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

Transcription

1 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 FAX

2 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 Petah Tikva Israel 2

3 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 3

4 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 was responsible for 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 20 th century pandemics and future projections Year Population Death toll per 100,000 people billion 50 million 2, billion 1 million billion 1 million 27 Next 6.5 billion million 26-2,777 Source: Kamps et al.(2006) Influenza Report 2006 ( 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 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). 4

5 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: 10/06/08) As of May , 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

6 Table 8.1: Cumulative number of confirmed human cases of avian influenza A (H5N1) reported to WHO (30 May 2008) Country Total Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Cases Deaths Azarbijan Bangladesh Cambodia China Djiboudi Egypt Indonesia Iraq Laos Myanmar Nigeria Pakistan Thailand Turkey Vietnam Total Source: Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. Available at: World. Accessed 10/06/08.

7 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 per 100,000 whereas the rate for healthy children is approximately 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 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 influenzarelated 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).

8 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 8 th 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 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 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). 8

9 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 , 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 firstline 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). 9

10 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 o o o o have significant cardiovascular disease (excluding people with hypertension only); have chronic renal disease; are immunocompromised; have diabetes mellitus; 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

11 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 Table : Treatment of H5N1 with antiviral combination therapy search strategy Source Study type Search terms PubMed SR (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND systematic [sb ] PubMed RCT (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND ((Clinical Trial[ptyp])) PubMed in vitro (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND in vitro PubMed animal (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) (Animals[Mesh:noexp]) PubMed case (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine OR rimantadine OR adamantane) AND (combined OR combination) AND (influenza) AND ((Humans[Mesh]) AND (Case Reports[ptyp])) PubMed general (oseltamivir OR zanamivir OR neuraminidase inhibitors) AND (amantadine 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 Cochrane CCT (oseltamivir or zanamivir) AND (amantadine or rimantadine) in Title, Abstract or Keywords. Study type: clinical trials Abbreviations: SR = systematic review; RCT = randomised controlled trial; CCT = controlled clinical trial Summary of available estimates of comparative effectiveness 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 years) the time to alleviation of symptoms was significantly reduced in the zanamivir group compared with the placebo group (Weighted median difference [WMD] days, 95% CI to days). A statistically significant difference was also observed in the healthy subgroup of patients (aged years) who were influenza positive (WMD days, 95% CI to days); the ITT high-risk (with concomitant disease) subgroup of patients aged 12 years 11

12 (WMD days, 95% CI to 0.05 days), and in the influenza positive high-risk subgroup of patients aged 12 years (WMD days, 95% CI to 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 nonsignificant 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 influenzapositive patients (confirmed influenza cases) the pooled hazard ratio for zanamivir was 1.17 (95% CI 1.00 to 1.37) compared to placebo. 12

13 In the random effects meta-analysis performed by Turner et al. (2003), in the healthy ITT subgroup (aged years) there was no statistically significant difference between zanamivir and placebo in the time to return to normal activities (WMD days, 95% CI to 0.02). In the healthy subgroup of patients with confirmed influenza positive, there was statistically significant difference between zanamivir and placebo of days (95% CI to 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 to 0.78) and 0.20 days (95% CI 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 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 highrisk individuals including both children and adults. The associated use of antibiotics was also 13

14 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

15 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 log 10 /ml vs log 10 /ml; median titres day 3, 0.83 log 10 /ml vs log 10 /ml; and median titres day 5, 0 log 10 /ml vs. 0 log 10 /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 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

16 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 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 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 MLD 50 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

17 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 : Summary of results survival after treatment with zanamivir Study Virus Model Treatment Regimen Results Conclusion Gubareva 1998 A/HK/156/97 (H5N1) Mouse 25 mg/kg/day 24 hrs preinfection, 4 hrs preinfection, twice daily T=9/10 C=1/10 Increased survival Leneva 2001 A/HK/156/97 (H5N1) Abbreviations: T = treatment; C = control Mouse 50 mg/kg/day for 5 days 4 hrs preinfection, twice daily for 5 days T=5/5 C=0/4 Completely protected 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 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 TCID 50 of 3.9 log 10 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 TCID 50 was 6.2 log 10 on day 3 after infection and 6.5 log 10 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 MLD 50 s 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 log 10 EID 50 ) and reached a peak on day 3 (log ). High titres continued to be present through to day 5 (7.5 log10 EID 50 ). 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

