17th Expert Committee on the Selection and Use of Essential Medicines Geneva, March 2009

Proposal for the inclusion of zanamivir for the treatment and prophylaxis of avian influenza in the WHO model list of essential medicines

FINAL REPORT

September 2008

Paul Carless BHSc., MMed.Sc.(Clin.Epid)

Yuanyuan Cheng PhD

Discipline of Clinical Pharmacology School of Medicine and Public Health Faculty of Health The University of Newcastle Level 5, Clinical Sciences Building Calvary Mater Newcastle Hospital Waratah, New South Wales AUSTRALIA 2298

TEL +61 2 4921 1856 FAX +61 2 4960 2088 WHO EML – Final Report – Zanamivir

Contributors:

Dr Meetali Kakad Senior Advisor in International Health Norwegian Knowledge Centre for the Health Services P.O. Box 7004, St. Olavs plass N-0130, Oslo, Norway

Dr Gunn Vist Researcher Norwegian Knowledge Centre for the Health Services P.O. Box 7004, St. Olavs plass N-0130, Oslo, Norway

Dr Richard Bellamy Consultant, Department of Infection and Travel Medicine James Cook University Hospital, Marton Road, Middlesbrough TS 4 3BW, United Kingdom

Ms Lauren Stockman Respiratory and Enteric Viruses Branch, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA

Professor Lilia Ziganshina WHO Expert Panel Member on Selection and Use of Essential medicines & Kazan State Medical Academy Department of Clinical Pharmacology and Pharmacotherapy, Kazan, Russia

Dr Heather McIntosh Centre for Reviews and Dissemination (CRD), University of York, York, YO10 5DD, UK NHS Quality Improvement Scotland, Delta House, 50 West Nile St, Glasgow, G1 2NP, UK

Dr Karla Soares-Weiser Rabin Medical Center Beilinson Campus Department of Internal Medicine E 49100 Petah Tikva Israel

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1. Summary statement of the proposal for inclusion, change or deletion Zanamivir is proposed for inclusion in the World Health Organization (WHO) Model List of Essential Medicines (EML) for the prevention and treatment of avian influenza (H5N1).

2. Name of the focal point in WHO submitting or supporting the application

3. Name of the organization(s) consulted and/or supporting the application Discipline of Clinical Pharmacology, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Clinical Sciences Building, NM2, Calvary Mater Newcastle Hospital, Edith Street, Waratah, 2298, New South Wales, Australia.

4. International non-proprietary name (INN, generic name) of the medicine INN: Zanamivir Chemical name: 5-acetylamino-4-[(aminoiminomethyl)-amino]-2,6anhydro-3,4,5-trideoxy - D-glycero-D-galacto-non-2-enonic acid.

5. Dosage form or strength proposed for inclusion Powder for oral inhalation: 5mg. Four 5mg blisters of powder on a Rotadisk® for oral inhalation via Diskhaler®. Packaged in carton containing five Rotadisk® (total of 10 doses) and one Diskhaler® inhalation device.

6. International availability – sources, if possible manufacturers Zanamivir is marketed worldwide under the trade name of Relenza® for the treatment and prophylaxis of influenza A and B virus. A detailed list of manufacturers and distributors is presented in Appendix A.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Listing is requested as an individual medicine

8. Information supporting the pubic health relevance (epidemiological information on disease burden, assessment of current use, target population) 8.1 Disease burden The World Health Organisation (WHO) estimates that epidemics of influenza result in 3-5 million cases of severe illness and between 250,000 to 500,000 deaths every year (WHO Influenza Fact Sheet, 2003). In the Unites States (US) alone influenza viruses are responsible for 20,000 to 50,000 deaths and up to 300,000 hospitalisations each year (Guralnik 2007; Osterholm 2005). In the United Kingdom (UK) it is estimated that influenza epidemics cause 12,000 to 13,800 deaths annually (NICE Technology Appraisal 67, 2005). Studies conducted across Europe have shown the influenza-associated seasonal excess mortality to be 16 per 100,000 of the population in Germany, 14 per 100,000 of the population in the Netherlands, and 21.6 per 100,000 of the population in Switzerland (Zucs 2005). However, in the developing world much less is known about the impact of influenza (WHO Influenza Fact Sheet, 2003).

In contrast to influenza epidemics, influenza pandemics are rare events that occur every 10 to

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50 years (Kamps 2006). Pandemics originate with the emergence of a new subtype of influenza virus which is able to cause disease, replicate in humans, and spread efficiently from person to person (Lazzari 2004). The first influenza pandemic was described in 1580 and since then at least 31 influenza pandemics have been recorded. During the last century, three influenza pandemics occurred – the ‘Spanish flu’ pandemic of 1918-19 was responsible for 20-40 million deaths, while the ‘Asian flu’ pandemic in 1957 and the ‘Hong Kong flu’ in 1968 each caused an estimated 1-4 million deaths (Lazzari 2004). Although the next influenza pandemic is expected to cause clinical disease in two billion people estimates of the death toll and the number of people that will require hospitalisation are less precise (Kamps 2006). However, it has been estimated that a pandemic similar to the 1918 pandemic may lead to 10 million hospitalisations and 1.7 million deaths in the United States alone (Martinello 2007). Scenarios modelled on the mild pandemic of 1968, anticipate that there will be between 2 million and 7.4 million cases of influenza. However, if the death toll associated with the 1918 influenza virus is translated to the current world population of 6.5 billion, there could be 180 million to 360 million deaths globally (Table 8.1.1) (Osterholm 2005).

Table 8.1.1: Death toll in the 20th century pandemics and future projections Year Population Death toll per 100,000 people 1918 1.8 billion 50 million 2,777 1957 3.8 billion 1 million 26 1968 4.5 billion 1 million 27 Next 6.5 billion 1.7 - 180 million 26 - 2,777 Source: Kamps et al.(2006) – Influenza Report 2006 (www.InfluenzaReport.com).

Avian influenza (H5N1) virus poses the most likely pandemic threat (Poland 2006). The avian H5N1 strain has become endemic in wild waterfowl and in domestic poultry in many parts of Southeast Asia, and is spreading across Asia into Europe and Africa (Kamps 2006). Recent research has revealed that just 10 amino acid alterations in the polymerase proteins differentiate the 1918-19 influenza virus sequences from that of avian viruses, and that a number of the same changes have been identified in recently circulating, highly pathogenic H5N1 viruses (Taubenberger 2005). However, to date the H5N1 avian influenza remains largely a disease of birds. This is evident in the fact that despite the infection of tens of millions of poultry over large geographical areas for more than two years, fewer than 200 human cases have been confirmed by a laboratory (WHO Avian Influenza Fact Sheet, 2006). The first human cases of avian influenza in Hong Kong in 1997 coincided with outbreaks of highly pathogenic H5N1 avian influenza in poultry (Fleming 2005). Of the 18 people identified with H5N1 disease, six died (Martinello 2007). Although H5 antibodies were detected in healthcare workers and family members with contact, indicating infection with the virus, no cases of severe disease occurred (Kamps 2006). To date, episodes of avian influenza have occurred in individuals or communities with close links with poultry, but none has occurred where human-to-human transmission was implicated beyond doubt (Fleming 2005).

To date, H5N1 disease has predominantly affected children and young adults (WHO Avian Influenza Fact Sheet, 2006). Of 116 patients for whom demographical data had been published by the WHO (December 2003 until 9 February 2006), 50% were 16 years old or younger, 75% were younger than 30 years, and 90% were younger than 40 years old. Whether, and to what extent, genetic composition plays a role in the susceptibility and resistance to infection with H5N1 influenza virus remains unknown (Kamps 2006).

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The number of avian influenza reported cases and deaths in humans worldwide is presented in Figure 8.1.

Figure 8.1: Documented avian influenza infections in humans

Source: EHA Consulting Group, Incorporated: http://www.ehagroup.com/epidemiology/illnesses/avian-influenza.asp(Accessed 10/06/08)

As of May 30 2008, the mortality rate associated with avian influenza was as high as 63% (Table 8.1) with a total of 383 cases and 241 reported deaths.

5 Table 8.1: Cumulative number of confirmed human cases of avian influenza A (H5N1) reported to WHO (30 May 2008) 2003 2004 2005 2006 2007 2008 Total Country Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Azarbijan 0 0 0 0 0 0 8 5 0 0 0 0 8 5 Bangladesh 0 0 0 0 0 0 0 0 0 0 1 0 1 0 Cambodia 0 0 0 0 4 4 2 2 1 1 0 0 7 7 China 1 1 0 0 8 5 13 8 5 3 3 3 30 20 Djiboudi 0 0 0 0 0 0 1 0 0 0 0 0 1 0 Egypt 0 0 0 0 0 0 18 10 25 9 7 3 50 22 Indonesia 0 0 0 0 20 13 55 45 42 37 16 13 133 108 Iraq 0 0 0 0 0 0 3 2 0 0 0 0 3 2 Laos 0 0 0 0 0 0 0 0 2 2 0 0 2 2 Myanmar 0 0 0 0 0 0 0 0 1 0 0 0 1 0 Nigeria 0 0 0 0 0 0 0 0 1 1 0 0 1 1 Pakistan 0 0 0 0 0 0 0 0 1 1 0 0 1 1 Thailand 0 0 17 12 5 2 3 3 0 0 0 0 25 17 Turkey 0 0 0 0 0 0 12 4 0 0 0 0 12 4 Vietnam 3 3 29 20 61 19 0 0 8 5 5 5 106 52 Total 4 4 46 32 98 43 115 79 86 59 31 24 383 241 Source: Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. Available at: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_05_28/en/index.html World. Accessed 10/06/08.

8.2 Disease burden in specific populations Influenza and pneumonia comprise the sixth leading cause of death in the United States and the fifth leading cause among adults age 65 and over. The fatality rate from influenza begins to rise in mid-life and is highest among persons who have chronic medical conditions, such as chronic obstructive lung disease, cardiovascular disease, and diabetes mellitus (Zimmerman 2005). Compared to the general population, influenza-related mortality in aged care facilities is frequently high during seasonal influenza epidemics because they contain a highly condensed population of elderly with underlying chronic illnesses (Glezen 1987).

In the United States, each year on average there are approximately 226,000 primary influenza-related respiratory and circulatory hospitalisations. However, in more severe epidemics influenza-related respiratory and circulatory hospitalisations may exceed 400,000 (Thompson 2004). Studies of the elderly from England and the United States, suggest that peak hospitalisation and primary care consultation rates coincides with peak influenza activity. Influenza outbreaks in nursing homes are frequently reported, with high attack rates and fatality rates over 50% as a result of severe pneumonia. Acute respiratory infections are the major cause of hospitalization in those with underlying chronic medical conditions (Drinka 1990; Ahmed 1995).

It has been reported that the influenza-related hospitalisation rate for those with high-risk conditions is approximately 800-1900 per 100,000 whereas the rate for healthy children is approximately 186 -1038 per 100,000 (Neuzil 2000a; Neuzil 2000b). Neuzil et al. claim that for every 100 children, an annual average of 6 to 15 outpatient visits and 3 to 9 courses of antibiotics were attributable to influenza (Neuzil 2000b).

Children play a significant role in transmitting influenza by spreading the virus to family members and classmates at day care centres and schools. It has been claimed that most flu epidemics are spread by school-aged child (Elveback 1976). During the 1976-1977 influenza epidemics up to 37% of all enrolled school children were absent from school due to influenza infection (Glezen 1980). A study by Monto et al. (1993) found that children aged between 5- 14 years were approximately four times more likely to be infected with influenza than adults (Monto 1993). The high incidence of influenza in children has significant and widespread economic consequences (Stephenson 2002).

There are many complications associated with influenza, such as secondary bacterial pneumonia, worsening of chronic respiratory and cardiac diseases, sinusitis, and otitis media. The Tecumseh Community Health Study estimated that 13.8 million to 16 million influenza- related excess respiratory illnesses occur annually in persons younger than 20 years of age (Sullivan 1993). More recently, neurologic complications of influenza in children, including encephalopathy and death, have been widely reported (Zimmerman 2005).

8.3 Economic impact of seasonal and avian influenza Influenza continues to place a significant burden on society every year. The annual US direct costs of influenza are estimated to be between US$1-3 billion, but indirect costs including loss of earnings amount to $10-15 billion. In 1989 the cost of influenza activity in France was estimated to be €2.1 billion. Based on the 1997 German Sickness Funds, costs of influenza (mainly direct medical and indirect cost attributed to loss of productivity and absenteeism) were €1 billion (Stephenson 2002).

WHO EML – Final Report – Zanamivir

The CDC (United States Centers for Disease Control) estimated that the economic impact of an avian influenza pandemic could exceed US$160 billion (McFee 2007). A study conducted by the US Congressional Budget Office (CBO), and published on the 8th December 2005, examined the possible macroeconomic effects that an influenza pandemic would have on the United States (Congressional Budget Office, December 8, 2005). Under assumptions based on the 1918-19 influenza pandemic, this study estimated that the consequences of a severe pandemic in the United States could include 200 million infected people, 90 million clinically ill, and two million dead. To calculate the supply impact of a severe pandemic, this study assumed that 30% of all workers would become ill and 2.5% would die, with 30% of workers missing an average of three weeks of work, resulting in a 5% decrease in the gross domestic product (GDP). With an estimated 18-45 million people requiring outpatient care, the economic costs could total US$675 billion (Poland 2006; Congressional Budget Office, December 8, 2005). In general terms, McFee (2007) claims that an avian influenza pandemic would cause incalculable losses in life, animal and human, economic burdens ranging from losses in tourism to severe deprivation resulting from the impact on food supplies, commerce, trade, and worker availability.

