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

PROPOSAL FOR THE INCLUSION OF AMANTADINE AND RIMANTADINE IN THE WORLD HEALTH ORGANISATION MODEL LIST

OF ESSENTIAL MEDICINES

2008

Sheree Kable BMed, PhD

Discipline of Clinical Pharmacology School of Medicine and Public Health

Faculty of Health University of Newcastle

Level 5, Clinical Sciences Building, NM2 Newcastle Mater Hospital

Edith Street, Waratah, 2298

New South Wales AUSTRALIA

Tel +61-02-49211294 Fax + 61-02-49602088

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Amantadine and rimantadine belong to the adamantane class of drugs which have antiviral effects against influenza A viruses. They inhibit the M2 ion channel membrane protein, inhibiting viral replication by blocking virus entry into cells. They have no activity against influenza B viruses. Development of resistance of influenza A to adamantanes is common, both spontaneously and during treatment of infected individuals. Amantadine is also used for anti-parkinsonian treatment, including drug induced extrapyramidal symptoms. 1. Summary statement of the proposal Amantadine and rimantadine are proposed for the inclusion in the World Health Organisation (WHO) Model List of Essential Medicines for the prophylaxis and treatment of influenza A, specifically the subtype H5N1 which has a high case fatality rate. 2. Name of focal point in WHO submitting or supporting the application 3. Name of the organisation consulted and/or supporting the application Discipline of Clinical Pharmacology, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Level 5, Clinical Sciences Building, NM2, Calvary Mater Hospital, Edith Street, Waratah, 2298, New South Wales, Australia. 4. International Nonpropriety Name of the medicines Amantadine hydrochloride (Anatomical Therapeutic Chemical N04BB01) Rimantadine hydrochloride (Anatomical Therapeutic Chemical J05AC02) 5. Formulation proposed for inclusion Amantadine is available in 25, 50 and100 mg tablets or capsules, and syrup form. Rimantadine is available in 100, 200, and 400 mg tablets or capsules, and syrup form. 6. International availability It is now available produced by over 70 companies under more than 30 trade names in more than 30 countries worldwide. The availability of rimantadine is more limited, being produced only in four countries (United States, Israel, Mexico and France). Additionally, amantadine is now broadly available in generic forms.1 See Appendix 1 for detailed lists. 7. Whether listing is requested as an individual medicine or as an example

of a therapeutic group Amantadine and rimantadine comprise the class of drugs known as adamantanes. 8. Information supporting the public health relevance: burden of illness and

potential for pandemic Illness due to influenza virus is characterized by sudden onset of high fever, myalgia, headache and severe malaise, non-productive cough, sore throat, and rhinitis infection. With most strains of virus ill usually lasts for about a week, and recovery occurs within one to two weeks without requiring any medical treatment. However,

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high risk individuals such as the elderly, young children and those with chronic medical conditions are particularly vulnerable to complications and death.2

Influenza rapidly spreads around the world in seasonal epidemics with 5-15% of the population affected in industrialised countries, which causes a substantial economic burden in hospital and other health care costs and lost productivity. These annual epidemics are thought to result in between three and five million cases of severe illness around the world each year. Between 250 000 and 500 000 people have fatal outcomes, primarily in those over 65 years of age, and mostly occur as a consequence of fulminant influenza virus pneumonia or of secondary respiratory bacterial infections.3,4

Frequent minor genetic changes of components occur in circulating viruses. Currently circulating influenza viruses that cause human disease are divided into two major groups, designated A and B. Influenza A are further defined by 2 different protein components (known as antigens) on the surface of the virus, labelled ‘H’ (haemagglutinin) and ‘N’ (neuraminidase) components. The most common subtypes currently important for humans are influenza A(H3N2) and A(H1N1), of which the former is currently associated with most deaths. 5 In the last century, however, the influenza A viruses have undergone major genetic changes three times, resulting in global pandemics and large tolls in terms of both disease and deaths. In 1918-1919 the “Spanish Flu” is thought to have killed at least 40 million people. Two other influenza A pandemics occurred in 1957 (“Asian influenza”) and 1968 (“Hong Kong influenza”). All three pandemics were associated with severe outcomes among healthy young people as well as those in high risk groups. In 1997 a new, highly pathogenic influenza subtype A(H5N1) occurred in Hong Kong. This was the first known instance of human infection with this virus, known as ‘avian flu’, which is directly transmitted from birds to humans. There were 18 cases reported with six fatalities. A further two cases occurred in Hong Kong (one fatal) in 2003, and one further fatal case in China.6 Since 2004, there have been human cases reported in six countries,: Cambodia, China, Indonesia, Thailand, Turkey, Viet Nam and Iraq, and generally follows geographical extension of outbreaks among avian populations. Viet Nam has been the most severely affected country, with more than 90 cases.5 The most recent reports were two fatal cases in Indonesia in May, 2008.7 The total number of human cases of avian Influenza A (H5N1) confirmed by laboratory testing up to 19 June 2008 was 385, of which 243 were fatal (63%).8 Case fatality is high in all age groups, but tends to highest in persons aged 10 to 39 years, in contrast with seasonal influenza, where mortality is highest in the elderly.9 It is not yet known why H5N1 causes such severe disease in children and young adults, multi-organ failure in addition to severe respiratory disease. All human cases have coincided with outbreaks of highly pathogenic H5N1 avian influenza in poultry. Efficient viral transmission among poultry has led to the spread of the virus, primarily in Asia, leading to the loss of greater than 100 million birds

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from disease and culling.10 Human-to-human transmission of the virus is exceptional but has been described, most recently in a family cluster in Thailand.11 There are a number of similarities of the H5N1 virus strains circulating in recent years to that of the 1918 pandemic, including the severity of disease, its concentration in the young and healthy, and the occurrence of primary viral pneumonia in the absence of secondary bacterial infection. However, adaptive changes would be necessary for strains to acquire improved transmissibility from human to human, which are expected to cause a loss in pathogenicity. Thus the high lethality of the current H5N1 strains are not likely to be retained in an H5N1-like pandemic virus. Conversely, no virus of the H5 subtype has ever circulated within the lifetime of today’s world population among humans, if ever, so vulnerability to an H5N1-like pandemic virus would be universal.12 Rapid international spread is certain once a virus with the appropriate characteristics emerges. In contrast to pandemics last century, spread along the routes of international air travel could compromise response capacity should large parts of the world experience almost simultaneous outbreaks. Many of the public health interventions that successfully contained SARS will not be effective against a disease that is far more contagious, has a very short incubation period, and can be transmitted prior to the onset of symptoms.1 2 It is not known whether rapid intervention with a pandemic vaccine, if available in time and if quantities are sufficient, could successfully interrupt transmission. Currently the world’s annual total production capacity for seasonal vaccine is limited to about 350 million doses, which realistically does not suffice to cover the global high-risk population.13 Thus effective anti-viral medication may be essential in formulating pandemic responses. 9. Treatment details

9.1 Indications for use

Amantadine and rimantadine may be used for both influenza A prophylaxis and treatment. They are not effective against influenza B. 9.2 Recommended dosages

9.2.1 Recommended dosages of amantadine for influenza A14

Amantadine is available in tablet 100 mg, capsule and syrup form. Dosages are the same for treatment and prophylaxis, with the exception that treatment is recommended for 5 days for treatment, and for 7 to 10 days after the last known exposure for prophylaxis.

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Adults and children, 10 to 65 years: 100mg twice daily for 5 days Elderly (over > 65 yrs): 100 mg once daily Children* - 10–12 years : 100 mg twice daily - 5-9 yrs:

1–9 years: 5 mg/kg/day (not to exceed 150mg/day, in 2 divided doses)

Patients with renal impairment - creatinine clearance (ml/min/1.73 m2)†: - 30–50: - 15–29: - <15:

200 mg 1st day and 100 mg each day thereafter 200 mg 1st day and 100 mg on alternate days 200 mg every 7 days

Patients on haemodialysis: 200 mg every 7 days (From CDC 2006a. WHO 2006) Contraindications and precautions:

• Amantadine should be used in caution in patients receiving treatment with neuropsychiatric drugs and those with seizure disorders.