18 Table : Summary of results virus titre in the lung of animals treated with zanamivir Study Virus Model Treatment Regimen Results Conclusion Gubareva 1998 A/HK/156/97 (H5N1) Mouse 25 mg/kg/day Reduced titre Leneva 2001 A/HK/156/97 (H5N1) Mouse mg/kg/day 24 hrs preinfection, 4 hrs preinfection, twice daily for 5 days 4 hrs preinfection, twice daily for 5 days Abbreviations: T = treatment; C = control * Log 10 TCID 50 /ml on day 5 Shown graphically for a range of concentrations of zanamivir (0-100µm) T=5.7 * C=7.2 * T=reduced C=0 Reduced titre 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 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 : Summary of results virus titre in the brain of animals treated with zanamivir Study Virus Model Treatment Regimen Results Conclusion Leneva 2001 A/HK/156/97 (H5N1) Abbreviations: T = treatment; C = control Data not shown Mouse 1 mg/kg/day 4 hrs preinfection, twice daily for 5 days T=not detected C=0 Prevented spread to brain 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 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= ). 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 (IC 50, nm). Le et al. found that zanamivir treatment reduced viral titres in animals infected with virus that was oseltamivir-sensitive (P= ) or oseltamivirresistant (P=0.018). 18

19 Table : 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 (oseltamivir resistant stain) T=reduced C=0 5 mg/kg/day 2 hrs postinfection, twice daily for 5 days Zanamivir reduced viral titre in oseltamivirresistant 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 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 : Summary of results resistance in animals treated with zanamivir Study Virus Model Treatment Regimen Virus resistant after trial Gubareva 1998 Leneva 2001 A/HK/156/97 (H5N1) A/HK/156/97 (H5N1) Mouse 25 mg/kg/day 24 hrs pre-infection, 4 hrs pre-infection, twice daily for 5 days Mouse 50 mg/kg/day 4 hrs pre-infection, twice daily for 5 days In vitro evidence of treatment for human and avian influenza (H5N1) Not resistant Not resistant 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 IC 50 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 IC 50 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

20 and the level of inhibition increased with increasing concentration. The mean EC 50 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 IC 50 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 , BCX-1827, BCX-1898, and BCX 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 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 Susceptibilities were determined by enzyme inhibition assays with chemiluminescent or fluorescent substrates with known NA inhibitorresistant 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 IC 50 s of 0.62 and 0.43 µm by the chemiluminescent and fluorescent 20

21 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 IC 50 s of 0.61 and 0.92 µm by the chemiluminescent and fluorescent assays, respectively, whereas the mean oseltamivir IC 50 s 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 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 IC 50 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, IC 50 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

22 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 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% Turner (2003) ID not reported NAIA30010 NAIA2009 NAIA3005 Pooled* Diarrhoea 1% 2% N=132 N=145 Nasal symptoms 20% 9% Cough 16% 8% Throat/tonsil discomfort & pain 11% 6% Subset with chronic respiratory disease Nasal symptoms, cough, throat/tonsil discomfort & pain 7/7 (100%) 5/12 (41.7%) Nasal symptoms, 30/577 (5%) 27/581 (5%) gastrointestinal 27/144 (19%) 23/144 (17%) symptoms, throat irritation, fever and cough 27/544 (5%) 30/533 (5%) Asthma, cough or viral respiratory infections 7.5% 7.8% (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