8.4 Prophylaxis and treatment of avian influenza (H5N1) The most effective interventions reported to reduce influenza morbidity and mortality are vaccination and the use of antiviral drugs (Lazzari 2004). Although vaccines are the most effective way to reduce the impact of a pandemic, human H5N1 vaccines are a relatively new development and information on their safety, immunogenicity, and their protective effects is relatively limited (WHO 1-3 October 2007). However, on 21 February 2008, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant marketing authorisation for the pre-pandemic, split virion, inactivated, influenza vaccination Prepandrix™ (ATC Code J07BB02)(European Medicines Agency 2008). This decision by the European Medicines Agency (EMEA) means that the GlaxoSmithKline (GSK) Prepandrix™ is the first vaccine to receive a licence for pre-pandemic use in all 27- member European states. The approved indication for Prepandrix™ is: active immunisation against H5N1 subtype of influenza A virus (European Medicines Agency 2008). In the case of the antiviral drugs, there are two classes available to treat avian influenza: neuraminidase inhibitors (oseltamivir and zanamivir), and adamantanes (M-blockers - amantadine and rimantadine). Although these antiviral agents were developed for the treatment and prophylaxis of seasonal influenza, the H5N1 virus has developed resistance to amantadine and rimantadine. Therefore, it is important and timely, to examine the efficacy, safety, and cost-effectiveness of zanamivir in the treatment and prophylaxis of avian influenza in adults and children.

9. Treatment details (dosage regimen, duration, reference to existing WHO and other clinical guidelines, need for special diagnostic or treatment facilities and skills) 9.1 Dosage regimen and duration The recommended dose of zanamivir for the treatment of influenza in adults and paediatric patients (7 years of age and older) is 10 mg twice daily (approximately 12 hours apart) for 5 days. Treatment should be initiated within two days after symptom onset. Two doses should be taken on the first day of treatment whenever possible provided there is at least 2 hours between doses. On subsequent days, doses should be about 12 hours apart (e.g. morning and evening) at approximately the same time each day (Relenza® Product Information: GlaxoSmithKline, September 2007).

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The recommended dose of zanamivir for prophylaxis of influenza in adults and paediatric patients 5 years of age and older in a household setting is 10 mg once daily for 10 days. The dose should be administered at approximately the same time each day (Relenza® Product Information: GlaxoSmithKline, September 2007).

The recommended dose of zanamivir for prophylaxis of influenza in adults and adolescents in a community setting is 10 mg once daily for 28 days. The dose should be administered at approximately the same time each day (Relenza® Product Information: GlaxoSmithKline, September 2007).

9.2 Reference to existing WHO and other clinical guidelines WHO guidelines The guidelines which were initially published online by the WHO on May 20 2006, are based on the current situation with sporadic H5N1 human infections and household clusters and do not apply to a pandemic scenario.

Recommendations for treatment of patients with confirmed or strongly suspected human infection with the H5N1 virus

Where neuraminidase inhibitors are available: o Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation). The quality of evidence if considered on a continuum is lower for the use of zanamivir compared to oseltamivir. o Clinicians should not administer amantadine or rimantadine alone as a first- line treatment (strong recommendation). o Clinicians might administer a combination of a neuraminidase inhibitor and an M2 inhibitor if local surveillance data show that the H5N1 virus is known or likely to be susceptible (weak recommendation), but this should only be done in the context of prospective data collection.

Recommendations for chemoprophylaxis

Where neuraminidase inhibitors are available: o In high risk exposure groups, including pregnant women, oseltamivir should be administered as chemoprophylaxis, continuing for 7–10 days after the last exposure (strong recommendation); zanamivir could be used in the same way (strong recommendation) as an alternative. o In moderate risk exposure groups, including pregnant women, oseltamivir might be administered as chemoprophylaxis, continuing for 7-10 days after the last exposure (weak recommendation); zanamivir might be used in the same way (weak recommendation). o In low risk exposure groups, oseltamivir or zanamivir should probably not be administered for chemoprophylaxis (weak recommendation). Pregnant women in the low risk group should not receive oseltamivir or zanamivir for chemoprophylaxis (strong recommendation). o Amantadine or rimantadine should not be administered as chemoprophylaxis (strong recommendation).

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NICE guidelines • Zanamivir and oseltamivir are not recommended for the treatment of influenza in children or adults unless they are considered to be ‘at risk’. o ‘At-risk’ adults and children is defined for the purpose of this guidance as those who are in at least one of the following groups: o have chronic respiratory disease (including asthma and chronic obstructive pulmonary disease); o have significant cardiovascular disease (excluding people with hypertension only); o have chronic renal disease; o are immunocompromised; o have diabetes mellitus; o are 65 years of age or older.

9.3 Need for special diagnostic or treatment facilities and skills The clinical picture of influenza is non-specific. Influenza-like illness can be caused by many microbial agents other than influenza virus, such as adenovirus, parainfluenza viruses, coronavirus, Mycoplasma pneumoniae, Chlamydia pneumoniae, and beta-hemolytic streptococcus (Chin 2008).

The availability and use of influenza rapid diagnostic tests by laboratories and clinics have dramatically increased in recent years. Screening tests for influenza virus infection generally generate results within 30 minutes. Many factors should be considered when selecting a test, such as tests with high sensitivity and specificity will provide better positive and negative predictive values, and the types of specimens that provide the most accurate results (CDC 2006).

Although the specific diagnosis of influenza requires laboratory confirmation, epidemics caused by influenza A have certain distinctive epidemiologic features which are helpful for making an etiologic diagnosis. In the Northern Hemisphere, influenza outbreaks and epidemics typically occur between November and March, whereas in the Southern Hemisphere, influenza activity occurs between April and September. In tropical regions, influenza can occur throughout the year (Cox 2000). Typically an influenza epidemic disseminates throughout a community over a five to six week period. High attack rates of acute respiratory disease among school children and high mortality among the aged and debilitated are almost pathognomonic of influenza A (Chin 2008).

10. Summary of comparative effectiveness in a variety of clinical settings 10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) MEDLINE (via PubMed: 1950 to June 2007) and the Cochrane Library (Issue 2, 2007) were searched to identify systematic, critical, and narrative reviews, randomised clinical trials, health technology assessments (HTA), economic evaluations, in vitro studies, animal studies, and case series/reports in which zanamivir was the antiviral drug studied (either as a single agent or in combination with another antiviral therapy). The reference lists of identified trials, reviews, reports and guidelines were thoroughly searched for any potentially relevant studies. Experts in the field were also contacted to identify any unpublished studies or reports.

Information from any influenza strain believed to be potentially relevant to H5N1 in the

10 WHO EML – Final Report – Zanamivir animal and in vitro studies was included (i.e. the studies provided information on the likelihood of H5N1 resistance to antivirals). Studies employing computer-modelling techniques were not included because these types of studies were considered beyond the scope of this project. Where genetic analysis studies were identified from in vitro or animal searches, they were included only if the studies documented actual drug-resistance mutations in H5N1 virus. We limited inclusion of clinical trials to randomised controlled trials only.

To maximise the sensitivity for the retrieval of all potentially relevant studies, the electronic databases were initially searched using an unrestricted search strategy employing the exploded MeSH terms (exp Influenza, Human/; exp Oseltamivir/) and specific text-word terms including ‘oseltamivir’, ‘H5N1’, and ‘avian influenza.’ To restrict and improve the specificity of these searches the following terms were used: ‘systematic[sb]’, ‘economic’, ‘in vitro’, ‘animal’, and ‘case series.’ In the case of antiviral combination therapy, a summary of the search terms used to identify relevant studies is presented in Table 10.1.1.

Table 10.1.1: Treatment of H5N1 with antiviral combination therapy search strategy Source Study type Search terms (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed SR OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND systematic [sb ] (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed RCT OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND ((Clinical Trial[ptyp])) (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed in vitro OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND in vitro (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed animal OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) (Animals[Mesh:noexp]) (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed case OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND ((Humans[Mesh]) AND (Case Reports[ptyp])) (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine PubMed general OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) (oseltamivir or zanamivir) AND (amantadine or rimantadine) in Title, Abstract Cochrane SR or Keywords Study types: Cochrane reviews, Other reviews (oseltamivir or zanamivir) AND (amantadine or rimantadine) in Title, Abstract Cochrane CCT or Keywords. Study type: clinical trials Abbreviations: SR = systematic review; RCT = randomised controlled trial; CCT = controlled clinical trial.

10.2 Summary of available estimates of comparative effectiveness 10.2.1 Zanamivir in the treatment of seasonal influenza Duration of symptoms - adults In the systematic review conducted by Turner et al. (2003), the results of the meta-analysis showed that in the ITT ‘healthy’ subgroup (patients aged 12-65 years) the time to alleviation of symptoms was significantly reduced in the zanamivir group compared with the placebo group (Weighted median difference [WMD] -0.78 days, 95% CI -1.31 to -0.26 days). A statistically significant difference was also observed in the ‘healthy’ subgroup of patients (aged 12-65 years) who were influenza positive (WMD -1.26 days, 95% CI -1.93 to -0.59 days); the ITT ‘high-risk’ (with concomitant disease) subgroup of patients aged ≥ 12 years

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(WMD -0.93 days, 95% CI -1.90 to 0.05 days), and in the influenza positive ‘high-risk’ subgroup of patients aged ≥ 12 years (WMD -1.90 days, 95% CI -3.08 to -0.90 days). Zanamivir significantly reduced the time to alleviated symptoms in all patient subgroups except for the ITT ‘high-risk’ adults where it was noted that trial NAI30008 dominated the meta-analysis since this trial recruited only ‘high-risk’ patients. The results of the analyses conducted by Turner et al. (2003) are presented in Appendix B. A summary of the studies included in the review by Turner et al. (2003) is presented in Appendix D.

The systematic review by Jefferson et al. (2006) examined the efficacy of inhaled zanamivir treatment versus placebo in adults. The pooled hazard ratio for time to alleviation of symptoms (TTAS) in the ITT population was 1.24 (95% CI 1.13 to 1.36), indicating that the zanamivir treated group are 24% more likely to have their symptoms alleviated than the placebo group by a given time point. For influenza positive patients, zanamivir treated patients were 33% more likely to have their symptoms alleviated compared to placebo (HR 1.33, 95% CI 1.29 to 1.37). The results of the analyses conducted by Jefferson et al. (2006) are presented in Appendix C.

Duration of symptoms - children The systematic review by Matheson et al. (2007) examined the role of the neuraminidase inhibitors in the prevention and treatment of influenza illness in children (≤ 12 years). Only one trial reported data for the time to resolution of illness (NA130009). The results of this trial showed that zanamivir significantly reduced the median duration of influenza-like illness by 24% (1.25 days) in children with laboratory-confirmed influenza (P<0.001) and by 10% (0.5 days) in the ITT population (P=0.011). No data were available for ‘at risk’ (asthmatic) children. A summary of the results of the study by Matheson et al. (2007) is presented in Appendix E.

Turner et al. (2003) examined the efficacy of zanamivir in children aged 5-12 years. For children in the ‘healthy’ subgroup, there was a statistically significant difference in the time to alleviation of symptoms in the zanamivir group compared with the placebo of -1.0 days (95% CI -1.5 to -0.5 days). For children in the ‘high-risk’ subgroup, a non-significant difference of -2.0 days (95% CI -6.9 to 2.9 days) was observed. Turner et al. (2003) suggested that due to the small number of individuals in the ‘high-risk’ subgroup analysis there is considerable uncertainty in the estimated treatment difference. For influenza positive children in the ‘healthy’ subgroup, the difference in the time to alleviation of symptoms in the zanamivir group compared with the placebo group of -1.0 days was statistically significant (95% CI -1.6 to -0.4 days). For influenza positive children in the ‘high-risk’ subgroup, a non- significant difference of -3.8 days (95% CI -7.6 to 0.1) was observed.

Zanamivir may be more effective at reducing the duration of influenza and influenza-like symptoms in adults and children up to 12 years of age, compared to placebo.

Time to return to normal activities - adults The systematic review conducted by Jefferson et al. (2006) found that zanamivir significantly increased the rate of return to normal activity. For the ITT population the pooled hazard ratio for zanamivir was 1.28 (95% CI 1.13 to 1.45) compared to placebo. In the case of influenza- positive patients (confirmed influenza cases) the pooled hazard ratio for zanamivir was 1.17 (95% CI 1.00 to 1.37) compared to placebo.

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In the random effects meta-analysis performed by Turner et al. (2003), in the ‘healthy’ ITT subgroup (aged 12-65 years) there was no statistically significant difference between zanamivir and placebo in the time to return to normal activities (WMD -0.51 days, 95% CI - 1.04 to 0.02). In the ‘healthy’ subgroup of patients with confirmed influenza positive, there was statistically significant difference between zanamivir and placebo of -0.46 days (95% CI -0.90 to -0.02 days). Differences in the ITT ‘high-risk’ and influenza positive ‘high-risk’ subgroups were not statistically significant, with a difference of 0.09 days (95% CI -0.95 to 0.78) and 0.20 days (95% CI -1.91 to 0.79), respectively.