• Amantadine should not be used by women who are breastfeeding. • Poor adherence rates secondary to adverse effects have been reported with

amantadine use. 9.2.1 Recommended dosages of rimantadine for influenza A1 4

Rimantadine is available in tablet and syrup form. Rimantadine has been used for as long as 7 weeks for chemoprophylaxis of seasonal influenza A (at doses of 100 mg twice daily in adults and children over 10 years of age) Adult: 100 mg twice a day Elderly (over > 65 yrs): 100 mg once daily Children < 10 years: 5 mg/kg, not exceeding 150 mg, once daily or

in two divided doses Patients with severe hepatic dysfunction or renal failure (creatinine clearance of 10 ml/min) should have the dose reduced to 100 mg daily. There are currently no data available regarding the safety of rimantadine in patients with renal or hepatic impairment.1 4 9.4 Reference to existing WHO and other clinical guidelines

The World Health Organisation published rapid advance guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus in 2006 which included recommendations for the use adamantanes, and these were updated in August 2007.1 4

,15 A summary of the recommendations for amantadine and rimantadine in these guidelines are shown in Table 9.4

* The recommended regimen in the British National Formulary (BNF) and in Japan is 100mg /d for patients > 10yrs of

age. † Exact dosages for creatinine clearance vary in differing countries

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Table 9.4 Summary of recommendations for use of amantadine and rimantadine for treatment or prophylaxis, WHO recommendations 2006 and 200714

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2006 Guidelines

Treatment

A. If neuraminidase inhibitors are available, clinicians should not administer amantadine or rimantadine alone as a first-line treatment to patients with confirmed or strongly suspected human infection with avian influenza H5N1 (strong recommendation, very low quality evidence)[Recommendations 3 and 5].

B. If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer amantadine as a first-line treatment to patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus (weak recommendation, very low quality evidence) [Recommendations 4 and 6].

Prophylaxis

C. If the virus is known or likely to be an M2 inhibitor resistant H5N1 virus, amantadine or rimantadine should not be administered as chemoprophylaxis against human infection with avian influenza A (H5N1) virus (strong recommendation, very low quality evidence) [Recommendations 16 and 20].

D. If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, amantadine might be administered as chemoprophylaxis against human infection with avian influenza A (H5N1) virus in high or moderate risk exposure groups (weak recommendation, very low quality evidence) [Recommendations 17 and 21].

E. If neuraminidase inhibitors are not available and even if the virus is known or likely to be susceptible, amantadine should probably not be administered as chemoprophylaxis against human infection with avian influenza A (H5N1) virus in low risk exposure groups (weak recommendation, very low quality evidence) [Recommendation 18 and 22].*

F. In pregnant women, the elderly, people with impaired renal function and individuals receiving neuropsychiatric medication or with neuropsychiatric or seizure disorders amantadine should not be administered as chemoprophylaxis against human infection with avian influenza A (H5N1) virus (strong recommendation, very low quality of evidence) [Recommendations 19 and 23].

2007 Update

When neuraminidase inhibitors are available, monotherapy with amantadine or rimantadine is not recommended. Although treatment may have had clinical benefit in isolated instances, monotherapy is associated with a high frequency of rapid resistance emergence, and globally the majority of A(H3N2) and some A(H1N1) influenza viruses currently show resistance. In addition, many A(H5N1) virus isolates show primary resistance. [Section 3.2, p7] * does not apply to pregnant women, the elderly, people with impaired renal function and individuals

receiving neuropsychiatric medication or with neuropsychiatric or seizure disorders. National and international agencies around the world have also produced guidelines for the use of antiviral agents in treatment and prevention of influenza A including: • European Medicines Agency16

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• US Centre for Disease Control and Prevention17 • Public Health Agency of Canada18 • Australian Government Department of Health and Aging19 • UK National Institute for Clinical Excellence20 • German Association for Control of Virus Diseases21 • Health Council of Netherlands22 • Belgian Health Care Knowledge Centre23 • World Health Organisation Regional Office for Africa24 The recommendations of these guidelines reflect those of the World Health Organisation guidelines shown in Table 9.4. All recommend neuraminidase inhibitors (oseltamivir and/or zanamivir) as first line pharmacotherapy for treatment or prophylaxis of influenza A. Some include the caveat that amantadine or rimantadine may be used for prophylaxis if the influenza strain is known or likely to be sensitive to adamantanes. 10. Comparative effectiveness 10.1 Identification of clinical evidence

Database searches were conducted in Medline, EMBASE, and the Cochrane Library. Terms used were:

1. adamantanes 2. amantadine 3. rimantadine 4. 1 or 2 or 3 5. influenza 6. 4 and 5 7. Date limited to 2000 - 2008

To identify studies pertaining to H5N1 influenza, the following terms were used: 8. Influenza A, H5N1 subtype 9. Influenza in birds 10. avian influenza (as keyword) 11. 7 or 8 or 9 12. 7 and 10

Internet searches were also conducted through http://www.google.com.au/ using the terms:

- influenza adamantanes

- influenza amantadine

- influenza rimantadine

- influenza guidelines

Abstracts of potentially relevant documents were examined, and the full text of pertinent documents obtained whenever possible. References of documents were also examined for potentially relevant papers.

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http://www.google.com.au/

10.2 Summary of available data

10.2.1 Extent of evidence

No controlled clinical trial has evaluated amantadine or rimantadine for the prophylaxis or treatment of H5N1 infection. Evidence for their use must therefore be based on the extrapolation of data from other studies conducted to evaluate the treatment and chemoprophylaxis of other influenza strains. Additional evidence is derived from small observational case series of H5N1 patients and results from in vitro and animal model studies of H5N1. Reviews

Four systematic reviews were located that examined amantadine and/or rimantadine in the treatment and prophylaxis of influenza A strains other than H5N1. Jefferson et al (2006)25 was a Cochrane systematic review that reported on treatment and prophylaxis in adults, including adverse effects. Two reviews examined treatment and prophylaxis in children and the elderly, Galvao et al (2008)26 in both adamantanes, and Turner et al (2003)27 in amantadine only. Jefferson et al (2008)28 reviewed the evidence for the use of adamantanes for prophylaxis and treatment of influenza A in adults, children, the elderly, (as well as neuraminidase inhibitors, and vaccines for prophylaxis), but relied on the previous reviews. Six other reviews were located, including a report of the Cochrane review (Jefferson et al, 2006b)29, but four of these were not original systematic reviews and relied primarily on the Turner et al (2003) and Jefferson et al (2006) reviews16,23, , 30 31

Wintermeyer and Nahata (1995)32 conducted a review of rimantadine which is largely superceded by the later Cochrane reviews, but is useful for the provision of adverse event data. Most trials included in the reviews were conducted prior to 1990, but in recent years resistant strains of influenza A viruses are becoming more prevalent around the world, with over 80% being resistant in parts of Asia since 2005 (see Section 10.2.3). Consequently, the reviews of effectiveness of adamantanes in prophylaxis and treatment of influenza A need to be interpreted in light of the prevalence of resistant strains in any given geographical area. Other studies

Six of five other trials were included, which either did not fit the criteria of the reviews or were published after them. Thirty five reports of studies of resistance of influenza A to adamantanes were found, eight of these concerning the H5N1 strain in humans or animals. Seven papers were primarily reports of adverse events associated with adamantane use. One case series was found describing patients with H5N1 infection treated with amantadine. There were also two in vitro studies, four animal studies and one human study describing the use of a combination of an adamantane and a neuraminidase inhibitor to treat influenza A.