23 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 /227 (4.0%) 14/228 (6.1%) (0.27, 1.49) (2006) Puhakka /293 (1.0%) 0/295 (0.0%) (0.37, ) Total 12/520 (2.3%) 14/523 (2.7%) (0.14, 13.49) Headache Matsumoto /77 (2.6%) 0/39 (0.0%) (0.12, 55.83) Monto 1999b 14/814 (1.7%) 9/422 (2.1%) (0.34, 1.87) Total 16/891 (1.8%) 9/461 (2.0%) (0.39, 1.97) Diarrhoea MIST 1998 Matsumoto 1999 Monto 1999b Puhakka /227 (0.9%) 2/77 (2.6%) 27/834 (3.2%) 6/293 (2.0%) 9/228 (3.9%) 2/39 (5.1%) 11/422 (2.6%) 6/295 (2.0%) (0.05, 1.01) 0.49 (0.07, 3.64) 1.25 (0.61, 2.55) 1.01 (0.32, 3.16) Nasal symptoms Nausea Bronchitis or pneumonia All types Total 37/1431 (2.6%) 28/984 (2.8%) (0.37, 1.63) MIST 1998 Monto 1999b Puhakka /227 (4.0%) 19/834 (2.3%) 35/293 (11.9%) 2/228 (0.9%) 14/422 (3.3%) 45/295 (15.3%) (1.00, 21.84) 0.68 (0.34, 1.37) 0.75 (0.47, 1.21) Total 63/1354 (4.7%) 61/945 (6.5%) (0.47, 2.06) MIST 1998 Makela 2000 Monto 1999b 4/227 (1.8%) 3/174 (1.7%) 20/834 (2.4%) 9/228 (3.9%) 5/182 (2.7%) 14/422 (3.3%) (0.13, 1.44) 0.62 (0.15, 2.64) 0.72 (0.36, 1.43) Total 27/1235 (2.2%) 28/832 (3.4%) (0.36, 1.10) MIST 1998 Monto 1999b Puhakka /227 (3.1%) 9/834 (1.1%) 9/293 (3.1%) 16/228 (7.0%) 11/422 (2.6%) 3/295 (1.0%) (0.17, 1.05) 0.41 (0.17, 0.99) 3.08 (0.83, 11.51) Total 25/1354 (1.8%) 30/945 (3.2%) (0.24, 2.26) MIST 1998 Matsumoto 1999 Puhakka /227 (36.6%) 21/77 (27.3%) 77/293 (26.3%) 98/228 (43.0%) 9/39 (23.1%) 80/295 (27.1%) (0.52, 1.11) 1.25 (0.51, 3.07) 0.96 (0.66, 1.38) Total 181/597 (30.3%) 187/562 (33.3%) (0.69, 1.14) Abbreviations: OR = pooled odds ratio; CI = confidence interval * Data were pooled using a random effects model.

24 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) 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) 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 for a 10-day course (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts (NICE 2007).

25 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 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

26 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 gain Zanamivir for this high-risk population is cost effective based on an $A per QALY Burls 2002 Burls 2000 Brady 2001 Scuffham 2002 All adults when influenza circulating High-risk adults when influenza circulating High-risk adults when influenza circulating All adults when influenza circulating High-risk adults when influenza circulating Elderly, prophylaxis and treatment Standard treatment (symptomatic treatment only) Standard treatment (symptomatic treatment only) Standard treatment (symptomatic treatment only) No intervention 65,000 per QALY gain 47,000 per QALY gain 31,500 per QALY gain (original model) 21,000 per QALY gain (modified model) $235,000 per QALY gain (low diagnostic rate of 14%) $95,000 per QALY gain (high diagnostic rate of 35%) $195,000 per QALY gain (low diagnostic rate of 14%) $77,000 per QALY gain (high diagnostic rate of 35%) 258,068 per LYG (chemoprophylaxis) Armstrong 2000 Healthy adults and high-risk Standard care ($16) per symptomfree day Abbreviations: NI = neuraminidase inhibitors; NR = not reported; QALY = quality adjusted life years benchmark. Zanamivir in high-risk group is unlikely to be cost-effective. However, there is great uncertainty in the model. NR It is not cost effective to prescribe zanamivir for the treatment of influenza in those who are not at risk of influenza-related complications. Zanamivir could be cost-effective in high-risk groups. But this is inconclusive. Chemoprophylaxis was most cost-effective 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. Zanamivir showed better cost effectiveness over standard care, compared to oseltamivir