Time to return to normal activities - children Matheson et al. (2007) report that in children with laboratory-confirmed influenza zanamivir significantly reduced the median time to return to normal activity by one day compared with placebo (P=0.022). A statistically significant reduction was also observed in the ITT population (P=0.019). However, data were only available from one trial (NAI30009).

Turner et al. (2003) report that in children aged 5-12 years zanamivir did not significantly reduce the time to return to normal activities compared to placebo in the ITT ‘healthy’ subgroup or the ITT ‘high-risk’ subgroup (WMD -0.5 days, 95% CI -1.3 to 0.3 days; WMD - 1.0 days, 95% CI -3.5 to 1.5 days), respectively.

In the influenza positive patients (confirmed influenza cases), the use of zanamivir did not significantly reduce the time to return to normal activities compared to placebo in the ITT ‘healthy’ subgroup (WMD -0.5 days, 95% CI -1.4 to 0.4) or in the ‘high-risk’ subgroup (WMD -2.5 days, 95% CI -4.4 to -0.6). Although there appeared to some evidence that zanamivir was more effective than placebo in reducing the time to return to normal activities in influenza positive ‘high-risk’ patients the analysis was based on the results of one trial with a subgroup analysis of 22 patients.

In summary, zanamivir may be more effective at reducing the time taken to alleviate symptoms and return to normal activities in adults and children compared with placebo.

Prevention of complications - adults Although Jefferson et al. (2006) report that all types of complication tended to be lower in zanamivir treated patients compared to placebo, data were only available from one study (Makela 2000) and the types of complication were not clearly defined. The trial by Makela et al. (2000) reported a lower incidence of complications of influenza in the zanamivir group compared to placebo. This difference was statistically significant for the ITT population with an odds ratio of 0.50 (95% CI 0.32 to 0.74). Zanamivir also significantly reduced complications in people with influenza-like illness with an odds ratio of 0.59 (95% CI 0.37 to 0.95). A similar trend was seen in the influenza-positive population, but the result did not reach statistical significance (OR 0.64, 95% CI 0.38 to 1.08).

In the systematic review by Turner et al. (2003), two previous pooled analyses of antibiotic use in patients treated with zanamivir were presented. Monto et al. (1999c) performed a pooled analysis by combining the number of individuals requiring antibiotics for complications from for each arm of eight trials. The use of antibiotics for the treatment of complications in the zanamivir group was statistically significantly reduced in ITT population (OR 0.71, 95% CI 0.56 to 0.90) and in the influenza positive ‘healthy’ subgroup (OR 0.70, 95% CI 0.52 to 0.96). Lalezari et al. (2001) performed a similar analysis focusing on ‘high- risk’ individuals including both children and adults. The associated use of antibiotics was also

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lower in zanamivir recipients, but the difference did not reach statistical significance (OR 0.57, 95% CI 0.31 to 1.03 for the ITT ‘high-risk’ population; OR 0.49, 95% CI 0.23 to 1.04 for the influenza positive ‘high-risk’ population).

Prevention of complications - children Trial NAI30009 showed that the use of zanamivir in children with laboratory-confirmed influenza reduced the risk of complications by a 30% reduced the risk of requiring antibiotics by a relative 20%. However these reductions were not statistically significant. No data were available for the ITT population (Matheson 2007).

Based on the ITT population in trial NAI30009, of the children treated with zanamivir less than 1% reported asthma exacerbations, compared with 1% treated with placebo (Turner 2003). It should be noted that only 36 children entered the trial with concurrent chronic respiratory conditions.

In summary, compared with placebo, zanamivir may be more effective at reducing the incidence of complications associated with influenza and the use of antibiotics in adults and children. However, there is limited data.

Zanamivir and rimantadine in the treatment of seasonal influenza – combination therapy Ison et al. (2003) conducted a multi-centre, randomised, placebo-controlled, double-blinded trial of nebulized zanamivir and oral rimantadine treatment of influenza infection in 41 hospitalised patients during two influenza seasons (January 1998-April 1999). The primary goals of the study were to assess the safety and antiviral efficacy of zanamivir in patients hospitalized with serious influenza infections. Male or female patients 10 years of age or older that were hospitalized with influenza A or B virus infection with symptoms of 4 days duration or less were eligible for participation. Prior to drug administration, influenza virus infection was established by conventional viral cultures and/or by detection of influenza viral antigens or nucleic acids in respiratory secretions.

Zanamivir 16 mg (as 16 mg/ml in normal saline) or placebo (normal saline) was administered by nebuliser with a mouthpiece attachment at an airflow rate of 6–7 litres/minute and completed within 10 minutes. Doses were given four times a day for 5 days. No dosage adjustment was made for renal or hepatic impairment. Patients discharged early were continued on the same treatment schedule with dry powder-inhaled zanamivir plus rimantadine or placebo plus rimantadine under blinded conditions to complete the 5-day course. A computer-generated block randomisation scheme was used and the sites were provided with the study drug and randomisation envelopes. The research pharmacist at each site, who was unblinded, prepared the study medication for dispensing in a blinded fashion to the patient care area. The investigators, nursing and respiratory therapy staff remained blinded. All patients with influenza A virus infection (40/41) also received rimantadine orally for 5 days. For patients 10 to 64 years of age, the dose of rimantadine was 100 mg twice daily. For persons with severe hepatic dysfunction or renal failure (CrCl ≤10 ml/min) and for persons 65 years of age or older, the dose was reduced to 100 mg once daily.

Of 41 infected patients enrolled in the trial two were negative for influenza by culture and serology (one in each trial arm) and were excluded from the efficacy analysis. Sixty-one percent of patients completed the study and received treatment for 5 days and follow-up at day 28 (11 zanamivir plus rimantadine and 14 placebo plus rimantadine treated patients). Six

14 WHO EML – Final Report – Zanamivir

patients withdrew from the study without completing 5 days of therapy, three patients died, and five patients were lost to follow-up.

Ison et al. (2003) found that that nebulised zanamivir plus rimantadine did not significantly reduce the rate of pharyngeal viral shedding compared to placebo plus rimantadine, although there was a tendency towards shorter time to cessation of viral shedding in the zanamivir plus rimantadine arm (P=0.37). The median time to no pharyngeal viral shedding was 4 days (95% CI 2 to 5 days) in the placebo plus rimantadine group and 2 days (95% CI 2 to 5 days) in the zanamivir plus rimantadine group. No significant differences were observed between the groups in pharyngeal or nasal virus titres (median titres day 1, 2.75 log10/ml vs. 2.21 log10/ml; median titres day 3, 0.83 log10/ml vs. 0.42 log10/ml; and median titres day 5, 0 log10/ml vs. 0 log10/ml, placebo + rimantadine and zanamivir + rimantadine, respectively).

Ison et al. (2003) report that on treatment day 3, no statistically significant differences were observed in the proportion of patients still hospitalised (95% vs. 94%), receiving supplemental oxygen (65% vs. 62%) or having resumed full ambulation. A higher proportion of patients in the zanamivir plus rimantadine group reported no/mild cough on day 3 of treatment (94% vs. 55%, P=0.01). There are no significant differences between the two groups on other clinical outcomes on day 3 of treatment or at follow-up on day 28.

Ison et al. (2003) found that all 43 viral isolates were sensitive to zanamivir in the neuraminidase-inhibition assay. The 43 viral isolates were also screened for M2 inhibitor resistance. Three resistant isolates were identified by ELISA, all of which were from patients treated with rimantadine monotherapy.

10.2.2 Zanamivir in the prophylaxis of seasonal influenza Prevention of symptoms Jefferson et al. (2006) examined the efficacy of zanamivir in the prophylaxis of influenza A and B. Compared to placebo, inhaled zanamivir 10 mg daily had no effect on reducing the risk of influenza-like illness (RR 1.51, 95% CI 0.77 to 2.95). Inhaled zanamivir 10 mg daily reduced the risk of symptomatic influenza by a relative 62% (RR 0.38, 95% CI 0.17 to 0.85). The addition of an intranasal dose did not seem to significantly enhance the prophylactic activity of zanamivir (RR 0.22, 95% CI 0.08 to 0.58). However, this result was based on a single study. Zanamivir conferred a 33% protective effect against symptomatic and asymptomatic influenza (RR 0.67, 95% CI 0.50 to 0.91), but this was based on a single study. The addition of an intranasal dose of zanamivir did not appear to enhance its activity (RR 0.77, 95% CI 0.38 to 1.56). However, zanamivir was found to have no effect against influenza-like illness (RR 1.51, 95% CI 0.77 to 2.95), compared with placebo. The results of the analyses conducted by Jefferson et al. (2006) are presented in Appendix C.

Turner et al. (2003) report that the results from trial NAIA2010, where outbreak prophylaxis with zanamivir was studied in the elderly in a residential setting, were inconclusive as only 2% of individuals experienced the outcome of interest. Turner et al. (2003) report that the results from trial NAIA3005 demonstrate convincing evidence that prophylactic zanamivir reduces the chance of an individual contracting influenza by 69% (95% CI 36% to 86%). The results of the analyses conducted by Turner et al. (2003) are presented in Appendix B.

In summary, compared with placebo, orally inhaled zanamivir appears to be more effective than placebo at preventing symptoms of influenza, but not of influenza-like illness.

15 WHO EML – Final Report – Zanamivir

Prevention of infection Jefferson et al. (2006) report that only one trial of zanamivir use in otherwise healthy adults to prevent influenza infection. The results of this trial failed to demonstrate the superiority of zanamivir in the prevention of infection (asymptomatic) compared to placebo (RR 1.63, 95% CI 0.99 to 2.67). There was no statistically significant difference in the rates of influenza infection between zanamivir and placebo.

Post-exposure prophylaxis (PEP) Jefferson et al. (2006) identified two trials which randomised contacts to receive treatment or placebo once a household member had reported influenza-like illness symptoms (index case). The first of these trials found that 10 mg of orally inhaled zanamivir significantly reduced symptomatic infection by 81% (95% CI 64% to 90%) in households and 82% in individuals. Zanamivir significantly reduced the duration of illness by 1.5 days, and no viral resistance was reported. The second trial found that zanamivir significantly reduced influenza by 79% (95% CI 57% to 89%) and influenza-like illness by 72% in contacts (95% CI 42% to 87%) compared with placebo. Zanamivir also shortened the duration of symptoms by 2.5 days.

Turner et al. (2003) analysed the data from two trials. The results of the meta-analysis showed zanamivir had a significant prophylactic effect in ITT population (OR 0.19, 95% CI 0.09 to 0.38), although the duration of zanamivir treatment varied in the two trials (5 days vs. 10 days). Post-exposure prophylaxis with zanamivir in patients with laboratory-confirmed influenza also showed a similar result to the ITT population with an OR of 0.18 (95% CI 0.07 to 0.43).

In summary, compared with placebo, post-exposure prophylaxis with zanamivir appeared to be more effective at reducing the duration and number of cases of symptomatic influenza and influenza-like illness in households and in individuals.

10.2.3 Treatment of avian influenza (H5N1) in animals – single agent therapy Survival after treatment with zanamivir Two studies of zanamivir treatment in animals fulfilled the inclusion criteria. These trials administered intranasal zanamivir. The result of these two studies is summarised in Table 10.2.3.1.

Gubareva et al. (1998) examined the effect of zanamivir on influenza infection with A/HongKong/156/97 in a mouse model. To detect differences between the infected and control groups, all mice were infected with 3 MLD50 of the virus. To assess morbidity and mortality Gubareva et al. first inoculated groups of mice with the A/HongKong/156/97 virus and then intra-nasally administered either zanamivir (25 mg/kg) or sterile distilled water. Mice treated with zanamivir had a mean survival day (MSD) of 11.3 compared to a MSD of 7.9 in the control group. In the second experiment, groups of 10 mice received prophylaxis and treatment with zanamivir (2.5 mg/kg or 25 mg/kg) or sterile water. Mice receiving prophylaxis and treatment with 25 mg/kg/day of zanamivir had a longer MSD and more survivors than did controls (MSD 16.1 vs. 8.7; 9/10 vs. 1/10 survivors; respectively). Mice receiving the lower dose of zanamivir (2.5 mg/kg/day) had a MSD of 14.1 and a survival rate of 60% (6/10).

Leneva et al. (2001) inoculated female BALD/c mice by intranasal administration of A/HK/156/97 (H5N1) virus in a volume of 100 ml. Zanamivir was administered intra-nasally twice daily for 5 days, with the first dose being given four hours before the mice were

16 WHO EML – Final Report – Zanamivir

exposed to virus. Groups of 5 or 10 mice were used for each dose. Leneva et al. found that at doses of 50 mg/kg, zanamivir completely protected mice infected with A/HK/156/97 (H5N1) from death, and at doses of 10 mg/kg, zanamivir increased the number of survivors (zanamivir = 5/5 vs. control = 0/4) and mean survival time to 10.6 days, compared to 6.0 days for the control group of mice. When doses of 1 mg/kg were used, weight loss and mean survival time for the treatment group did not differ from those of the control groups.