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10.2.2 Prophylaxis

Adults

Twenty prophylaxis trials were identified in Jefferson et al (2006),25 all of which were published before 1990 and examined laboratory confirmed influenza (i.e. serological and/or isolation of influenza virus from nasal fluids) or influenza-like illness (ILI). Given the age of the trials, the quality was reasonable, with 17 stating that allocation was randomised and all except one stating they were double blind. However, the studies used a large variety of outcomes, and many showed large differences between the number of subjects randomised and the numbers reported in outcomes (see Table 10.2.2.1). Prophylaxis with amantadine prevented 61% of laboratory confirmed influenza A cases and prevented 25% influenza-like illness. There was no effect on the occurrence of asymptomatic cases confirmed by laboratory but one trial found reduced viral nasal shedding/persistence in upper airways at 2-5 days. The point estimates of prophylaxis with rimantadine showed a 72% reduction of confirmed influenza and 35% of influenza-like illness, but these results did not reach statistical significance which may have been due to the smaller number of participants in only three trials. The effectiveness of amantadine compared with rimantadine was examined in two trials, but no statistically significant difference was found in either confirmed cases of influenza or influenza-like illness. Table 10.2.2.1 Prophylaxis with amantadine and rimantadine from Jefferson et al (2006)25 No. trials No. subjects Relative risk (95% CI) Amantadine vs. placebo Influenza cases* 11 4645 0.39 (0.24, 0.65) ILI cases 15 17496 0.75 (0.64, 0.87) Viral nasal shedding 2-5 days 1 79 0.68 (0.53, 0.87) Influenza cases (asymptomatic) 4 963 0.85 (0.40, 1.80) Rimantadine vs. placebo Influenza cases* 3 688 0.28 (0.08, 1.08) ILI cases 3 688 0.65 (0.35, 1.20) Influenza cases (asymptomatic) 1 265 1.39 (0.45, 4.27) Amantadine vs. rimantadine Influenza cases* 2 455 0.89 (0.48, 1.65) ILI cases 2 455 0.88 (0.57, 1.35) * confirmed by serological and/or isolation of influenza virus from nasal fluids ILI = influenza-like illness Children or adolescents

Turner et al (2003) identified three trials of amantadine for prophylaxis in children or adolescents under 18 years of age. It did not meta-analyse the trials due to heterogeneity of methodology and outcomes (attempted meta-analysis also showed p=0.06, I2 = 64.7%). Two of the three trials, Finklea et al (1967) and Quilligan et al

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(1966) showed a reduction of the risk of influenza infection, by 68% and by 88% respectively. The third trial, Leung et al (1979) did not show a significantly reduced risk, though this may have been due to lack of power as only 40 participants were included. Galveo et al (2008) included two trials using amantadine, one of which was included in the Turner et al (2003) review (Finklea et al, [1967]). The baseline risk of influenza in these trials was 0.10, calculated from the control event rate. Meta-analysis of the two amantadine trials in Galveo et al (2008) showed that prophylaxis with amantadine prevented 89% of cases (Table 10.2.2.2). Galveo et al (2008) also included three trials using rimantadine for influenza prophylaxis. Prophylaxis with rimantadine failed to reach statistical significance, though the three trials were small and may not have been sufficiently powered to detect a difference (point prevalence showing 51% prevention). The trials for amantadine and rimantadine were heterogeneous (p = 0.05, I2 = 56.8%) and could not be combined in meta-analysis. Table 10.2.2.2 Prophylaxis with amantadine and rimantadine in children and adolescents (1 to 19 years) from Galveo et al (2008) 26 and Turner et al (2003)27

Review / Trial No. trials No. subjects Relative risk (95% CI) Amantadine Turner et al (2003) Quilligan et al (1966) * - 169 0.32 (0.12, 0.64) Finklea et al (1967)* - 237 0.12 (0.02, 0.89) Leung et al (1979)* - 40 0.88 (0.39, 1.93) Galveo et al (2008) Amantadine vs placebo† 2 773 0.11 (0.04, 0.30) Rimantadine Galveo et al (2008) Rimantadine vs placebo* 3 178 0.49 (0.21, 1.15) * one trial confirmed influenza by complement fixation and/or Hemagglutination inhibition titre,

and one by isolation of influenza virus from nasal fluids † influenza identified by “laboratory proved infection” Elderly

Turner et al (2003) included two trials using amantadine for prophylaxis of influenza A in the elderly. In one identified study (Peterrsson et al 1980)33 no influenza occurred. In the other study, (Leeming, 1969)34, influenza occurred in only one of four hospital wards studied, an acute rehabilitation ward, and did not show a significant reduction in influenza cases in the treated group. Galveo et al (2008) included three trials of rimantadine, two comparing rimantadine to placebo (Monto et al, 1995 and Patriarca et al, 1984) and the third comparing rimantadine to zanamivir, a neuraminidase inhibitor (Schilling et al, 1998). Rimantadine did not show a significant reduction of influenza cases any of the studies, either including or excluding the Schilling et al (1998) trial.

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When the results of the three trials comparing amantadine or rimantadine to placebo were pooled the resulting relative risk was not significantly different to placebo, though again this may be due to low power (see Table 10.2.2.3). Table 10.2.2.3 Prophylaxis with amantadine or rimantadine in the elderly from Galveo et al (2008)2 6 and Turner et al (2003)27 Review / Trial No. trials No. subjects Relative risk (95% CI) Amantadine Turner et al (2003) Leeming (1969) - 54 0.61 (0.26, 1.35) Rimantadine Galveo et al (2008) Including Schilling et al 1998 3 191 0.74 (0.13, 4.07) Excluding Schilling et al 1998 2 75 0.44 (0.12, 1.63) Pooled result (random effects): amantadine or rimantadine

Monto (1995) Patriarca (1984)

Leeming (1969)

3 245 0.55 (0.27, 1.12)

Chi-square for heterogeneity: p = 0.1015 I2 statistic with 95% uncertainty interval = 0% (95%CI = 0% to 72.9%) Other trials

Hayden et al (1989)35 was excluded from the Jefferson et al (2006) and the Galveo et al (2008) reviews because it included children and adults but did not give outcomes by age groups. They conducted a randomized, double-blind, placebo-controlled study among families with a case of influenza A in one member. All the family members (including the index patient) were given either rimantadine (28 families) or placebo (208 families) for 10 days. Rimantadine was found to be ineffective in protecting family members from influenza A infection. Gravenstein et al (2005)36 evaluated the efficacy and tolerability of zanamivir versus rimantadine in a prospective double-blind, randomized, controlled trial of residents of long-term care facilities for 3 influenza seasons (1997 to 2000). Following the declaration of an influenza outbreak, subjects were randomized to inhaled zanamivir 10 mg or rimantadine 100 mg once daily for 14 days. Symptomatic, laboratory-confirmed influenza occurred in 3% of zanamivir subjects and 8% of rimantadine subjects during chemoprophylaxis (P = .038; additional protective efficacy for zanamivir over rimantadine = 61%) and rimantadine-resistant variants were common. Summary of prophylaxis trials

Overall, amantadine appears to prevent up to 61% of cases of influenza A when given for prophylaxis in adults, and may reduce the case rate in children up to 88%, but no trials have been found in the elderly. Rimantadine has not been convincingly demonstrated to prevent influenza A in adults, children, or the elderly though this may be due to small sample sizes of trials, but neuraminidase inhibitors are more likely to be effective.

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10.2.3 Treatment

Adults

Thirteen published treatment trials were identified in Jefferson et al (2006). All were published before 1990 except one (Ito et al, 2000)37 though the quality was reasonable considering their age. The allocation was stated to be random in 11 of the 13 trials, though the method was not reported. Again, there was a lack of information on subjects randomised but not included in results. Treatment with oral amantadine reduced the duration of fever by almost one day. Some studies reported fever outcomes as dichotomous variables, and meta-analysis of these showed a 79% reduction of cases with fever at 48 hours. However, amantadine was as effective as aspirin or other standard medications (antipyretic or antiinflammatory drugs) in reducing duration of fever. There were no difference with oral amantadine treatment compared with placebo in the duration of hospital stay, nor any effect on viral nasal shedding or persistence of influenza A viruses in the upper airways up to 5 days after treatment. (Table 10.2.2.1). One trial also examined the effect of inhaled amantadine compared with placebo, but showed no difference in symptom scores or viral shedding. Treatment with rimantadine also shortened duration of fever compared to placebo by 1.24 days, and there was a reduction of cases with fever at 48 hours by 84%. As with amantadine, there was no effect on nasal shedding or persistence of influenza A viruses in the upper airways after up to five days of treatment (Table 10.2.2.1). There was no difference shown in treatment with amantadine compared with rimantadine in duration of fever, though there were only two trials identified and both involved small numbers (less than 20 subjects in each arm) so the result may be due to lack of statistical power. Table 10.2.3.1 Treatment with amantadine or rimantadine from Jefferson et all (2006)25 No.