27 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 At-risk Non-NIs treatment $US107.34/QALY gain - zanamivir dominated the Zanamivir is the drug of choice for use in atrisk patients. control therapy. Lynd Depending on the population and the perspective, the ICERs for antiviral treatment strategies ranged from $US5,000/QALY for amantadine in test-and-treat studies to greater than $US400,000/QALY for zanamivir or oseltamivir treatment in children. Sander 2005 Otherwise healthy adults usual care and oseltamivir Wailoo 2008 Otherwise healthy adults No treatment and oseltamivir Oseltamivir dominated zanamivir in cost per QALY gain. 49,405 per QALY gain compared to no treatment Oseltamivir dominates zanamivir in cost per QALY gain. Antiviral treatment or prophylaxis for influenza is likely to be more cost effective in specific populations at specific times during the influenza season, and during influenza seasons when the population prevalence reaches epidemic levels or there is mismatch between the vaccine and the circulating virus. Oseltamivir is a cost-effective treatment for influenza compared to usual care and to zanamivir in the otherwise healthy adult population. 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 gain Abbreviations: QALY = quality adjusted life years Recommended by NICE for for 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. 27

28 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 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 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 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: 28

29 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

30 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 coadministration 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

31 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

32 References American Academy of Pediatrics Committee on Infectious Diseases. Antiviral therapy and prophylaxis for influenza in children. Pediatrics 2007; 119: Ahmed A, Nicholson K, Nyugen V. Reduction in mortality associated with influenza vaccine during epidemic. Lancet 1995; 346: Armstrong E, Khan Z, Perry A, et al. The cost-effectiveness of zanamivir and oseltamivir for influenza treatment. Formulary 2000; 35: Brady B, McAuley L, Shukla, V. Economic evaluation of zanamivir for the treatment of influenza. Technology Report No. 13. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); Burls A, Clark W, Stewart A, et al. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation. Health Technology Assessment 2002; 6: Burls A, Clark W, Stewart A, et al. Zanamivir for the treatment of influenza in adults. Supplement. NICE; CDC. Rapid diagnostic testing for influenza Available at: (Accessed 11/06/2008) Chin T. Influenza: epidemiology, prevention and control. Available at: (Accessed 10/06/2008). Congressional Budget Office. A potential influenza pandemic: possible macroeconomic effects and policy issues. December ; Available at: Cox N, Subbarao K. Global epidemiology of influenza: past and present. Ann. Rev. Med. 2000; 51: Drinka P, Gravenstein S, Langer E et al. Mortality following isolation of various respiratory viruses in nursing home residents. Infect Control Hosp Epidemiol. 1990; 20: Elveback L, Fox J, Ackerman E, et al. An influenza simulation model for immunization studies. Am J Epidemiol. 1976; 103: Fleming D, Fleming D. Influenza pandemics and avian flu.[erratum appears in BMJ Nov 19;331(7526):1182]. [Review]. BMJ. 2005; 331(7524): Freund B, Gravenstein S, Elliott M, et al. Zanamivir: a review of clinical safety. Drug Safety 1999; 21: GlaxoSmithKline. Submission to NICE for Relenza (zanamivir) in the treatment of influenza. Relenza NICE submission document;