Table 10.2.3.1: Summary of results – survival after treatment with zanamivir Study Virus Model Treatment Regimen Results Conclusion Gubareva A/HK/156/97 Mouse 25 24 hrs pre- T=9/10 Increased 1998 (H5N1) mg/kg/day infection, 4 C=1/10 survival hrs pre- infection, twice daily for 5 days Leneva A/HK/156/97 Mouse 50 4 hrs pre- T=5/5 Completely 2001 (H5N1) mg/kg/day infection, C=0/4 protected twice daily for 5 days Abbreviations: T = treatment; C = control

Virus titre in the lung of animals treated with zanamivir Two studies of zanamivir treatment in animals fulfilled the inclusion criteria. These trials administered intranasal zanamivir. The result of these two studies is summarised in Table 10.2.3.2.

Gubareva et al. (1998) investigated the systemic spread of the A/HongKong/156/97 (H5N1) virus through the bloodstream by measuring virus titres in the lung, blood, and brain, after infection with A/HongKong/156/97 (H5N1) in groups of eight mice. Virus was found in the blood at an average TCID50 of 3.9 log10 on day 3 after infection and 3.6 on day 6 after infection, around a 3 log lower concentration than in the lungs, where the average TCID50 was 6.2 log10 on day 3 after infection and 6.5 log10 on day 6 after infection. Gubareva et al. claim that the experiments conducted during their study indicate that the A/HongKong/156/97 (H5N1) virus can spread systemically through the bloodstream and can be found in brain tissue without prior adaptation to the mouse host, although not with the full virulence displayed in the lungs.

Leneva et al. (2001) examined the pathogenicity of the avian viruses by comparing their levels of growth in the lungs and brains of infected mice. Mice were infected with 5 MLD50s of different viruses. The titres of virus in the lungs and brains were then determined. On day 1, mice infected with A/HK/156/97 (H5N1) virus had high titres in the lungs (6.0 to 6.5 log10 EID50) and reached a peak on day 3 (log10 8.5). High titres continued to be present through to day 5 (7.5 log10 EID50). In mice treated with 10 or 50 mg/kg/day of zanamivir, virus titre levels in the lungs was statistically significantly lower than in the control mice.

17 WHO EML – Final Report – Zanamivir

Table 10.2.3.2: Summary of results – virus titre in the lung of animals treated with zanamivir Study Virus Model Treatment Regimen Results Conclusion Gubareva A/HK/156/97 Mouse 25 24 hrs pre- T=5.7* Reduced titre 1998 (H5N1) mg/kg/day infection, 4 C=7.2* hrs pre- infection, twice daily for 5 days Leneva A/HK/156/97 Mouse 10-50 4 hrs pre- T=reduced† Reduced titre 2001 (H5N1) mg/kg/day infection, C=0 twice daily for 5 days Abbreviations: T = treatment; C = control * Log10 TCID50/ml on day 5 † Shown graphically for a range of concentrations of zanamivir (0-100µm)

Virus titre in the brain of animals treated with zanamivir Only one study of zanamivir in the treatment of animals fulfilled the inclusion criteria. This trial administered intranasal zanamivir. The results of this study is summarised in Table 10.2.3.3.

Leneva et al. (2001) found that in the brains of mice infected with A/HK/156/97 (H5N1) and treated with different doses of zanamivir virus was not detected in the brain after treatment with 1 mg/kg, 10 mg/kg, or 50 mg/kg of zanamivir on any day after infection.

Table 10.2.3.3: Summary of results – virus titre in the brain of animals treated with zanamivir Study Virus Model Treatment Regimen Results Conclusion Leneva A/HK/156/97 Mouse 1 mg/kg/day 4 hrs pre- T=not Prevented 2001 (H5N1) infection, detected spread to twice daily C=0† brain for 5 days Abbreviations: T = treatment; C = control † Data not shown

Virus titre levels obtained from nasal wash samples of animals treated with zanamivir Only one study of zanamivir in the treatment of animals fulfilled the inclusion criteria. This trial administered intranasal zanamivir. The results of this study is summarised in Table 10.2.3.4.

Le et al. (2005) assessed the growth of a highly oseltamivir-resistant viral clone of A/Hanoi/30408/2005 (H274Y, clone 9) and of an oseltamivir-sensitive clone (H274, clone 7) in ferrets. Viral titres were higher in animals infected with the oseltamivir-sensitive virus (P=0.000099). Oseltamivir treatment reduced viral titres in animals infected with the drug sensitive virus (P=0.048), but not in animals infected with the resistant virus (P=0.23). However, all of the viral clones, including those highly resistant to oseltamivir, were sensitive to zanamivir (IC50, 0.5–3.1 nM). Le et al. found that zanamivir treatment reduced viral titres in animals infected with virus that was oseltamivir-sensitive (P=0.0000019) or oseltamivir- resistant (P=0.018).

18 WHO EML – Final Report – Zanamivir

Table 10.2.3.4: Summary of results – virus titre (nasal wash samples) measured in one study Study Virus Model Treatment Regimen Results Conclusion Le 2005 A/Hanoi/30408 Ferret 5 mg/kg/day 2 hrs post- T=reduced Zanamivir (oseltamivir infection, C=0 reduced viral resistant stain) twice daily titre in for 5 days oseltamivir- resistant strain* Abbreviations: T = treatment; C = control * Quality of effect measurement: Data is from a brief communication in Nature, some details were not clear. Results are based on isolation of oseltamivir-resistant (either high resistance or low resistance) and oseltamivir-sensitive strains of virus from a single patient.

Virus resistance in animals Two studies reported virus resistance in animals treated with antiviral agents. The results of these studies is summarised in Table 10.2.3.5.

Gubareva et al. (1998) report that virus isolated from zanamivir-treated mice at the end of therapy did not differ from stock virus in NA inhibition or plaque reduction assays. However, parallel experiments with rimantadine demonstrated rapid emergence of drug-resistant mutants.

Leneva et al. (2001) report that on day 7 after treatment with 50 mg/kg of zanamivir, the residual virus in the lungs of mice infected with A/HK/156/97 (H5N1), A/Teal/HK/W312/97 (H6N1), and A/Quail/HK/G1/97 (H9N2) (P3) was examined for sensitivity to zanamivir by both ELISA and NA inhibition assay. Leneva et al. found that each of the residual viruses examined was as sensitive to zanamivir as the original virus. These results suggest the viruses were not resistant to zanamivir.

Table 10.2.3.5: Summary of results – resistance in animals treated with zanamivir Study Virus Model Treatment Regimen Virus resistant after trial Gubareva A/HK/156/97 Mouse 25 mg/kg/day 24 hrs pre-infection, 4 Not resistant 1998 (H5N1) hrs pre-infection, twice daily for 5 days Leneva 2001 A/HK/156/97 Mouse 50 mg/kg/day 4 hrs pre-infection, Not resistant (H5N1) twice daily for 5 days

10.2.4 In vitro evidence of treatment for human and avian influenza (H5N1) Of the studies identified in the literature search, four fulfilled the inclusion criteria and provided in vitro evidence of zanamivir treatment for human and avian influenza (H5N1). A summary of the results from the included in vitro studies is presented in Appendix F.

Gubareva et al. (1998) reported that in neuraminidase (NA) inhibition assays, the NA of A/HongKong/156/97 was highly sensitive to zanamivir, with an IC50 of 1 nM (0.3 ng/mL). Gubareva et al. then assessed the effect of zanamivir on virus release during replication by a plaque reduction assay on MDCK cell monolayers. The IC50 for plaque size was 1 nM (0.3 ng/mL), and only “pinpoint” plaques were observed at 10 nM (3.0 ng/mL). Gubareva et al. claimed that this result demonstrated that A/HongKong/156/97 is more sensitive to the effects of zanamivir than are highly virulent chicken viruses previously studied.

Leneva et al. (2001) found that zanamivir inhibited the replication of A/Quail/HK/G1/97 (H9N2), A/Chicken/HK/G9/97 (H9N2), and A/Teal/HK/W312/97 (H6N1) in MDCK cells, 19 WHO EML – Final Report – Zanamivir

and the level of inhibition increased with increasing concentration. The mean EC50 were similar for all of the viruses tested and ranged from 8.5 to 14.0 mM. Leneva et al. also estimated the efficacies of zanamivir against the H6N1 and H9N2 viruses in NA inhibition tests. The NA inhibition assays demonstrated that zanamivir efficiently inhibited the enzyme activities of the H6N1 and H9N2 viruses. The IC50 were 5.0 nM against A/HK/156/97 (H5N1), 7±1 nM against A/Quail/HK/G1/97 (H9N2), 10±2 nM against A/CK/HK/ G9/97 (H9N2), and 7.5±2.5 nM against A/Teal/HK/W312/97. Therefore, zanamivir inhibited both NA activity and virus replication in MDCK cells for each virus, with the levels of inhibition for the different viruses being comparable.

Sidwell et al. (2007) conducted a study to ascertain the efficacy of T-705 (6-fluoro-3- hydroxy-2-pyrazinecarboxamide), oseltamivir carboxylate, zanamivir, and ribavirin against the avian influenza A (H5N1) virus both in vitro and in a mouse model. The following viruses were studied: influenza A/Duck/MN/1525/81 and A/Gull/PA/4175/83 (gull/PA) (H5N1), influenza A/Hong Kong/213/2003 × Ann Arbor/6/60 and A/Vietnam/1203/04 × Ann Arbor/6/60. Sidwell et al. found that oseltamivir carboxylate inhibited viral replication in all viruses but higher concentrations were required for A/Duck/MN/1525/81 and A/Gull/PA/4175/83 viruses. However, the experimental compound T-705 was less potent in reducing viral yield than both the neuraminidase inhibitors but more so than ribavirin.

Smee et al. (2001) studied the influenza virus neuraminidase inhibitory effects of a novel series of cyclopentane derivatives designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923. These compounds were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells. Inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC50) determined. Overall, zanamivir and oseltamivir carboxylate were slightly less potent (usually threefold or less) than the cyclopentane derivatives against the H1N1 viruses. The activities of zanamivir and oseltamivir carboxylate were similar against 12 influenza A (H3N2) strains, with 50% inhibition at 0.65 µM or less. Against two strains of influenza A (H5N1) virus zanamivir and oseltamivir carboxylate were 10-fold less potent (0.2 to 0.26 µM) than the cyclopentane derivatives but were still highly active inhibitors of these viruses. Zanamivir and oseltamivir carboxylate were as potent as the cyclopentane derivatives against the influenza B virus strains.

10.2.5 Resistance evaluations by in vitro study and/or sequence data Of the studies identified in the literature search two fulfilled the inclusion criteria. A summary of the results from the included in vitro studies is presented in Appendix F.

McKimm-Breschkin et al. (2003) established the baseline susceptibilities prior to and shortly after the introduction of the NA inhibitors (zanamivir, oseltamivir carboxylate, oseltamivir phosphate) by testing 1,054 clinical influenza isolates (influenza A virus subtypes N1 and N2, and influenza B) recovered from 1996 to 1999. Susceptibilities were determined by enzyme inhibition assays with chemiluminescent or fluorescent substrates with known NA inhibitor- resistant viruses as controls. Viruses selected for screening were representative of the major strains circulating worldwide and were in proportion to the virus subtypes circulating in different regions of the world during that period: 139 influenza A virus subtype N1 isolates, 767 influenza A virus subtype N2 isolates, and 148 influenza B virus isolates. McKimm- Breschkin et al. found that the N2 viruses were generally more sensitive to oseltamivir in both assays, with mean IC50s of 0.62 and 0.43 µM by the chemiluminescent and fluorescent 20 WHO EML – Final Report – Zanamivir

assays, respectively, whereas the mean IC50s of zanamivir were 2.17 and 1.48 µM, respectively. The N1 viruses were slightly more sensitive to zanamivir, with mean zanamivir IC50s of 0.61 and 0.92 µM by the chemiluminescent and fluorescent assays, respectively, whereas the mean oseltamivir IC50s were 0.92 and 1.54 µM, respectively. For influenza B viruses the mean IC50s of zanamivir were approximately twofold lower than those of oseltamivir carboxylate by the chemiluminescent assay (2.57 and 5.21 µM, respectively) and nearly sixfold lower than those of oseltamivir carboxylate by the fluorescent assay (2.02 and 12.46 µM, respectively). Thus, the influenza B viruses had lower levels of sensitivity to oseltamivir by the fluorescent assay than by the chemiluminescent assay but by both assays had reduced susceptibilities to both drugs compared to the susceptibilities of the N1 and N2 viruses. Based on the results of their study McKimm-Breschkin et al. concluded that recently circulating human influenza A and B viruses, collected before introduction of the NA inhibitors into clinical use, were all susceptible to both zanamivir and oseltamivir carboxylate and that, in contrast to the M2 inhibitors (amantadine and rimantadine), there was no evidence for naturally occurring resistance.