trials No.

subjects Statistical

Method Effect size (95% CI)

Amantadine vs. placebo Duration of fever ≥ 37oC (days) 7 542 WMD -0.99 (-1.26, -0.71) Duration of hospital stay (days) 1 36 WMD -0.90 (-2.20, 0.40) Cases with fever at 48 hours 2 85 RR 0.21 (0.07, 0.66) Viral nasal shedding at 2 - 5 days* 3 170 RR 0.96 (0.72, 1.27) Amantadine vs. standard medications†

Duration of fever ≥ 37oC (days) 2 78 WMD 0.25 [-0.37, 0.87] Rimantadine vs. placebo Duration of fever ≥ 37oC (days) 3 82 WMD -1.24 (-1.71, -0.76) Cases with fever at 48 hours 4 122 RR 0.16 (0.05, 0.53) Viral nasal shedding at 2 - 5 days* 3 152 RR 0.67 (0.22, 2.07) Amantadine vs. rimantadine Duration of fever ≥ 37oC (days) 1 40 WMD 0.20 (-0.56, 0.96) Cases with fever at 48 hours 2 73 RR 0.99 (0.23, 4.37) WMD = weighted mean difference; RR = relative risk * or persistence in upper airways † antipyretic or antiinflammatory drugs

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Children or adolescents

Turner et al (2003) identified two trials of amantadine for treatment of children or adolescents under 18 years of age (Kitomoto 196838 and Kitomoto 197139). Both of these trials were included in the Galveo et al (2008) review, which also identified one trial of rimantadine for the treatment of children and adolescents. Table 10.2.2.2 summarises the results of amantadine and rimantadine treatment in children from Galveo et al (2008). Table 10.2.2.2 Treatment with amantadine and rimantadine in children from Galveo et all (2008) 26

No. trials

No. subjects

Statistical Method

Effect size (95% CI)

Amantadine or rimantadine vs. placebo Fever day on day 3 3 173 RR 0.39 [0.20, 0.79] Rimantadine vs. placebo Cough day on 7 1 69 RR 0.83 [0.63, 1.10] Malaise day on 6 1 69 RR 1.04 [0.63, 1.70] Conjunctivitis day on 5 1 69 RR 0.17 [0.01, 3.49] Eye symptoms day on 5* 1 69 RR 0.58 [0.10, 3.24] * pain on movement and visual distortion There was no difference in the risk of fever on day three when the two with amantadine trials were combined, but when the rimantadine trial was included in analysis a reduction of 61% was demonstrated. Other symptoms were not reported in the amantadine trials. The rimantadine trial examined the symptoms of cough, malaise, conjunctivitis and other eye symptoms, but none showed significant differences with treatment compared with placebo. Elderly

There were no trials of amantadine or rimantadine for the treatment of influenza A in the elderly identified that were of sufficient quality to be included in the Galveo et al (2008) review. Other trials

Kawai et al (2005)40 compared amantadine with oseltamivir for treatment of influenza A, with no placebo arm. They showed that the duration of fever was reduced if amantadine was given in the first 12 hours of onset of symptoms compared with after 12 hours. However, a further study by the same authors, Kawai et al (2007)41 showed that the duration of fever in patients with influenza A treated with amantadine had increased over three influenza seasons (2003–2004, 2004–2005, and 2005–2006) in all age groups, but there was no corresponding decrease in the effectiveness of oseltamivir. The authors concluded that the most likely explanation was the emergence of adamantane resistant virus strains. Shobugawa et al (2008)42 studied children with laboratory confirmed influenza A, and of 50 children treated with amantadine, 15 were found to have strains resistant to amantadine after treatment. In the children with resistant strains fever recurred at day

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4 from diagnosis, and was significantly higher than the remaining 35 with amantadine sensitive strains, and was also higher than children treated with oseltamivir or no antiviral medication. In Hayden et al (1989)35 all family members including the infected index patient were given either rimantadine or placebo for 10 days. In the treatment group, rimantadine-resistant strains of influenza A virus (H3N2 subtype) were recovered from eight index patients, six contacts with secondary illnesses and five contacts treated with rimantadine. This study supports the conclusion that if rimanadine is used for both treatment and postexposure prophylaxis in families, rapid selection and apparent transmission of drug-resistant influenza A viruses can occur. In a report of the index and co-primary patients in the same study, Hayden et al (1991)43 showed that treatment with rimantadine reduced the duration of fever and missed days of work or school. However, the one third of rimantadine recipients who shed resistant virus had slower resolution of illness than those with rimantadine sensitive virus. Doyle et al (1998)44 conducted randomized double-blind experimental study of rimantadine treatment with subjects cloistered for 8 days and challenged with a rimantadine-sensitive strain of influenza A H1N1 virus. In the treatment group, who received rimantadine for 8 days, 17 of 51 subjects (38%) became ill, and 26 of 54 (53%) in the placebo group. Though a beneficial effect of rimantadine was documented for virus shedding, symptom load, and sinus pain, there was no effect on nasal patency, mucociliary clearance, nasal signs, or on symptoms and signs of otologic complications. Summary of treatment trials

Treatment with amantadine for influenza A shortens the duration of fever by approximately one day, but there is no evidence for a significant reduction of mortality or serious complications such as pneumonia. Treatment with standard medications such as aspirin or other antipyretics appear to be as effective in reducing fever duration as amantadine. 10.2.4 Case series of H5N1 infection

Chan (2002)45 reported on 18 cases of H5N1 infection in Hong Kong in 1997. Information on antiviral therapy was not available for six patients. Three patients did not have any viral treatment and recovered, and one was treated with acyclovir late in the course of illness but subsequently died. The remaining eight patients were treated with amantadine at varying stages; four died and four recovered (see A.2 in Appendix 2). The authors stated that amantadine was used for most of the patients with severe infections, and the majority of those patients were already at a critical stage of the disease when the drug was administered. Thus it is difficult to draw any conclusions regarding the efficacy of amantadine in H5N1 infections from this case series. 10.2.5 Combination treatment with a neuraminidase inhibitor

A number of in vitro and animal studies have demonstrated a greater antiviral effect of adamantanes on influenza A when combined with a neuraminidase inhibitor

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(oseltamivir or zanamivir) The latter have a different mechanism of action to the adamantanes, blocking the function of the viral neuraminidase protein and thus preventing the virus from budding from the host cell. There is also the potential to decrease the development of drug-resistance based on the reduced probability of the appearance of viral mutants with resistance to both classes simultaneously. In vitro studies

Govorkova et al (2004)46 tested combinations that paired a neuraminidase (NA) inhibitor (zanamivir, oseltamivir, or peramivir) with rimantadine against infection of MDCK cells (Madin Darby Canine kidney cells; a polarized immortalized epithelial cell line) with H1N1 (A/NewCaledonia/20/99) and H3N2 (A/Panama/2007/99) subtypes of influenza A virus. All three combinations showed additive and synergistic effects with no cytotoxicity. Ilyushina et al (2006)47 tested three viruses, H1N1 (A/Nanchang/1/99), H3N2 (A/Panama/2007/99) and H5N1 (A/Hong Kong/156/97) subtypes, in vitro and found that virus yields in cells were significantly reduced when treated with the combination of amantadine and low doses of oseltamivir. After multiple passages in MDCK, treatment with either drug alone resulted in reduced sensitivity to that drug, but when amantadine was used combined with the higher concentrations of oseltamivir (1µM for H1N1, ≥0.1µM for H3N2, and ≥0.01µM for H5N1 virus) virus replication was completely blocked. Thus amantadine used in combination with oseltamivir reduced the emergence of drug-resistant influenza variants in vitro. Animal studies

