiological and nuclear safety; hazardous materials; search and rescue; emergency services; and dams)
9. Government (e.g. services, facilities, information networks, assets and key national sites and monuments)
10. Manufacturing (e.g. defence industrial base, chemical industry)

National planning for critical infrastructure protection is under way. Some provinces and territories may be using modified definitions of the critical infrastructure sectors, but the concepts are similar.

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* Public Safety Canada. About Critical Infrastructure. Available at: http://www.publicsafety.gc.ca/prg/em/nciap/about-eng.aspx. Accessed Dec. 23, 2008.

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