33 Glezen W, Cough R. Interpandemic influenza in the Houston area, N Engl J Med. 1978; 298: Glezen W, Cough R, Taber L. Epidemiological observations of influenza B virus infections in Houston, Texas. Am J Epidemiol. 1980; 111: Glezen P, Decker M, Perrotta D. Survey of underlying conditions of persons hospitalised with acute respiratory disease during the influenza epidemics in Houston Am Rev Respir Dis. 1987; 136: Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. Antimicrobial Agents and Chemotherapy 2004; 48(12): Gravenstein S. Johnston S. Loeschel E. et al. Zanamivir: A review of clinical safety in individuals at high risk of developing influenza-related complications. Drug Safety 2001; 24: Gubareva LV, McCullers JA, Bethell RC, Webster RG. Characterization of influenza A/HongKong/156/97 (H5N1) virus in a mouse model and protective effect of zanamivir on H5N1 infection in mice. Journal of Infectious Diseases 1998; 178: Guralnik M, Rosenbloom RA, Petteruti MP, Lefante C, Guralnik M, Rosenbloom RA et al. Limitations of current prophylaxis against influenza virus infection. [Review] [44 refs]. Am J Ther. 2007; 14(5): Hayden F, Gubareva L, Monto A, et al. Inhaled Zanamivir for the prevention of influenza in families. N Engl J Med. 2000; 343(18): Hayden F, Osterhaus A, Treanor J, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med. 1997; 337: Highlights of prescribing information. Available at: (Accessed 24/02/2008). Hedrick J, Barzilia A, Behre U, et al. Zanamivir in the treatment of symptomatic influenza A and B in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J. 2000; 19: Hurt AC, Barr IG, Hartel G, Hampson AW. Susceptibility of human influenza viruses from Australasia and South East Asia to the neuraminidase inhibitors zanamivir and oseltamivir. Antiviral Research 2004; 62: Inoue T, Watanabe K, Chonabayashi N, et al. Pharmacoeconomics of antiviral therapy for influenza in a Japanese hospital setting. Clin Drug Invest. 2005; 25: Ison MG, Gnann JW, Nagy-Agren S, Treanor J, Paya C, Steigbigel R, Elliot M, Weiss HL, Hayden FG. For the NIAID Collaborative Antiviral Study Group. Antiviral Therapy 2003; 8:

34 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. Kaiser L, Henry D, Flack N, et al. Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. Clin Infect Dis. 2000; 30: Kamps BS, Hoffmann C, Preiser W, Behrens G, Gottschalk R, Gurtler L et al. Influenza Report ; Available at: Lalezari J, Camion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch Intern Med. 2001; 161: Lazzari S, Stohr K. Avian influenza and influenza pandemics. Bulletin of the World Health Organisation. 2004; 82(4): A. Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KHL, Pham ND, Ngyen HH, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. Isolation of drug-resistant H5N1 virus. Nature 2005; 437:1108. Levena IA, Goloubeva O, Fenton RJ, Tisdale M, Webster RG. Efficacy of zanamivir against avian influenza A viruses that possess genes encoding H5N1 internal proteins and are pathogenic in mammals. Antimicrobial Agents and Chemotherapy 2001; 45 (4): Lynd L, Goeree R and O Brien B. Antiviral agents for influenza A. Comparison of Costeffectiveness data. Pharmacoeconomics 2005; 23: Makela M, Pauksens K, Rostila T, et al. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect. 2000; 40: Martinello RA, Martinello RA. Preparing for avian influenza. [Review] [77 refs]. Curr Opin Pediatr. 2007; 19(1): Matheson J, Harnden AR, Perera R, Sheikh A, Symmonds-Abrahams M. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database of Systematic Reviews 2007, Issue 1. Mauskopf J, Cates S, Griffin A, et al. Cost effectiveness of zanamivir for the treatment of influenza in a high risk population in Australia. Pharmacoeconomics 2000;17: McFee RB, McFee RB. Avian influenza: the next pandemic?[review]. Dis Mon. 2007; 53(7): McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, Hayden F, Zambon M. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrobial Agents and Chemotherapy 2003; 47(7):