Levena et al (2000)48 found that the combination of rimandatine with GS4104 (the active ingredient of oseltamivir) significantly increased the number of survivors and the survival time in mice infected with an influenza A/H9N2. The mice that received the combination of 0.1 mg/kg per day GS4104 and of 1 mg/kg per day rimantadine had the best survival rate when compared with those mice that received only one of the drugs. The combination effect of a 5-day-treatment course of rimantadine and oseltamivir on mice infected with an H3N2 influenza A virus (A/Aichi/2/68) was studied by Galabov et al (2006).49 When mice were infected with high doses of virus titre, treatment with oseltmivir or rimantadine individually had no effect, but when applied in combination resulted in a survival rate of 66-87%. Mashi et al (2007)50 studied the effect of the combination of oseltamivir and amantadine in mice infected with H3N2 (A/Hongkong/1/68) or H1N1 (A/PR/8/34). Whereas survival with either drug used alone was 50-60%, the combination of both resulted in complete protection. The combination of amantadine with oseltamivir required 15-fold less oseltamivir than monotherapy to confer complete protection. The authors comment that amantadine-based combination chemoprophylaxis was also effective against amantadine-resistant H1N1 (A/PR/8/34) virus. Conversely, another study did not find a difference in survival using combination therapy compared with oseltamivir monotherapy in mice infected with amantadine resistant virus. Ilyushina et al (2007)51 treated mice with amantadine, oseltamivir or in

15

http://en.wikipedia.org/wiki/Neuraminidase

http://en.wikipedia.org/wiki/Budding

combination for five days. After 24 hours of treatment the mice were challenged lethal doses of either amantadine-sensitive or amantadine-resistant H5N1 recombinant virus (A/Vietnam/1203/04). Combination treatment provided greater protection than monotherapy from the amantadine sensitive virus, with 60% survival (amantadine 15 mg/kg/day and oseltamivir 10 mg/kg/day) and 90% survival (amantadine 30 mg/kg/day and oseltamivir 10 mg/kg/day), and spread of the virus to the brain was prevented by both combinations. However, the efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Human studies

Morrison et al (2007)52 conducted a randomized, cross-over, open-label trial to determine the pharmacokinetics and adverse event profiles of amantadine and oseltamivir when given in combination compared with monotherapy. Subjects (N = 17) were randomly allocated to six groups and administered amantadine 100 mg bid, oseltamivir 75 mg bid and a combination of both in three separate treatment periods of 5 days each, with washout periods between of 5 to 7 days between treatments. The order of treatment was pre-determined for each group, with all six possible combinations represented, and subjects served as their own control. Co-administration with amantadine or oseltamivir had no clinically significant effect on the pharmacokinetics of either drug. There was no evidence of an increase in adverse events, though a much larger trial would be needed to rule out a synergistic increase. 10.2.6 Resistance

Influenza A viruses undergo continual antigenic drift (as a result of point mutations) and shift (from genetic reassortment between two strains). These changes in genetic subtype commonly results in resistance to antiviral medication, particularly the adamantines.‡ Because the mechanism of action of the antiviral effect of amantadine and rimantadine are the same, there is complete cross-resistance, i.e. resistance to one adamantane also indicates resistance to the other.53

Herlocher et al (2003) has shown that resistance of an H3N2 influenza A virus to amantadine can be generated within 6 days, during a single course of treatment, in a ferret model.54 Up to 30% of individuals who receive amantadine or rimantadine for the treatment of influenza virus infection can excrete viruses resistant to these drugs and has been demonstrated in children,55 nursing home residents,56,57 immuno-compromised patients,58,59 and in the community.3 5

,4 3

Resistance to adamantanes has been increasing markedly since the year 2000 in the two most common strains of influenza, H1N1 and H3N2. High proportions of resistant H3N2 in particular have been reported in recent years in the United States and Canada60, ,61 62 as well as Japan,63 and up 100% resistance in a number of areas of Asia64, , ,65 66 67 (see Tables A.2.1 and A.2.2, Appendix 2). Amantadine-resistant strains demonstrate a similar level of virulence and transmissibility to sensitive ones.63

Resistance has also increased markedly from the H5N1 influenza subtype in isolates

‡ drug resistant viruses emerge as a result of single-amino-acid substitutions at position 26, 27, 30, 31, or 34 within

the transmembrane domain of the M2 protein

16

from humans as well as avian sources. Table 10.2.6 shows the variation in reported resistance of the H5N1 influenza subtype to adamantanes in Asia since 2001. Table 10.2.6 Adamantane resistant variants among H5N1 influenza A virusesCountry Literature

Source 2001 2002 2003 2004 2005 2006

Puthavathana 200568 6 (100%)

Li 200469 1 (100%)

Li 2004 7 (100%) Li 2004 † 1 (100%)

Thailand

Baranthi 200770 58 (100%)

Cheung 200671 * 2 (0%) 37(81%) 54 (100%) 82 (83%)

Li 2004 4 (100%) Li 2004 † 8 (100%) Hurt 2007 (South) 72 28 (100%)

Vietnam

Hurt 2007 (North) 11 (100%)

Hong Kong Cheung 2006 * 61 (0%) 121 (22%) 45 (13%) 4 (0%)

Cheung 2006 * 3 (0%) 9 (44%) 35(11%) 76 (6%) China

He 2007 (North)73 0/1 (0%) 1 (100%) 4 (100%)

Cheung 2006 * (100%) Cambodia Hurt 2007 6(100%)

Laos Cheung 2006 * (100%)

Cheung 2006 * (100%) Malaysia

Hurt 2007 2(100%)

Myanmar Hurt 2007 2( 0%)

Indonesia Li 2004 † 6 (16.7%) Note: Isolates were from humans only unless otherwise indicated. Isolates collected in seasons spanning consecutive years are placed in the cell of the most recent year.

* human and avian isolates † avian isolates Resistance to adamantanes appears to develop both through wild antigenic drift as well as in response to adamantane exposure. Widespread use of amantadine and rimantadine has been discouraged, particularly when neuraminidase inhibitors are available, because of rapid emergence of resistance.14,17 The alleged administration of amantadine to poultry and other livestock in China and Southeast Asia to combat H9 viruses may be a factor in widespread resistance in these areas.74

Previous data on prophylaxis and treatment will not apply to viral strains that are resistant to amantadine and rimantadine. Thus the predominant strains of influenza in a given geographical region would need to be considered before the use of adamantanes. 11. Evidence on safety Use of amantadine is associated with a number of adverse effects, the most common being central nervous system and gastrointestinal effects. Central nervous system effects also dominate the adverse reactions with rimantadine, though gastrointestinal problems may occur less often than with amantadine. Generally, rimantadine appears

17

to be tolerated somewhat better than amantadine, which may be related to differing pharmacokinetic properties.75 Smith and Roberts (2002)76 cite the proportion of patients who discontinue medication due to adverse effects as 15% for amantadine (range 11%–19%) and 6% for rimantadine range (3%–8%). Elderly patients are at greater risk of adverse event compared with other adults and children, primarily because of higher plasma concentrations due to renal impairment, so dosage needs to be adjusted according to renal function in this group (see Section 9.2).77,78

11.1 General prescribing advice

Amantadine

The undesirable effects of amantadine usually appear within the first one to four days of treatment and promptly disappear in 24 to 48 hours after discontinuation of amantadine.79

Table 11.1.1 tabulates the adverse reactions of amantadine as detailed in product information. There is a tendency towards more frequent undesirable effects, particularly affecting the central nervous system, with increasing doses, though this has not been proven unequivocally. Table 11.1.1 Adverse effects of amantadine 79

Body system Frequency* Effects Common depression, anxiety, nervousness, nervous excitement, increased

drive, difficulty in concentration, dizziness, light-headedness, headache, insomnia, lethargy, fatigue, weakness, ataxia, slurred speech, elevation of mood, agitation, hallucinations, nightmares.

Rare confusion, psychosis, tremor, convulsions, disorientation, dyskinesia

Very rare neuroleptic malignant syndrome.

Central nervous system

Other NMS-like symptoms, delirium, hypomanic state and mania. Very common peripheral oedema, livedo reticularis. Common palpitations, orthostatic hypotension

Cardiovascular system

Very rare heart insufficiency, congestive cardiac failure, congenital heart lesions

Blood and bone marrow

Very rare leucopenia, neutropenia, reversible elevation of liver function tests

Common indigestion, dry mouth, anorexia, nausea, vomiting, constipation Gastrointestinal tract Rare diarrhoea. Common diaphoresis. Rare rash, eczematoid dermatitis, exanthema. Very rare photosensitisation

Skin

Other hair loss Common transient blurring of vision Rare corneal lesions

Sense organs

sudden loss of vision, oculogyric crisis Urogenital tract Rare urinary retention, urinary incontinence. Liver Very rare abnormal liver function tests. Respiratory system Other dyspnoea. *Very common: ≥ 1/10 Common: ≥1/100 and < 1/10 Uncommon: ≥ 1/1,000 and < 1/100

Rare: ≥ 1/10,000 and < 1/1,000 Very rare: < 1/10,000 Other: frequency has not been assessed.