Hurt et al. (2004) analysed human influenza viruses (influenza A strains H1N1, H1N2, H3N2 and influenza B strains) isolated from Australasia (Australia and New Zealand) and South East Asia to determine their sensitivity to the NA inhibitor drugs zanamivir and oseltamivir. A total of 532 strains isolated between 1998 and 2002 were tested using a fluorescence-based assay to measure the relative inhibition of NA activity over a range of drug concentrations. Hurt et al. found that based on median IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were more sensitive to both the NA inhibitors than were influenza B strains. Influenza A viruses with a N1 subtype and influenza B strains both demonstrated a greater sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A strains with a N2 subtype were more susceptible to oseltamivir carboxylate. For each of the neuraminidase types, IC50 values for viruses from Australasia and South East Asia were found to be comparable. Hurt et al. concluded that the use of the NA inhibitors did not appear to have a significant impact on the susceptibility of the viruses tested to zanamivir or oseltamivir carboxylate.

11. Summary of comparative evidence on safety 11.1 Description of adverse effects/reactions Matheson et al. (2007) identified one trial (NA130009) that reported adverse event data. The results of this trial showed that in the ITT population there was no significant difference in the rate of adverse events in children treated with zanamivir compared to placebo. Additional information provided from children without acute influenza-like illness showed that nasal symptoms, cough and throat/tonsil discomfort and pain were more frequently reported with zanamivir than placebo. In addition, in a subset of children with chronic respiratory disease, lower respiratory adverse events (asthma, cough or viral respiratory infections which could include influenza-like symptoms) were reported more frequently in zanamivir treated children than placebo (100% vs. 41.7%).

Gravenstein et al. (2001) reported that while treating participants at high-risk of influenza with zanamivir, the pattern and incidence of adverse events were similar to that identified in otherwise healthy individuals, and similar to placebo. The ‘high-risk’ population was defined as being ≥65 years of age, or with chronic respiratory disease (including asthma requiring regular medication and chronic obstructive pulmonary disease), significant cardiovascular

21 WHO EML – Final Report – Zanamivir disease (excluding hypertension alone), diabetes mellitus and those who were immunocompromised.

Jefferson et al. (2006) claimed that zanamivir was not associated with any adverse event when used in the treatment of influenza in healthy adults. However, this may be due to the difficulty in separating adverse events from certain complications of influenza and the relatively small denominators in the analysis.

Zanamivir is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) given that serious cases of bronchospasm, including fatalities, have been reported.

A summary of adverse events reported in the systematic reviews by Matheson et al. (2007), Turner et al. (2003), and Jefferson et al. (2006) is displayed in Tables 11.1 and 11.2.

Table 11.1: Summary of adverse events reported in the systematic reviews Trials Adverse events Zanamivir Placebo Matheson NAI30009 N=224 N=247 (2007) Nausea <1% 2% Vomiting 3% 3% Diarrhoea 1% 2% ID not N=132 N=145 reported Nasal symptoms 20% 9% Cough 16% 8% Throat/tonsil discomfort & pain 11% 6% Subset with chronic respiratory disease Nasal symptoms, 7/7 (100%) 5/12 (41.7%) cough, throat/tonsil discomfort & pain Turner NAIA30010 Nasal symptoms, 30/577 (5%) 27/581 (5%) (2003) NAIA2009 gastrointestinal 27/144 (19%) 23/144 (17%) NAIA3005 symptoms, throat irritation, fever and cough 27/544 (5%) 30/533 (5%) Pooled* Asthma, cough or viral respiratory 7.5% 7.8% infections (95% CI 6.2%, 9.2%) (95% CI 6.4%, 9.7%) * Data were pooled for each arm of the trials separately on the log odds scale rather using the log OR. Pooled result converted to the percentage scale for ease of interpretation.

22 Table 11.2: Summary of adverse events reported in Jefferson et al. (2006) Outcome Trials Adverse events Zanamivir Weight (%) OR (95% CI)* Jefferson Cough MIST 1998 9/227 (4.0%) 14/228 (6.1%) 67.3 0.63 (0.27, 1.49) (2006) Puhakka 2003 3/293 (1.0%) 0/295 (0.0%) 32.7 7.12 (0.37, 138.46) Total 12/520 (2.3%) 14/523 (2.7%) 100.0 1.40 (0.14, 13.49) Headache Matsumoto 1999 2/77 (2.6%) 0/39 (0.0%) 7.1 2.62 (0.12, 55.83) Monto 1999b 14/814 (1.7%) 9/422 (2.1%) 92.9 0.80 (0.34, 1.87) Total 16/891 (1.8%) 9/461 (2.0%) 100.0 0.87 (0.39, 1.97) Diarrhoea MIST 1998 2/227 (0.9%) 9/228 (3.9%) 17.6 0.22 (0.05, 1.01) Matsumoto 1999 2/77 (2.6%) 2/39 (5.1%) 11.6 0.49 (0.07, 3.64) Monto 1999b 27/834 (3.2%) 11/422 (2.6%) 43.9 1.25 (0.61, 2.55) Puhakka 2003 6/293 (2.0%) 6/295 (2.0%) 26.8 1.01 (0.32, 3.16) Total 37/1431 (2.6%) 28/984 (2.8%) 100.0 0.78 (0.37, 1.63) Nasal MIST 1998 9/227 (4.0%) 2/228 (0.9%) 16.4 4.67 (1.00, 21.84) symptoms Monto 1999b 19/834 (2.3%) 14/422 (3.3%) 37.6 0.68 (0.34, 1.37) Puhakka 2003 35/293 (11.9%) 45/295 (15.3%) 45.9 0.75 (0.47, 1.21) Total 63/1354 (4.7%) 61/945 (6.5%) 100.0 0.98 (0.47, 2.06) Nausea MIST 1998 4/227 (1.8%) 9/228 (3.9%) 21.6 0.44 (0.13, 1.44) Makela 2000 3/174 (1.7%) 5/182 (2.7%) 14.6 0.62 (0.15, 2.64) Monto 1999b 20/834 (2.4%) 14/422 (3.3%) 63.8 0.72 (0.36, 1.43) Total 27/1235 (2.2%) 28/832 (3.4%) 100.0 0.63 (0.36, 1.10) Bronchitis or MIST 1998 7/227 (3.1%) 16/228 (7.0%) 35.6 0.42 (0.17, 1.05) pneumonia Monto 1999b 9/834 (1.1%) 11/422 (2.6%) 36.0 0.41 (0.17, 0.99) Puhakka 2003 9/293 (3.1%) 3/295 (1.0%) 28.4 3.08 (0.83, 11.51) Total 25/1354 (1.8%) 30/945 (3.2%) 100.0 0.73 (0.24, 2.26) All types MIST 1998 83/227 (36.6%) 98/228 (43.0%) 44.7 0.76 (0.52, 1.11) Matsumoto 1999 21/77 (27.3%) 9/39 (23.1%) 7.9 1.25 (0.51, 3.07) Puhakka 2003 77/293 (26.3%) 80/295 (27.1%) 47.4 0.96 (0.66, 1.38) Total 181/597 (30.3%) 187/562 (33.3%) 100.0 0.88 (0.69, 1.14) Abbreviations: OR = pooled odds ratio; CI = confidence interval * Data were pooled using a random effects model.

The safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine, amantadine, and oseltamivir. This may be attributed to the low bioavailability of zanamivir due to the oral inhalation route of administration. The potential advantages of this include a reduced risk of drug-drug interactions, other non-target organ toxicities (e.g. brain) and drug clearance issues. Freund et al. (1999) claim the safety profile of zanamivir supports its use in the management of influenza.

Post-marketing reports (mostly from Japan) of delirium and abnormal behaviour leading to injury in patients with influenza who were treated with zanamivir, prompted GlaxoSmithKline to amend the ‘WARNINGS AND PRECAUTIONS’ sections of the zanamivir product information. These events were reported primarily among paediatric patients. The underlying mechanism has not been established. Influenza can be associated with a variety of neurologic and behavioural symptoms which can include seizures, hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. Patients with influenza should be closely monitored for signs of abnormal behaviour. If neuropsychiatric symptoms occur whilst patients are receiving zanamivir treatment, the risks and benefits of continuing treatment should be evaluated for each patient (MedWatch 2008).

11.2 Identification of variation in safety due to health systems and patient factors Individuals with underlying airways disease Concerns regarding bronchospasm and decreased pulmonary function after inhalation of zanamivir in patients with underlying airways disease, including asthma and chronic obstructive pulmonary disease, prompted warnings about the use of zanamivir in this patient population. Potential risks and benefits should be carefully weighed before treatment. Monitoring of respiratory function should be considered if treatment is commenced (American Academy of Paediatrics Committee on Infectious Diseases 2007).

Paediatric patients Children and adolescents with influenza may be at an increased risk of seizures, confusion, or abnormal behaviour early in their illness. These events may occur after zanamivir treatment or may occur when as a consequence of influenza infection. Paediatric patients should be closely observed for signs of unusual behaviour (MedWatch 2008).

11.3 Summary of comparative safety against comparators Zanamivir is well tolerated and has an adverse event profile similar to that of placebo, when given for both the treatment and prophylaxis of influenza. Most adverse events reported are mild or moderate in nature. Patients with underlying pulmonary disease and paediatric patients should be under close observation while on zanamivir treatment.

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group 12.1 Range of costs of the proposed medicine Zanamivir (10 mg inhaled twice daily for 5 days) had an average wholesale price of $44.40 (Smith 2002). The price of zanamivir currently listed in the British National Formulary (BNF) is £24.55 for a 10-day course (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts (NICE 2007).

WHO EML – Final Report – Zanamivir

12.2 Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained) Literature searches of Medline, EMBASE, the NHS Economic Evaluation Database, and Google Scholar™ on comparative cost-effectiveness of zanamivir were performed. The NICE review by Turner et al. (2006) identified six published studies which investigated the cost-effectiveness of zanamivir. All relevant cost-effectiveness studies/reviews on zanamivir are presented in Table 12.2. However, most of these studies were not directly comparable (i.e. different methodologies and perspectives chosen, comparative treatments and population investigated, countries where studies were conducted, and the severity of influenza varied from year to year). These differences resulted in wide variation in the estimates of the ICERs for zanamivir antiviral treatment relative to supportive care/oseltamivir therapy (Refer to Table 12.2).

25 Table 12.2: Summary of cost-effectiveness studies on zanamivir (Turner et al. 2003) Study Patient group Comparator Base case result Conclusion Mauskopf 2000 High-risk adults Placebo £5,674 (A$11,715) per QALY Zanamivir for this high-risk population is cost gain effective based on an $A78 000 per QALY benchmark. Burls 2002 All adults when influenza Standard treatment £65,000 per QALY gain Zanamivir in high-risk group is unlikely to be circulating (symptomatic treatment £47,000 per QALY gain cost-effective. However, there is great High-risk adults when influenza only) uncertainty in the model. circulating Burls 2000 High-risk adults when influenza Standard treatment £31,500 per QALY gain NR circulating (symptomatic treatment (original model) only) £21,000 per QALY gain (modified model) Brady 2001 All adults when influenza Standard treatment $235,000 per QALY gain (low It is not cost effective to prescribe zanamivir circulating (symptomatic treatment diagnostic rate of 14%) for the treatment of influenza in those who are High-risk adults when influenza only) $95,000 per QALY gain (high not at risk of influenza-related complications. circulating diagnostic rate of 35%) Zanamivir could be cost-effective in high-risk $195,000 per QALY gain (low groups. But this is inconclusive. diagnostic rate of 14%) $77,000 per QALY gain (high diagnostic rate of 35%) Scuffham 2002 Elderly, prophylaxis and No intervention £258,068 per LYG Chemoprophylaxis was most cost-effective treatment (chemoprophylaxis) when used during the peak 4 weeks of the influenza season. At best, chemoprophylaxis with NIs were between 30 and 50 times more costly than vaccination. Armstrong 2000 Healthy adults and high-risk Standard care £10.53 ($16) per symptom- Zanamivir showed better cost effectiveness free day over standard care, compared to oseltamivir

Abbreviations: NI = neuraminidase inhibitors; NR = not reported; QALY = quality adjusted life years WHO EML – Final Report – Zanamivir

Table 12.2 (continued): Summary of cost-effectiveness studies on zanamivir (Turner et al. 2003) Study Patient group Comparator Base case result Conclusion Inoue 2005 Otherwise healthy adults Non-NIs treatment $US107.34/QALY gain - Zanamivir is the drug of choice for use in at- At-risk zanamivir dominated the risk patients. control therapy. Lynd 2005 - - Depending on the population Antiviral treatment or prophylaxis for and the perspective, the influenza is likely to be more cost effective in ICERs for antiviral treatment specific populations at specific times during strategies ranged from the influenza season, and during influenza $US5,000/QALY for seasons when the population prevalence amantadine in test-and-treat reaches epidemic levels or there is mismatch studies to greater than between the vaccine and the circulating $US400,000/QALY for virus. zanamivir or oseltamivir treatment in children. Sander 2005 Otherwise healthy adults usual care and Oseltamivir dominated Oseltamivir is a cost-effective treatment for oseltamivir zanamivir in cost per QALY influenza compared to usual care and to gain. zanamivir in the otherwise healthy adult population. Wailoo 2008 Otherwise healthy adults No treatment and £49,405 per QALY gain oseltamivir compared to no treatment Oseltamivir dominates zanamivir in cost per QALY gain. Rothberg 2003 Healthy adults No antiviral treatment $133,000 per QALY gain Antiviral therapy with either amantadine or zanamivir is cost-effective for healthy, young patients with influenza-like illness during the influenza season, depending on the prevalence of influenza B. Raftery 2001 N/A N/A £9,300-31,500 per QALY Recommended by NICE for 2000-1 for gain adults at risk. Cost per QALY below £30,000 could be seen as requiring rationing at a more detailed level, perhaps within some overall guidelines for use. Abbreviations: QALY = quality adjusted life years

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13. Summary of regulatory status of the medicine Zanamivir was the first neuraminidase inhibitor (NI) commercially developed and is currently marketed by GlaxoSmithKline under the trade name of Relenza®. Zanamivir (Relenza®) has gained regulatory approval for use in over 70 countries.