35 MedWatch 2008: Safety alerts for drugs, biologics, medical devices, and dietary supplements. Available at: (Accessed 15/06/2008) MIST. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet 1998; 352: Monto A, Fleming D, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis. 1999b;180: Monto A, Robinson D, Herlocher M, et al. Zanamivir in the prevention of influenza among healthy adults - a randomized controlled trial. JAMA. 1999a; 282(1):31-5. Monto AS, Sullivan KM. Acute respiratory illness in the community. Frequency of illness and the agents involved. Epidemiol Infect. 1993; 110: Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. J Antimicrob Chemotherapy. 1999c; 44: Murphy K, Eivindson A, Pauksens K, et al. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomised, placebo-controlled, multicentre study. Clin Drug Invest. 2000; 20: Neuzil K, Wright P, Mitchel E, et al. Burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr. 2000a; 137: Neuzil K, Mellen B, Wright P, et al. The effect of influenza on hospitalization, outpatient visits, and courses of antibiotics in children. N Engl J Med. 2000b; 342: National Institute for Health and Clinical Excellence (NICE). Influenza (prophylaxis) - amantidine, oseltamivir and zanamivir: appraisal consultation document. Available at: (Accessed 22/06/2008). National Institute for Clinical Excellence (NICE). Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza. Technology Appraisal Osterholm MT. Preparing for the next pandemic. N Engl J Med. 2005; 352(18): Poland GA. Vaccines against Avian Influenza - A race against time. N Engl J Med. 2006; 354(13): Raftery J. NICE: faster access to modern treatments? Analysis of guidance on health technologies. BMJ 2001; 323: Rothberg M, He S, Rose D. Management of influenza symptoms in healthy adults. Costeffectiveness of rapid testing and antiviral therapy. J Gen Intern Med. 2003; 18:

36 Sander B, Gyldmark M, Hayden F et al. Influenza treatment with neuraminidase inhibitors. Cost-effectiveness and cost-utility in healthy adults in the United Kingdom. Eur J Health Econom. 2005; 50: Scuffham PA, West PA. Economic evaluation of strategies for the control and management of influenza in Europe. Vaccine 2002;20: Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong H, Morrey JD, Furuta Y. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrobial Agents and Chemotherapy. 2007; 51(3): Smee DF, Huffman JH, Morrison AC, Barnard DL, Sidwell RW. Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities. Antimicrobial Agents and Chemotherapy 2001; 45 (3): Smith K and Roberts M. Cost-effectiveness of newer treatment strategies for influenza. Am J Med. 2002;113: Stephenson I, Zambon M. The epidemiology of influenza. Occup. Med. 2002; 52: Sullivan K, Monto A, Longini I, Jr. Estimates of the US health impact of influenza. Am J Public Health. 1993; 83: Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes.[see comment]. Nature. 2005; 437(7060): Thompson W, Shay D, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004; 292: 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): Van de Vyver N, Janssens W, De Sutter A, Michiels B, Govaerts F, Hulstaert F, Lambert M- L, Peleman R, Ramaekers D. Antiviral agents in seasonal and pandemic influenza. Literature study and development of practice guidelines. Good Clinical Practice (GCP). Brussels: Belgian Health Care Knowledge Centre (KCE); KCE reports 49C (D/2006/10.273/67). Wailoo A, Sutton A, Cooper N, et al. Cost-effectiveness and value of information analyses of neuraminidase inhibitors for the treatment of influenza. Value in Health 2008; 11: World Health Organisation. Influenza - Fact Sheet: No Available at: World Health Organisation. Avian influenza ("bird flu") - Fact sheet. Available at: February Zimmerman R. Recent changes in influenza epidemiology and vaccination recommendations. The Journal of Family Practice 2005; 54: S

37 Zucs P, Buchholz U, Haas W, Uphoff H. Influenza associated excess mortality in Germany, Emerging Themes in Epidemiology. 2005; 2(6):

38 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 38

39 Results of the meta-analyses performed by Turner et al. (2003) Appendix B 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) 39

40 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) 40

41 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) 41

42 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) 42

43 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) 43

44 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 years, 15% vaccinated): NAIA3005 Source: Turner et al. (2003) 44