18

Central nervous system adverse events are the most common reactions. Hallucinations, confusion nightmares, gastrointestinal disturbances or other atropine-like side effects are more common when amantadine is administered concurrently with anticholinergic agents or l-dopa, or when the patient has an underlying psychiatric disorder. Psychotic decompensation has been reported in isolated cases of patients receiving amantadine and concomitant neuroleptic medication or l-dopa. Generally, administration of amantadine concurrently with drugs or other substances acting on the central nervous system (e.g. alcohol) may result in additive CNS toxicity. 79

Amantadine has also been noted as being a cause of serotonin syndrome, which is a clinical triad of cognitive behavioural changes, autonomic dysfunction and neuromuscular dysfunction.80 The Australian Drug Evaluation Committee (ADEC) has received 161 reports of serotonin syndrome associated with amantadine use, as of 2004.81

Rimantadine

Rimantadine appears to produce fewer CNS adverse effects and sleep disturbance problems than amantadine. Table 11.1.2 lists the major adverse effect of rimantadine. Higher than recommended doses appear to be associated with more frequent adverse effects.82

Table 11.1.2 Adverse effects of rimantadine82

Body system Frequency* Effects Common Insomnia, dizziness, headache, fatigue, and nervousness. Uncommon Ataxia, somnolence, agitation, and depression Rare Euphoria, hyperkinesia, tremor, hallucination, confusion,

and convulsions

Central nervous system

Other Rigors and decreased sensitivity to stimulation with higher than recommended doses.

Cardiovascular system

Uncommon

Pallor, palpitations, hypertension, cerebrovascular disorder, cardiac failure, pedal oedema, heart block tachycardia, and syncope

Common Nausea, vomiting, anorexia, dry mouth, and abdominal pain

Gastrointestinal tract

Uncommon

Diarrhoea, dyspepsia and taste changes (At higher than recommended doses, constipation, dysphagia, and stomatitis)

Skin Rash Uncommon Tinnitus Sense organs Other Increased lacrimation and eye pain have been reported in

patients receiving higher than recommended doses Urogenital tract Increased micturition frequency with higher than

recommended dose Uncommon Dyspnea Respiratory

system Rare Bronchospasm and cough Uncommon Non-puerperal lactation Endocrine and

reproductive Other Diaphoresis and fever *Very common: ≥ 1/10 Common: ≥1/100 and < 1/10 Uncommon: ≥ 1/1,000 and < 1/100

Rare: ≥ 1/10,000 and < 1/1,000 Very rare: < 1/10,000 Other: frequency has not assessed / unknown

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11.2 Adverse events in randomised trials

Adults

Wintermeyer and Nahata (1995) found that CNS effects occurred in 8.4% of adults treated with rimantadine, and GI adverse effects occurred in 3.1%.32 Table 11.2 shows the adverse effects reported in the review of amantadine and rimantadine use in adults by Jefferson et al (2006).25 Increased risk of gastrointestinal effects with both amantadine and rimantadine were prominent in prophylaxis trials, and no difference was demonstrated between amantadine and rimantadine. Increased central nervous system (CNS) activity was demonstrated in the pooled amantadine prophylaxis trials, which drew from nine trials with over 5000 patients. Increased CNS activity was not demonstrated in pooled amantadine treatment or rimantadine trials, though the patient numbers were much smaller. Decreased CNS activity was not demonstrated for amantadine or rimantadine compared with placebo. There was a greater risk of both increased CNS activity and decreased CNS activity with amantadine compared with rimantadine, though the 95% confidence intervals for the latter were extremely wide as it was based on only one trial of only 33 patients. Local nasal irritation with inhaled amantadine was demonstrated in one trial. Withdrawals due to adverse effects were significantly higher with amantadine compared with placebo and compared with rimantadine, while all adverse effects were higher with rimantadine compared with placebo.

20

Table 11.2 Adverse effects with amantadine and rimantadine administration: from Jefferson et al (2006)2 5 Type of

trial No.

trials No.

subjects Odds Ratio

(95% CI) Gastrointestinal effects

P 5 2336 2.56 (1.37, 4.79) Amantadine T 2 594 1.34 (0.32, 5.61)

Rimantadine P 2 357 4.39 (1.43, 13.52) Amantadine vs. rimantadine P 1 130 1.28 (0.51, 3.16) Increased CNS activity

P 9 5002 2.54 (1.50, 4.31) Amantadine T 2 465 0.77 (0.23, 2.53) P 3 652 1.58 (0.78, 3.19) Rimantadine T 1 14 1.00 (0.10, 10.17)

Amantadine vs. rimantadine P 2 422 3.11 (1.67, 5.78) Decreased CNS activity

P 7 3797 1.73 (0.86, 3.45) Amantadine T 3 491 0.65 (0.31, 1.38) P 2 243 1.31 (0.23, 7.50) Rimantadine T 1 31 0.20 (0.01, 5.24)

Amantadine vs. rimantadine T 1 33 22.58 (1.13, 452.21) Dermatological changes

P 3 918 1.55 (0.39, 6.20) Amantadine T 2 465 1.40 (0.14, 13.78)

Local nasal irritation Inhaled amantadine T 1 20 12.50 (1.09, 143.43) Insomnia Amantadine vs. standard meds* T 1 47 0.92 (0.26, 3.20 ) All adverse effects Amantadine P 6 4274 1.70 (0.99, 2.93) Rimantadine P 3 558 1.96 (1.19, 3.22) Amantadine vs. rimantadine P 2 339 1.60 (0.28, 9.26) Withdrawals due to adverse effects Amantadine P 6 2276 2.54 (1.60, 4.06) Rimantadine P 3 625 1.10 (0.48, 2.51) Amantadine vs. rimantadine P 3 631 2.49 (1.26, 4.93) * standard meds = analgesics antipyretics P = prophylaxis trial; T = treatment trial The comparative toxicities of equivalent doses of amantadine and rimantadine were examined in a double-blind, placebo-controlled study in healthy adults by Hayden et al (1983).83 Amantadine was associated more often with adverse central nervous system symptoms (33% of amantadine versus 9% of rimantadine recipients) and sleep disturbance (39% versus 13%; P less than 0.001), but not gastrointestinal symptoms (19.5 versus 16.0%).

21

Children

Galveo et al (2008)26did not demonstrate any increased risk of adverse events in children. However, in children younger than 10 years of age, Wintermeyer and Nahata (1995)32 found CNS-related adverse effects occurred in 3.2%, and gastrointestinal adverse effects occurred in 8.4% Elderly

Galveo et al (2008)26 did not demonstrate any increased risk of adverse events in the elderly. Wintermeyer and Nahata (1995)32 found the incidence of CNS-related adverse effects in elderly patients ranged from 4.9% doses of 100 mg per day to 12.5% with 200 mg per day, while gastrointestinal adverse effects occurred in 2.9% at 100 mg per day and 17.0% at 200 mg per day. Adverse events in other studies

Dolomore (2003)84 reported on a retrospective case-control study of adverse events in a group of 242 residents of a long term care facility in New York State. Adverse events occurred in 25 of the residents, but no difference in characteristics were found compared with a randomly selected control group in the same facility. However, as the control group was not matched to the adverse event group, these results may not be reliable. In contrast to product information, however, the majority of adverse events occurred between days 8 to 14. Keyser et al (2000)85 was a retrospective cohort study of 167 residents of a long-term care facility for the elderly in New York, U.S. who received sequential therapy with amantadine then rimantadine during the 1997-1998 influenza season. Twenty-nine (18.6%) of the patients experienced an adverse effect with amantadine compared with 3 patients (1.9%) with rimantadine (P<0.01). Drug use was discontinued due to adverse events in 17.3% (n = 27) of the amantadine courses and 1.9% (n = 3) of the rimantadine courses (P<0.001). Confusion was the most frequently observed adverse event (amantadine, 10.6%; rimantadine, 0.6%; P<0.001). Case reports