Zananivir was first approved for use in Australia in 1999. Zanamivir is TGA (Therapeutic Goods Administration) approved for the treatment of influenza A and B infections in adults and children (aged 5 years and older). Treatment should commence no later than 48 hours after the onset of the initial symptoms of infection. The Australian Drug Evaluation Committee (ADEC) 1-2 June 2006 recommended approval of zanamivir for the prophylaxis of influenza A and B in adults and children (aged 5 years and older). Zanamivir is currently TGA approved for the prophylaxis of influenza A and B during community outbreaks only in circumstances where such prophylaxis is justified (e.g. when vaccine that antigenically matches circulating influenza is not available or there is a pandemic).

Zanamivir was initially approved for marketing by the US Food and Drug Administration (FDA) on 26 July 1999. Current (February 2008) FDA approved indications for zanamivir are for the treatment of influenza A and B in adults and children (aged 7 years and older) who have been symptomatic for no more than 2 days, and prophylaxis for influenza A and B in adults and children (aged 5 years and older). Safety and efficacy for treatment of influenza has not been established in children less than 7 years of age. Although zanamivir can be administered in the treatment and prophylaxis of avian influenza in adults and children this is not a FDA-approved indication. FDA approved dosage and administration is summarised in Table 13.1.

Table 13.1: FDA approved dosage and administration of zanamivir Indication Dose Treatment of influenza 10 mg twice daily for 5 days Prophylaxis: Household setting 10 mg once daily for 10 days Community outbreaks 10 mg once daily for 28 days Source: Relenza® product information – February 2008

In 1999, zanamivir was approved by the European Commission (EC) and Health Canada for the treatment of uncomplicated acute illness due to influenza A and B virus is patients aged 7 years ad older who have been symptomatic for no more than 2 days. On 4 January 2006 the Therapeutic Products Program of Health Canada approved zanamivir for use for the prophylaxis of influenza in patients aged 7 years and older.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) British Pharmacopoeia (British National Formulary) – Yes International Pharmacopoeia – Yes United States Pharmacopoeia – Yes

15. Proposed (new/adapted) text for the WHO Model Formulary The following information was sourced from the PI for zanamivir (Relenza®) and relate specifically to the use of zanamivir in seasonal influenza (Australia TGA approved indication). This information can be sourced directly from: http://www.mims.com.au.

28 WHO EML – Final Report – Zanamivir

Indications Treatment Treatment of infections due to influenza A and B viruses in adults and children aged 5 years and older. Treatment should commence as soon as possible but no later than 48 hours after the onset of the initial symptoms of infection (see Precautions).

Prophylaxis Vaccination remains the primary method of preventing and controlling influenza. Zanamivir is indicated for prophylaxis of infection due to influenza A and B in adults and children (greater than or equal to 5 years) to reduce transmission among individuals in households with an infected person. Prophylaxis of influenza A and B during community outbreaks only in circumstances where such prophylaxis is justified (e.g. when vaccine that anti-genically matches circulating influenza is not available or there is a pandemic).

Contraindications It is not recommended for routine prophylaxis against influenza infection.

Precautions Zanamivir is a specific treatment for infections due to influenza A or B viruses. Use of zanamivir should be limited to patients who have characteristic symptoms of influenza when influenza A or B virus infections have been documented locally.

Asthma or other severe chronic respiratory diseases Treatment of influenza in patients with severe asthma or other severe chronic respiratory diseases with zanamivir has not been adequately assessed due to the limited number of patients studied.

Bronchospasm There have been some reports of patients being treated for influenza who have experienced bronchospasm and/or decline in respiratory function after the use of zanamivir. The decline in respiratory function is considered to be possibly related to zanamivir although the causal relationship is difficult to assess as influenza infection can be associated with increased airways hyper-responsiveness, and in some patients concurrent medical conditions were present. Decline in respiratory function should be considered as a potential risk when patients with chronic obstructive pulmonary disease or asthma are considered for treatment with zanamivir. If a decision is made to prescribe zanamivir, the patient should be made aware of the risks of bronchospasm and decline in respiratory function, and should have a fast acting bronchodilator available. Patients scheduled to take inhaled bronchodilators at the same time as zanamivir should be advised to use their bronchodilators before taking zanamivir (see Dosage and Administration). Any patient who experiences a decline in respiratory function and/or symptoms of bronchospasm (such as worsening wheezing and shortness of breath) after use of zanamivir should discontinue the drug and seek medical evaluation.

Neuropsychiatric events Influenza can be associated with a variety of neurological and behavioural symptoms which can include events such as seizures, hallucinations, delirium and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. There have been post-marketing reports (mostly from Japan) of delirium and abnormal behaviour leading to injury in patients with influenza who were receiving neuraminidase

29 WHO EML – Final Report – Zanamivir

inhibitors, including zanamivir.

Patients with influenza should be closely monitored for signs of abnormal behaviour. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.

Use in pregnancy (Category B1) There is limited experience with the use of zanamivir during pregnancy reported during clinical trials and post-marketing experience. The safe use of zanamivir during pregnancy has not been established.

Adverse reactions In clinical studies, including those studies with high risk patients (the elderly, and patients with chronic medical conditions), the adverse events reported were similar in the zanamivir and placebo groups.

Post-marketing experience The following events have been identified during post approval use of zanamivir (Relenza®) for the treatment of influenza: General: very rare (< 1/10,000): allergic type reaction, including facial and oropharyngeal oedema. Respiratory: very rare (< 1/10,000): bronchospasm, dyspnoea. Skin: very rare (< 1/10,000): rash, urticaria.

Interactions The potential for clinically significant drug-drug interactions resulting from zanamivir co- administration has been evaluated in a number of in vitro screens for effects on antiviral activity and pharmacokinetic disposition. These evaluations have found that in vitro activity of zanamivir (e.g. with aspirin, ibuprofen, paracetamol, codeine, oxymetazoline, phenylephrine, diphenhydramine, promethazine or Augmentin (amoxicillin trihydrate/ potassium clavulanate) as well as the renal excretion of zanamivir (e.g. with cimetidine, ibuprofen, cefuroxime, pseudoephedrine and paracetamol) is unlikely to be affected by drugs administered in influenza patients.

Dosage and administration Treatment of influenza The recommended dose of zanamivir is two oral inhalations (2 x 5 mg) twice daily for five days providing a total daily inhaled dose of 20 mg. Treatment should begin as soon as possible after onset of symptoms for maximum benefit, and at the latest should commence within 48 hours of symptom onset. Administration is by oral inhalation.

Prophylaxis of influenza The recommended dose of zanamivir is two inhalations (2 x 5 mg) once daily, providing a total daily inhaled dose of 10 mg, for ten days. This may be increased up to 28 days if the period of exposure risk extends beyond ten days. Relenza® Rotadisks® are for pulmonary administration by oral inhalation only, using the Diskhaler® device provided. Patients scheduled to take inhaled drugs, e.g. fast acting bronchodilators, at the same time as zanamivir, should be advised to administer that drug prior to administration of zanamivir (see Precautions).

30 WHO EML – Final Report – Zanamivir

Renal impairment No alteration of dosage or frequency of administration is required.

Hepatic impairment There is currently no experience in this patient population. Zanamivir is not hepatically metabolised and no dose modification is required.

Use in the elderly Experience with zanamivir in the elderly (greater than or equal to 65 years) is limited. However, based on the pharmacokinetic properties of zanamivir no dose modification is required.

Use in children No dose modification is required. When zanamivir is prescribed for children, it should be used only under adult supervision.

Supplied Relenza® Rotadisk®: Powder for inhalation, 5 mg/blister (circular foil disk, four blisters per disk equivalent total daily dose): 5's (provided with Diskhaler® inhalation device for oral inhalation).

Storage Store below 30 deg. C.

31 WHO EML – Final Report – Zanamivir

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Appendix A

Manufacturers and distributors of zanamivir Trade name Contact Relenza GSK, Australia GlaxoSmithKline, Pharmaceticals Division Relenza GSK, Austria GlaxoSmithKline Pharma Relenza GSK, Belgium GlaxoSmithKline SA/N.V Relenza GSK, Brazil GlaxoSmithKline Brasil Ltda Relenza GSK, Canada GlaxoSmithKline Inc. Relenza GSK, Czech Republic GlaxoSmithKline Relenza GSK, Finland GlaxoSmithKline Oy Relenza GSK, France Laboratoires GlaxoSmithKline Relenza GSK, Germany GlaxoSmithKline GmbH & Co Relenza GSK, Greece GlaxoSmithKline Relenza GSK, Hong Kong GlaxoSmithKline Ltd Relenza GSK, Hungary GlaxoSmithKline Kft Relenza GSK, Italy GlaxoSmithKline S.p.A. Relenza GSK, Mexico GlaxoSmithKline Mexico S.A. de C.V. Relenza GSK, New Zealand GlaxoSmithKline Relenza GSK, The Netherlands GlaxoSmithKline BV Relenza GSK, Norway GlaxoSmithKline A/S Relenza GSK, South Africa GlaxoSmithKline SA (Pty) Ltd Relenza GSK, Singapore GlaxoSmithKline Pte Ltd Relenza GSK, Spain GlaxoSmithKline Relenza GSK, Sweden GlaxoSmithKline AB Relenza GSK, Switzerland GlaxoSmithKline Relenza GSK, Turkey GlaxoSmithKline Relenza GSK, UK GlaxoSmithKline Relenza Glaxo Wellcome, Portugal Relenza Glaxo Wellcome, USA

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Appendix B Results of the meta-analyses performed by Turner et al. (2003)

Median number of days to the alleviation of symptoms for ‘healthy’ individuals in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

Median number of days to the alleviation of symptoms for ‘healthy’ individuals in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

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Median number of days to the alleviation of symptoms for ‘high-risk’ individuals in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

Median number of days to the alleviation of symptoms for ‘high-risk’ individuals in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

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Median number of days to the alleviation of symptoms for children in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

Median number of days to the alleviation of symptoms for children in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

Median number of days to return to normal activities for ‘healthy’ individuals in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

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Median number of days to return to normal activities for ‘healthy’ individuals in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

Median number of days to return to normal activities for ‘high-risk’ individuals in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

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Median number of days to return to normal activities for ‘high-risk’ individuals in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

Median number of days to return to normal activities for children in the zanamivir treatment trials (ITT group)

Source: Turner et al. (2003)

Median number of days to return to normal activities for children in the zanamivir treatment trials (influenza positive group)

Source: Turner et al. (2003)

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Complications requiring use of antibiotics

Source: Turner et al. (2003)

Complications requiring use of antibiotics

Source: Turner et al. (2003)

Number of individuals developing pneumonia

Source: Turner et al. (2003)

Outbreak prophylaxis in the elderly in a residential home setting: NAIA2010

Source: Turner et al. (2003)

Seasonal prophylaxis in a healthy population (aged 18–64 years, 15% vaccinated): NAIA3005

Source: Turner et al. (2003)

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Previous exposure prophylaxis in the general population (ITT group): NAI30010a and NAIA/B2009

Source: Turner et al. (2003)

Previous exposure prophylaxis in the general population (influenza positive index cases): NAI30010

Source: Turner et al. (2003)

Number of individuals with adverse events to treatment

Source: Turner et al. (2003)

Number of trial withdrawals

Source: Turner et al. (2003)

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Appendix C

Summary of the results of the meta-analyses performed by Jefferson et al. (2006)

Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006, Issue 3.