There have been a number of case reports of visual impairment with amantadine, including corneal endothelial oedema, corneal deposits, superficial punctate keratitis and corneal abrasions, and occurred up to eight months after beginning treatment. In all cases, visual acuity recovered and lesions improved within a few weeks of cessation of amantadine.86

There have also been case reports of recurrent déjà vu experiences with amantadine treatment,87 and seizures with rimantadine treatment, both in patients with and without a prior history of epilepsy.3 2

22

11.3 Pregnancy and breastfeeding

Teratogenic potential

Use of amantadine is not recommended during pregnancy due to possible teratogenic effects. In several studies in rats amantadine was shown to be embryo-toxic and teratogenic when given in daily doses over 1.5 to 3 times the equivalent human dose in milligrams per kilogram.88 Several case reports describe foetal malformations associated with adamantane usage. Tetralogy of Fallot and tibial hemimelia occurred in an infant exposed to amantadine during the first trimester of pregnancy.77 Another report described a child born with a single cardiac ventricle after the mother had taken amantadine throughout her first trimester.88 A single case reported a child with an inguinal hernia.89 The teratogenic potential of rimantadine in animals has not been studied. No human studies of pregnancy outcomes after exposure to rimantadine have been published, and there have been no reports of outcomes following inadvertent exposure during pregnancy.8 2 Breastfeeding

Amantadine is excreted in human milk, but the effects on the nursing infant from exposure to the drug in milk have not been determined, nor has the safety and efficacy of amantadine in newborns and infants less than 1 year of age.88

No reports describing the use of rimantadine during human lactation or measuring the amount excreted into milk have been located. In rodent studies, drug concentrations in rat milk were found to be twice that of serum, and adverse effects were noted in the nursing offspring.82

12. Cost and cost-effectiveness

12.1 Cost

Costs of amantadine and rimantadine vary around the world. Table 12.1 shows pricing information from a number of sources in recent years. Generally amantadine costs substantially less than rimantadine, and is available in a wider range of preparations in a greater number of countries (See Appendix 1).

23

Table 12.1 Costs of amantadine and rimantadine Source / Year Country Quantity* Amantadine Rimantadine

Lee 200290 United States 5 day course - US$ 17.50 Scuffham 200291 England and P: 4 weeks € 24.4† Wales T: 7 days € 6.1† France P: 4 weeks € 22.3† T: 7 days € 5.6† Germany P: 4 weeks € 19.0† T: 7 days € 4.8† Smith 20027 6 United States 7 days US$ 4.87 US$ 26.41 Rothberg 200392‡ United States 5 day course US$ 1.57 US$ 20.40

P: 6 weeks (100mg/day) ₤ 15.38 - Turner 20032 7 United Kingdom

T: 1 course§ ₤ 3.38 -

Colgan et al 200393 United States P: 42-day Branded US$ 106 US$ 171 Generic US$ 28-$31 US$ 154 T: 5 days Branded US$ 18 US$ 29 Generic US$ 4 - $5 US$ 26 NICE guidelines2 0 United Kingdom 100 mg capsules ₤ 2.40 150 ml (15x100mg doses) ₤ 5.05 Hueston 200494 United States 5 day course US$ 10.50 US$ 24.80

Rothberg 2005a95 || United States 1 prescription US$ 1.57 -

Rothberg 2005b96 || United States 5 day course US$ 6.40-8.59#

-

PBS 200897 Australia 100x 100 mg capsules A$ 42.53 - P = prophylaxis course : T = treatment course * Dosing according to manufacturers recommendations unless otherwise specified † Given as a price for ‘Ion-channel inhibitors’ ‡ Average wholesale price § average price; actual duration was dependent on length of illness

|| Average wholesale price plus an acquisition cost # Amounts vary for differing ages (2-15years) and weights 12.2 Cost-effectiveness

Table 12.2 shows a summary of cost-effectiveness studies of adamantanes for the treatment of influenza A. These studies varied widely in the countries in which the studies were conducted, the methods of analysis, the populations studied, and the changing nature of influenza from year to year. This has resulted in a wide variety of incremental cost-effectiveness ratios, and results that are not directly comparable. In all the of the studies, however, resistance of influenza A to adamantanes was not modelled, i.e. all models assumed full sensitivity, which is unlikely due to the rise of resistant strains particularly in Asian countries (see Section 10.4.2 Resistance). Thus, all estimates in the literature are likely to underestimate the actual cost-effectiveness when a proportion of resistant strains are present. Lynd et al (2005)98 conducted a review of cost-effectiveness studies for influenza treatment, but found that it is not possible to make definitive conclusions about the cost effectiveness of antiviral drugs for the treatment of influenza because of the wide variations in the parameters of the studies. However, they also suggested that antiviral treatment or prophylaxis is likely to be most cost effective in specific populations (e.g.

24

25

the institutionalised elderly), at specific times during the influenza season (i.e. when the population prevalence of influenza is at its peak), during influenza seasons when the prevalence reaches epidemic levels, or when there has been a mismatch between the vaccine and the circulating virus. It still remains that in areas where adamantane sensitive strains of influenza A predominate, amantadine remains the least expensive of the available anti-viral drugs, followed by rimantadine, with neuraminidase inhibitors oseltamivir and zanamivir being the most expensive options.27, 76., 95, 99

Table 12.2 Cost-effectiveness studies of adamantanes for the treatment of influenza A

Study/ Amantadane

used Country or

Region Patient group Comparator Base case result Comments/Conclusions

Scuffham 20029 1 Rimantadine

England and Wales, France, Germany

Elderly: prophylaxis and treatment

No intervention Prophylaxis: € 53,991 per life year gained € 35,228 per hospitalisation averted € 214.4 per IDA Treatment:† € 328.3 per IDA

Chemoprophylaxis was most cost-effective when used during the peak 4 weeks of the influenza season. At best, prophylaxis with adamantanes were between 6 and 10 times more costly. Resistance not modelled.

Smith 20027 6 Amantadine and rimantadine

United States Adults: average age 32 years

No testing or treatment: Testing then treatment

Amantadine treatment without testing: US$ 9.06 per IDA US$ 11.60 per QAD gained

In younger patients, amantadine is favoured if the likelihood of influenza A is>67%; Amantadine treatment of influenza without rapid testing is reasonable economically in febrile patients with typical symptoms during influenza season. Rimantadine treatment was dominated Resistance not modelled.

Lee 20029 0 Amantadine and rimantadine

United States Healthy employed adults 18 to 50 years of age

Vaccination and no antiviral

Rimantadine US$ 30.97 with vaccination US$ 4.61 without vaccination Units of quality of life gained or illness averted not stated.

Amantadine was excluded as dominated by rimantadine due to higher incidence of side effects and less efficacy. Rimantadine for influenza appear to justify its cost. Resistance not modelled.

Turner 20032 7 United Kingdom No intervention Prophylaxis: ₤ 158,691 per QALY ₤ 282 per IDA

Amantadine Vaccine only Prophylaxis: ₤ 909,210 per QALY ₤ 1,007 per IDA

Healthy adult population (aged 12–65 years)

Standard treatment‡

Treatment: ₤ 6,190 per QALY ₤ 5.05 per IDA

No intervention Prophylaxis: ₤ 37,710 per QALY ₤ 209 per IDA

Vaccine only Prophylaxis: ₤ 124,854 per QALY ₤ 429 per IDA

High risk (aged ≥ 65 years and/ or with concomitant disease)

Standard Treatment: ₤ 4535 per QALY

Quality of amantadine studies used was low, and in very specific populations (e.g. children were largely institutionalised and elderly populations limited to those hospitalised and living in residential care). The cost per QALY gained for seasonal prophylaxis of the residential population with amantadine was relatively low and must be balanced against the requirement to assess renal function of elderly (to reduce the risk of adverse reactions), and the potential for developing drug resistance Resistance not modelled.