Zanamivir prophylaxis (inhaled 10 mg daily) versus placebo: influenza-like illness Study Zanamivir Placebo Relative Risk (Random) n/N n/N 95% CI Kaiser 2000 4/144 2/48 0.67 (0.13, 3.53) Monto 1999a 33/553 19/554 1.74 (1.00, 3.02) Pooled estimate of effect 1.51 (0.77, 2.95) Test for heterogeneity chi-square = 1.15 df = 1 p = 0.28 I2 = 13.0% Test for overall effect z = 1.19 p = 0.2 Source: Jefferson et al. (2006)

Zanamivir prophylaxis (inhaled 10 mg daily) versus placebo: influenza (symptomatic) Study Zanamivir Placebo Relative Risk (Random) n/N n/N 95% CI Kaiser 2000 16/144 9/48 0.59 (0.28, 1.25) Monto 1999a 14/553 53/554 0.26 (0.15, 0.47) Pooled estimate of effect 0.38 (0.17, 0.85) Test for heterogeneity chi-square = 2.90 df = 1 p = 0.09 I2 = 65.5% Test for overall effect z = 2.35 p = 0.02 Source: Jefferson et al. (2006)

Zanamivir prophylaxis (inhaled 10 mg daily) versus placebo: influenza (symptomatic & asymptomatic) Study Zanamivir Placebo Relative Risk (Random) n/N n/N 95% CI Kaiser 2000 16/144 9/48 0.59 (0.28, 1.25) Monto 1999a 53/553 77/554 0.69 (0.50, 0.96) Pooled estimate of effect 0.67 (0.50, 0.91) Test for heterogeneity chi-square = 0.13 df = 1 p = 0.72 I2 = 0.0% Test for overall effect z = 2.58 p = 0.01 Source: Jefferson et al. (2006)

Zanamivir treatment versus placebo: time to alleviation of symptoms (ITT) Study Zanamivir Placebo Log[Hazard ratio] Hazard ratio (Random) N N (SE) 95% CI Hayden 1997 273 144 0.11 (0.12) 1.11 (0.88, 1.40) MIST 1998 227 228 0.26 (0.10) 1.30 (1.06, 1.60) Makela 2000 174 182 0.41 (0.12) 1.50 (1.19, 1.89) Matsumoto 1999 77 39 0.29 (0.24) 1.33 (0.83, 2.16) Monto 1999b 834 422 0.15 (0.07) 1.17 (1.01, 1.35) Puhakka 2003 293 295 0.21 (0.84) 1.23 (0.24, 6.34) Pooled estimate of effect 1.24 (1.13, 1.36) Test for heterogeneity chi-square = 4.41 df = 5 p = 0.49 I2 = 0.0% Test for overall effect z = 4.48 p < 0.00001 Source: Jefferson et al. (2006)

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Zanamivir treatment versus placebo: time to alleviation of symptoms (influenza cases only) Study Zanamivir Placebo Log[Hazard ratio] Hazard ratio (Random) N N (SE) 95% CI Boivin 2000 17 10 0.64 (0.40) 1.90 (0.87, 4.15) Hayden 1997 173 89 0.22 (0.15) 1.25 (0.93, 1.67) MIST 1998 161 160 0.29 (0.02) 1.33 (1.29, 1.38) Makela 2000 136 141 0.47 (0.14) 1.60 (1.22, 2.10) Matsumoto 1999 44 29 0.00 (0.29) 1.00 (0.57, 1.75) Monto 1999b 481 241 0.24 (0.10) 1.27 (1.05, 1.55) Puhakka 2003 222 213 0.15 (0.10) 1.17 (0.97, 1.41) Pooled estimate of effect 1.33 (1.29, 1.37) Test for heterogeneity chi-square = 5.89 df = 6 p = 0.44 I2 = 0.0% Test for overall effect z = 18.52 p < 0.00001 Source: Jefferson et al. (2006)

Zanamivir treatment versus placebo: time to return to normal activity (influenza cases only) Study Zanamivir Placebo Log[Hazard ratio] Hazard ratio (Random) N N (SE) 95% CI Hayden 1997 173 89 0.00 (0.15) 1.00 (0.75, 1.34) MIST 1998 161 160 0.25 (0.14) 1.29 (0.98, 1.68) Makela 2000 136 141 0.19 (0.14) 1.21 (0.93, 1.59) Pooled estimate of effect 1.17 (1.00, 1.37) Test for heterogeneity chi-square = 1.66 df = 2 p = 0.44 I2 = 0.0% Test for overall effect z = 1.91 p = 0.06 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events - cough Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 9/227 14/228 67.3 0.63 (0.27, 1.49) Puhakka 2003 3/293 0/295 32.7 7.12 (0.37, 138.46) Pooled estimate of effect 1.40 (0.14, 13.49) Test for heterogeneity chi-square = 2.45 df = 1 p = 0.12 I2 = 59.2% Test for overall effect z = 0.29 p = 0.8 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events - headache Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI Matsumoto 1999 2/77 0/39 7.1 2.62 (0.12, 55.83) Monto 1999b 14/814 9/422 92.9 0.80 (0.34, 1.87) Pooled estimate of effect 0.87 (0.39, 1.97) Test for heterogeneity chi-square = 0.54 df = 1 p = 0.46 I2 = 0.0% Test for overall effect z = 0.33 p = 0.7 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events - diarrhoea Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 2/227 9/228 17.6 0.22 (0.05, 1.01) Matsumoto 1999 2/77 2/39 11.6 0.49 (0.07, 3.64) Monto 1999b 27/834 11/422 43.9 1.25 (0.61, 2.55) Puhakka 2003 6/293 6/295 26.8 1.01 (0.32, 3.16) Pooled estimate of effect 0.78 (0.37, 1.63) Test for heterogeneity chi-square = 4.52 df = 3 p = 0.21 I2 = 33.6% Test for overall effect z = 0.66 p = 0.5 Source: Jefferson et al. (2006)

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Zanamivir versus placebo: adverse events – nasal symptoms (congestion, rhinitis, dry or sore throat) Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 9/227 2/228 16.4 4.67 (1.00, 21.84) Monto 1999b 19/834 14/422 37.6 0.68 (0.34, 1.37) Puhakka 2003 35/293 45/295 45.9 0.75 (0.47, 1.21) Pooled estimate of effect 0.98 (0.47, 2.06) Test for heterogeneity chi-square = 5.33 df = 2 p = 0.07 I2 = 62.5% Test for overall effect z = 0.06 p = 1.0 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events – nausea Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 4/227 9/228 21.6 0.44 (0.13, 1.44) Makela 2000 3/174 5/182 14.6 0.62 (0.15, 2.64) Monto 1999b 20/834 14/422 63.8 0.72 (0.36, 1.43) Pooled estimate of effect 0.63 (0.36, 1.10) Test for heterogeneity chi-square = 0.50 df = 2 p = 0.78 I2 = 0.0% Test for overall effect z = 1.63 p = 1.0 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events – bronchitis or pneumonia Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 7/227 16/228 35.6 0.42 (0.17, 1.05) Monto 1999b 9/834 11/422 36.0 0.41 (0.17, 0.99) Puhakka 2003 9/293 3/295 28.4 3.08 (0.83, 11.51) Pooled estimate of effect 0.73 (0.24, 2.26) Test for heterogeneity chi-square = 7.31 df = 2 p = 0.03 I2 = 72.6% Test for overall effect z = 0.54 p = 0.6 Source: Jefferson et al. (2006)

Zanamivir versus placebo: adverse events – all types Study Zanamivir Placebo Weight Odds Ratio (Random) n/N n/N (%) 95% CI MIST 1998 83/227 98/228 44.7 0.76 (0.52, 1.11) Matsumoto 1999 21/77 9/39 7.9 1.25 (0.51, 3.07) Puhakka 2003 77/293 80/295 47.4 0.96 (0.66, 1.38) Pooled estimate of effect 0.88 (0.69, 1.14) Test for heterogeneity chi-square = 1.33 df = 2 p = 0.51 I2 = 0.0% Test for overall effect z = 0.96 p = 0.3 Source: Jefferson et al. (2006)

Zanamivir versus placebo: use of relief medications and antibiotics Study Zanamivir Placebo Odds Ratio (Random) n/N n/N 95% CI Aoki 2000 34/482 26/240 0.62 (0.37, 1.07) Matsumoto 1999 51/77 29/39 0.68 (0.29, 1.60) Pooled estimate of effect 0.64 (0.41, 1.01) Test for heterogeneity chi-square = 0.02 df = 1 p = 0.88 I2 = 0.0% Test for overall effect z = 1.93 p = 0.05 Source: Jefferson et al. (2006)

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Zanamivir (10 to 20 mg daily) versus placebo: mean nasal viral titres (at 24 hours since randomisation) Study Zanamivir Mean (SD) Placebo Mean (SD) Weighted Mean N N Difference (Random) 95% CI Boivin 2000 17 2.19 (1.61) 10 2.79 (1.74) -0.60 (-1.92, 0.72) Puhakka 2003 212 3.67 (1.95) 202 4.06 (1.81) -0.39, -0.75, -0.03) Pooled estimate of effect -0.40 (-0.75, -0.06) Test for heterogeneity chi-square = 0.09 df = 1 p = 0.76 I2 = 0.0% Test for overall effect z = 2.27 p = 0.02 Source: Jefferson et al. (2006)

Zanamivir (10 to 20 mg daily) versus placebo: mean nasal viral titres (at 48 hours since randomisation) Study Zanamivir Mean (SD) Placebo Mean (SD) Weighted Mean N N Difference (Random) 95% CI Boivin 2000 17 1.68 (1.53) 10 1.73 (1.55) -0.05 (-1.25, 1.15) Puhakka 2003 212 2.70 (1.94) 202 3.71 (1.75) -1.01 (-1.37, -0.65) Pooled estimate of effect -0.71 (-1.58, 0.16) Test for heterogeneity chi-square = 2.24 df = 1 p = 0.13 I2 = 55.4% Test for overall effect z = 1.59 p = 0.1 Source: Jefferson et al. (2006)

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Appendix D Summary of treatment trials included in the review by Turner et al. (2003) Trial Patient characteristics Trial design arms Treatment Follow-up duration (days) (days) NAIA2005 Previously healthy adults of at least 13 years of age. Present within N=132 (10 mg inhaled + placebo intranasal twice daily) 5 28 NAIB2005 48 hours after onset of symptoms. Influenza was confirmed to be N=141 (10 mg inhaled + 6.4 mg intranasal twice daily) Hayden (1997) circulating before recruitment started in each centre. No ‘high-risk’ N=144 (inhaled + intranasal placebo) individuals. Vaccinated individuals were excluded from the study. NAIB2007 At least 13, 16 or 18 years old (depending on centre). Present within N=188 (10 mg inhaled twice daily) 5 5 48 hours after onset of symptoms. Around 13% of participants N=183 (10 mg inhaled + 6.4 mg intranasal twice daily) considered ‘high risk’. N=183 (placebo) NAIA2008 Previously healthy persons at least 13 or 18 years old (depending on N=419 (10 mg inhaled + 6.4 mg intranasal twice daily) 5 21 NAIB2008 centre). Present within 48 hours after onset of symptoms. Note that N=415 (10 mg inhaled + 6.4 mg intranasal 4 times daily) Monto (1999b) 13% of participants considered ‘high risk’, 0.8% of the study N=422 (placebo) population vaccinated. NAIB3001 Previously healthy persons at least 12 years old. Present within 36 N=227 (10 mg inhaled twice daily) 5 28 MIST (1998) hours after onset of symptoms. Influenza activity in area confirmed. N=228 (placebo) Boivin (2000) Recruitment started when influenza activity was seen to be increasing. Note that 17% of participants considered ‘high risk’, 6% of the study population vaccinated. NAIA3002 Previously healthy persons at least 12 years old. Present within 48 N=412 (10 mg inhaled twice daily) 5 28 hours after onset of symptoms. Note that 14% of participants N=365 (placebo) considered ‘high risk’. NAIB3002 At least 12 years old. Present within 48 hours after onset of N=174 (10 mg inhaled twice daily) 5 28 Makela (2000) symptoms. Recruitment started when influenza was known to be N=182 (placebo) circulating locally. Note that 9% of participants considered ‘high risk’, 4% of the study population were vaccinated. NAI30008 Persons with asthma or COPD, at least 12 years old. Recruitment N=262 (10 mg inhaled twice daily) 5 28 Murphy (2000) started when influenza was known to be circulating in the community. N=263 placebo Present within 36 hours after onset of symptoms, 23% of the study population vaccinated. NAI30009 Previously healthy children 5–12 years old. Present within 36 hours N=224 (10 mg inhaled twice daily) 5 28 Hedrick (2000) after onset of symptoms. Recruitment started when influenza was N=247 (placebo) known to be circulating in the community. Influenza was confirmed to be circulating before recruitment started in each centre. Note that 8% of participants considered ‘high risk’, 2% of study population vaccinated. Source: Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Heath Technology Assessment 2003; 7 (35): 1-194.

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Summary of treatment trials included in the review by Turner et al. (2003) (continued) Trial Patient characteristics Trial design arms Treatment Follow-up duration (days) (days) Puhakka (2003) A randomized, double-blind, placebo-controlled, parallel group trial N=293 (10 mg inhaled twice daily) 5 NR performed at Finnish Defense Forces. Only investigator-prescribed N=295 (placebo) paracetamol was allowed. The study was conducted (2000-2001) over two influenza seasons with A/H3N2 and A/H1N1 respectively as dominant strains. Matsumoto Double-blind, randomised, placebo-controlled trial of the treatment N=39 (placebo) 5 28 (1999) efficacy of inhaled and intranasal zanamivir was carried out in 28 N=77 (10 mg inhaled twice daily, and 10 mg inhaled + centres in Japan during January to March 1995. The dominant strain 6.4 mg intranasal twice daily) was A/H3N2. Source: Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Heath Technology Assessment 2003; 7 (35): 1-194.

Summary of prophylaxis trials include in the review by Turner et al. (2003) Trial Patient characteristics Trial design arms Treatment Follow-up duration (days) (days) NAIA2009 Randomised double-blind, placebo-controlled multicentre trial N=146 (inhaled 5 mg twice daily + intranasal sprays 16 5 NAIB2009 (Europe and North America) investigating the prophylactic effect of mg/ml per nostril 0.1 ml per spray) Kaiser (2000) zanamivir after close contact with a person with ILI of no longer than N=141 (placebo inhaled + active spray) 4 days duration. Asymptomatic persons aged 13–65 years who had N=144 (inhaled + placebo spray) been exposed were eligible. None of the participants were N=144 (placebo spray and inhalation) vaccinated against influenza. NAIA2010 Randomised unblinded study of chemoprophylaxis with zanamivir Influenza A 14 versus standard care in a 735-bed nursing home. Randomisation N=65 (10 mg inhaled + 4.4 mg intranasal twice daily) was at a ward (of which there were 14) and not an individual level. N=23 (100 mg rimantadine once daily) Once existence of an outbreak was established (treatment was given Influenza B only in the ward where the outbreak had occurred). Persons who N=35 (10 mg inhaled + 4.4 mg intranasal twice daily) refused to take part in the study were given rimantadine N=17 (no drug) automatically when influenza A was confirmed in their ward. Age group of participants and percentage vaccinated not reported. Source: Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Heath Technology Assessment 2003; 7 (35): 1-194.

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Summary of prophylaxis trials included in the review by Turner et al. (2003) (continued) Trial Patient characteristics Trial design arms Treatment Follow-up duration (days) (days) NAIA3005 Randomised double-blind, placebo-controlled trial of zanamivir for N=553 (10 mg inhaled once daily) 28 Monto (1999a) the prevention of influenza in healthy adults (2 mid-western USA N=554 (placebo) university communities). Persons aged 18–64 years were eligible for participation as long as they did not have a chronic condition for which influenza vaccination was recommended (although other vaccinated persons were eligible for inclusion). 15% of participants vaccinated. Source: Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Heath Technology Assessment 2003; 7 (35): 1-194.

Summary of treatment & prophylaxis trial included in the review by Turner et al. (2003) Trial Patient characteristics Trial design arms Treatment Follow-up duration (days) (days) NAI30010 Eligible families were those with two to five members, including at N=163 (10 mg inhaled twice daily) 5 28 Hayden least one adult and at least one child between 5 and 17 years old. N=158 (placebo) (2000) Once laboratory confirmed influenza activity had been documented in the community, families in which one member contracted an ILI (the ‘index case’) began to take the study drug. The treatment trial consisted of the ‘index cases’ only. Present within 36 hours after onset of symptoms. Note that 7% of participants considered ‘high risk’, 10% of the study population were vaccinated. Source: Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Heath Technology Assessment 2003; 7 (35): 1-194.

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Appendix E Zanamivir for treating influenza in children Study Study factor/s N Results Matheson 2007 NAI30009: Double-blind RCT. Efficacy, ITT Reduction in median time to resolution of illness Matheson NJ, Harnden AR, Perera R, safety and tolerability of a five day Zanamivir = 224 Z = 4.5 days (ITT) Sheikh A, Symmonds-Abrahams M. course of twice daily inhaled zanamivir Control = 247 C = 5.0 days (ITT) [10% (0.5 days); P=0.011] Neuraminidase inhibitors for preventing (or placebo) in the treatment of and treating influenza in children. naturally acquired, symptomatic LC-ILI Z = 4.0 days (LC-ILI) Cochrane Database of Systematic influenza infection in 471 children aged Zanamivir = 164 C = 5.25 days (LC-ILI) [24% (1.25 days); P<0.001] Reviews 2007, Issue 1. 5 to 12 years. Control = 182 By influenza serotype Influenza A Z = 4.0 days C = 5.0 days [1.0 day (95% CI 0.0,1.5); P=0.049] Influenza B Z = 4.0 days C = 6.0 days [2.0 days (95% CI 1.0,3.5); P<0.001] By area (LC-ILI) North USA Z = 4.0 days C = 5.0 days [1.0 day (95% CI 0,1.5); P 0.026] Europe/Israel Z = 4.0 days C = 5.5 days [1.5 days (95% CI 0.5,3.0); P=0.004] Time to return to normal activity No data available Secondary complications Overall rate (LC-ILI) Z = 16% C = 23% [RRR=30%; NSS][ARR=7%; NSS] Antibiotic use (LC-ILI) Z = 12% C = 15% [RRR=20%; NSS] Asthma exacerbation rate Z < 1% C = 1% Abbreviations: LC-ILI = laboratory-confirmed influenza; Z = zanamivir; C = placebo; children (aged ≤12 years); ‘high-risk’ (children with concomitant disease); NSS = not statistically significant.

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Zanamivir for treating influenza in children Study Study factor/s N Results [median differences] Turner 2003 NAI30009: Double-blind RCT. Efficacy, ‘Healthy’ ITT Median (SE) days to the alleviation of symptoms* Turner D, Wailoo A, Nicholson K, safety and tolerability of a five day Zanamivir = 202 Cooper N, Sutton A, Abrams K. course of twice daily inhaled zanamivir Control = 233 ‘Healthy’ ITT: -1.0 days (95% CI: -1.5, -0.5) Systematic review and economic (or placebo) in the treatment of naturally ‘Healthy’ LC-ILI decision modelling for the prevention acquired, symptomatic influenza Zanamivir = 152 and treatment of influenza A and B. infection in 471 children aged 5 to 12 Control = 172 ‘Healthy’ LC-ILI: -1.0 days (95% CI -1.6, -0.4) Health Technology Assessment years. ‘High-risk’ ITT 2003;7(35) Zanamivir = 22 Control = 14 ‘High-risk’ ITT: -2.0 days (95% CI -6.9, 2.9) ‘High-risk’ LC-ILI Zanamivir = 12 Control = 10 ‘High-risk’ LC-ILI: -3.8 days (95% CI -7.6, 0.1) ‘Healthy’ ITT Median (SE) number of days to return to normal activities* Zanamivir = 202 Control = 233 ‘Healthy’ ITT: -0.5 days (95% CI -1.3, 0.3) ‘Healthy’ LC-ILI Zanamivir = 154 Control = 172 ‘Healthy’ LC-ILI: -0.5 days (95% CI -1.4, 0.4) ‘High-risk’ ITT Zanamivir = 22 Control = 14 ‘High-risk’ ITT: -1.0 days (95% CI -3.5, 1.5) ‘High-risk’ LC-ILI Zanamivir = 12 Control = 10 ‘High-risk’ LC-ILI: -2.5 days (95% CI: -4.4, -0.6) Abbreviations: LC-ILI = laboratory-confirmed influenza; T = zanamivir; C = placebo *‘published re-analysis’: the median provided on request from GlaxoSmithKline, which does allow for censored observations and is consistent with the Hoffman La Roche trial results.

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Zanamivir for treating influenza in children Study Study factor/s N Results [median differences] Van de Vyver 2006 NAI30010: Double-blind RCT. The ‘High-risk’ ITT Median (SE) days to the alleviation of symptoms* Van de Vyver N, Janssens W, De Sutter treatment and prevention of influenza in Zanamivir = 22 A, Michiels B, Govaerts F, Lambert M-L, families (2–5 members with at least 1 Control = 14 ‘High-risk’ ITT: -2.0 days (95% CI -6.9, 2.9) et al. Antiviral agent in seasonal and adult and at least 1 child 5-17 years old) ‘High-risk’ LC-ILI pandemic influenza. Literature study and in which one member developed ILI Zanamivir = 12 development of practice guidelines. (Index case) were randomised to a five Control = 10 ‘High-risk’ LC-ILI: -3.8 days (95% CI -7.6, 0.1) Good Clinical Practice (GCP). Brussels: day course of twice daily inhaled 10mg ‘High-risk’ ITT Median (SE) number of days to return to normal activities* Belgian Health Care Knowledge Centre zanamivir or placebo. The treatment trial Zanamivir = 22 (KCE); 2006. KCE reports 49 C consisted of the ‘index cases’ only. Control = 14 ‘High-risk’ ITT: -1.0 days (95% CI -3.5, 1.5) (D/2006/10.273/67). (includes meta- ‘High-risk’ LC-ILI analyses from Turner et al. 2003) Zanamivir = 12 Control = 10 ‘High-risk’ LC-ILI: -2.5 days (95% CI: -4.4, -0.6) Abbreviations: LC-ILI = laboratory-confirmed influenza; T = zanamivir; C = placebo; children (aged ≤12 years); ‘high-risk’ (children with concomitant disease). *‘published re-analysis’: the median provided on request from GlaxoSmithKline, which does allow for censored observations and is consistent with the Hoffman La Roche trial results.

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Appendix F

Summary of results – in vitro evidence of zanamivir treatment for human and avian influenza (H5N1) Study Virus Assay Comparisons Outcome: Outcome: Conclusions Viral replication Neuraminidase inhibition inhibition Gubareva 1998 A/HK/156/97 (H5N1) 1. Plaque assay None studied Inhibited viral replication NA was inhibited Zanamivir inhibited both NA 2. NA inhibition activity and virus replication. Leneva 2001 A/HK/156/97 (H5N1) 1. ELISA 1. H5N1 with avian Inhibited viral replication in NA was inhibited for all Zanamivir inhibited both NA 2. Plaque assay strains all viruses. Concentrations viruses and activity and virus replication 3. NA inhibition required in each virus were concentrations required of H5N1 and avian viruses. similar. were similar for all viruses. Smee 2001 1. A/Duck/MN/1525/81 1. Inhibition of 1. Viruses Inhibited viral replication in Not studied Zanamivir and oseltamivir (H5N1) cytopathic effect 2. Zanamivir vs. all viruses. Required inhibited virus replication of 2. A/Gull/PA/4175/83 2. Virus yield oseltamivir concentrations of all viruses. (H5N1) reduction zanamivir and oseltamivir 3. H1N1 (5 strains) 3. Time-of- were similar. 4. H3N2 (12 strains) addition studies Sidwell 2007 1. A/Hong Kong/213/03 x 1. Inhibition of 1. Viruses Zanamivir inhibited viral Not studied Zanamivir and oseltamivir Ann Arbor/6/60 cytopathic effect 2.Experimental replication in all viruses. inhibited virus replication of 2. A/Vietnam/1203/04 x 2. Virus yield substance T-705 vs. Required concentrations of all viruses, but higher Ann Arbor/6/60 reduction assay zanamivir and zanamivir and oseltamivir concentrations were 3. A/Duck/MN/1525/81 oseltamivir and were similar. required for the duck/MN ribavirin and gull/PA viruses. T-705 4. A/Gull/PA/4175/83 required higher (All H5N1) The experimental substance T-705 was less concentrations than potent in reducing viral zanamivir and oseltamivir. yield than the neuraminidase inhibitors but more so than ribavirin. Abbreviations: NA = neuraminidase

56 WHO EML – Final Report – Zanamivir

Summary of results - resistance evaluations by in vitro study and/or sequence data Study Virus Assay Comparisons Outcome: Outcome: Outcome: Conclusions Viral Neuraminidase Change in replication inhibition sensitivity inhibition McKimm- 1. A/N1 (human, 139 1. NA inhibition 1. Viruses N/A N2 viruses were No altered sensitivity H1N1 and H3N2 viruses Breschkin 2003 strains) by fluorescence 2. Zanamivir vs. generally more in viruses that had circulating 1996-1999 were 2. A/N2 (human, 767 2. NA inhibition oseltamivir sensitive to variations in susceptible to zanamivir & strains) by chemilumin- oseltamivir than sequence residues. oseltamivir. This is before escent zanamivir. Slight the drugs were introduced differences seen for use in the area. Some between assay variants were seen but no types. N1 viruses evidence of naturally were slightly occurring resistance to more sensitive to these two drugs. zanamivir than oseltamivir. Hurt 2004 1. A/H1N1 (human, 235 1. NA inhibition 1. N1 vs. N2 N/A N1 viruses were No significant After NA inhibitors were in strains) by fluorescence 2. Year of more sensitive to decline in sensitivity use in the region, no 2. A/H3N2 (human, 160 isolation zanamivir than in Australasia strains significant impact on strains) 3. Australasia oseltamivir. N2 by year of isolation. susceptibility of viruses to 3. A/H1N2 (human, 9 vs. South East strains were more zanamivir or oseltamivir. strains) Asia sensitive to oseltamivir. Similar susceptibility of Australasia & South East Asia strains. Abbreviations: NA = neuraminidase

57 WHO EML – Final Report – Zanamivir

Summary of in vitro evidence of combination treatment for human and avian influenza (H5N1)

Summary of results - combinations of NA inhibitor plus rimantadine (data from H1N1 and H3N2) Study Virus Assay Comparisons Outcome: Outcome: Conclusions Viral replication Neuraminidase inhibition inhibition Govorkova 1. A/New Caledonia/20/99 1. Extra-cellular 1. zanamivir + Combination of Not studied Combination treatment with 2004 (H1N1) virus yield rimantadine vs. rimantadine & zanamivir or zanamivir or oseltamivir with 2. A/Panama/2007/99 reduction assay single drug rimantadine and rimantadine markedly (H3N2) 2. ELISA to 2. oseltamivir + oseltamivir resulted in reduces the extracellular determine the rimantadine vs. complete reduction in H1N1 and H3N2 virus yield. cell-associated single drug H1N2 and H3N2 Synergism or additive virus reduction extracellular viral yield. effects seen at a range of Interactions were mainly concentrations. synergistic or additive. Abbreviations: NA = neuraminidase

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