26

27

Study/ Amantadane

used Country or

Region Patient group Comparator Base case result Comments/Conclusions

treatment‡ ₤ 2.99 per IDA Turner 2003 (cont) Elderly in residential

care No intervention Prophylaxis: ₤ 4,511 per QALY

₤ 194 per IDA Vaccine only Prophylaxis: ₤ 28,920 per QALY

₤ 109 per IDA Standard

treatment‡ Treatment: ₤ 5057 per QALY

₤ 2.99 per IDA Children

(aged ≤ 12 years) No intervention Prophylaxis: ₤ 92,716 per QALY

₤ 309 per IDA Vaccine only Prophylaxis: ₤ 450,240 per QALY

₤ 550 per IDA Standard

treatment‡ Treatment: ₤ 6117 per QALY

₤ 5.96 per IDA Rothberg 20039 2 Amantadine

United States Non-institutionalised adults over 65 years

No intervention US$ 1129 dollars per QALY saved Assumed no vaccination. Resistance not modelled.

Rothberg 20059 5 Amantadine

United States Healthy working adults No intervention US$ 234 per person per year, resulting in 0.0102 QADs gained 22941

Less expensive than vaccination (marginal cost-effectiveness ratio of an extra $113 per QAD gained). Resistance not modelled.

Rothberg 20059 6 Amantadine

United States Children No antiviral therapy

US$ 121 saved per child US$ 800 - 1800 per QALY saved for older children (excludes parental work loss)

Amount saved mostly by avoiding parental work loss. Assumes influenza A predominant. Resistance not modelled

QAD = quality adjusted day; QALY = quality adjusted life year; IDA = illness day avoided * Excluding deaths † There was no difference in the numbers of cases, hospitalisations, deaths or life-years gained from treatment with antivirals. Therefore, the costs of averting these events are

indefinable. ‡ Standard treatment = symptomatic treatment and/or antibiotics only

13. Summary of regulatory status of the medicine Amantadine Amantadine was originally licensed for sale on prescription in the United States for prophylaxis against influenza A in 1966 (see Appendix 1).100 The regulatory status of amantadine in each country is difficult to ascertain, but appears to be available on prescription in most countries with western cultures such as Canada, the United Kingdom, Australia, Scandinavian countries and western Europe. In some other countries amantadine is available without prescription, particularly in Asia, in some cases being an ingredient in some over-the-counter cold remedies.74,101

. Rimantadine Rimantadine was first approved for sale on prescription in the United States in1993.102 In contrast to amantadine, rimantadine is not as widely available, being produced only four countries.1 Regulatory status for rimantadine is difficult to ascertain, but in the United States and Europe is only available on prescription. 14. Availability of pharmacopoeial standards 15. Proposed text for the WHO Model Formulary

28

Appendix 1: Tradename Lists

Table A.1.1 Amantadine Trade Name List1 Name, Form & Strength Contact

Adekin Desitin, Ger. Aman (FM) Hexal, Ger. Amantadine - 100 MG - Capsule Bdh Amantadine - 100 MG - Capsule, Liquid Filled Qualitest Pharmaceuticals Amantadine - 100 MG - Capsule H.L. Moore Amantadine Capsules BP 2007 Amantadine Hydrochloride - 50 MG/5 ML - Solution

Zenith Goldline Pharmaceuticals

Amantadine Hydrochloride - 50 MG/5 ML - Solution

King Pharmaceuticals

Amantadine Hydrochloride - 50 MG/5 ML - Solution

Pharmaceutical Associates

Amantadine Hydrochloride - 50 MG/5 ML - Syrup Alpharma Amantadine Hydrochloride - 50 MG/5 ML - Syrup Morton Grove Pharmaceuticals Amantadine Hydrochloride - 50 MG/5 ML - Oral Syrup

Qualitest Pharmaceuticals

Amantadine Hydrochloride - 100 MG - Capsule Invamed Amantadine Hydrochloride - 100 MG - Oral Capsule, Liquid Filled

Actavis Totowa

Amantadine Hydrochloride - 100 MG - Capsule, Liquid Filled

Bolar Pharmaceutical


Rosemont Pharmaceutical

Amantadine Hydrochloride - 100 MG - Oral Capsule, Liquid Filled

Sandoz


Teva Pharmaceuticals

Amantadine Hydrochloride - 100 MG - Capsule Rugby Laboratories Amantadine Hydrochloride - 100 MG - Capsule Schein Pharmaceutical Amantadine Hydrochloride - 100 MG - Capsule Solvay Pharmaceuticals Amantadine Hydrochloride - 100 MG - Capsule Solvay Pharmaceuticals Amantadine Hydrochloride - 100 MG - Capsule Solvay Pharmaceuticals Amantadine Hydrochloride - 100 MG - Gel/Jelly Zenith Goldline Pharmaceuticals Amantadine Hydrochloride - 100 MG - Tablet Upsher-Smith Laboratories Amantadine Hydrochloride - 100 MG - Tablet Vangard Labs Amantadine Hydrochloride Capsules USP 29 Amantadine Hydrochloride Syrup USP 29 Amantadine Oral Solution BP 2007 Amanta (FM) Azupharma, Ger. Amanta ABZ, Ger. Amantagamma Worwag, Ger. Amantan Altana, Belg. Amant Faromed, Austria Amantidine Hydrochloride - 100 MG - Capsule American Health Amantix Merz, Pol. Amazolon - 50 MG - Tablet Sawai Seiyaku (Japan) Amazolon - 100 MG - Tablet Sawai Seiyaku (Japan) Amixx (DI) Krewel, Ger. AMT (FM) Acis, Ger. Antadine - 100 MG - Capsule, Liquid Filled Knoll Pharmaceutical Antadine (FM) Boots, Austral. Antadine (FM) Sanofi Omnimed, S.Afr. Antiflu-Des - 25 MG - Capsule Chinoin Antiflu-Des Chinoin, Mex.

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A-Parkin Dexxon, Israel Atarin Leiras, Fin. Atenegine - 50 MG - Tablet Tsuruhara Atenegine - 100 MG - Tablet Tsuruhara Cerebramed (FM) Orion, Ger. Contenton (FM) SmithKline Beecham, Ger. Endantadine - 100 MG - Capsule Linson Pharmaceuticals Endantadine Linson, Canad. Fluviatol Boehringer Ingelheim Promeco, Mex. Grippin-Merz (FM) Merz, Ger. Hofcomant (FM) Sevens, Gr. Hofcomant Kolassa, Austria InfectoFlu Infectopharm, Ger. Infex (DI) Merz, Ger. Influ-A - 100 MG - Tablet Trima Ltd. Influ-A (FM) Trima, Israel Kinestrel Psicofarma, Mex. Lysovir Alliance, UK Mantadan Boehringer Ingelheim, Ital. Mantadine (FM) Du Pont, UK Mantadix (FM) Du Pont, Belg. Mantadix BMS, Fr. Mantaviral (FM) Karibion, Spain Mantidan Eurofarma, Braz. Noctal (DI) UCB, Austria Padiken (FM) Kener, Mex. Paritrel - 100 MG - Tablet Trima Ltd. Paritrel Trima, Israel Parkadina Basi, Port. PK-Merz (FM) Grunenthal, Chile PK-Merz (FM) Pharmacare, Gr. PK-Merz Kolassa, Austria PK-Merz Megapharm, Israel PK-Merz Merz, Cz. PK-Merz Merz, Ger. PK-Merz Merz, Hong Kong PK-Merz Merz, Hung. PK-Merz Merz, Malaysia PK-Merz Merz, Mex. PK-Merz Merz, Philipp. PK-Merz Merz, Switz. Prayanol Sanitas, Chile Profil Atral, Port. Protexin (FM) Landerlan, Spain Rosel Wermar, Mex. Symadine - 100 MG - Capsule, Liquid Filled Solvay Pharmaceuticals Symadine (FM) Solvay, USA Symmetrel - 10 MG/ML - Syrup Bristol-Myers Squibb Symmetrel - 50 MG/5 ML - Syrup Endo Laboratories Symmetrel - 50 MG/5 ML - Syrup Endo Laboratories Symmetrel - 50 MG/5 ML - Syrup Novartis Symmetrel - 100 MG - Capsule Bristol-Myers Squibb Symmetrel - 100 MG - Capsule, Liquid Filled Ciba-Geigy Symmetrel - 100 MG - Capsule, Liquid Filled Ciba-Geigy Symmetrel - 100 MG - Capsule, Liquid Filled Endo Laboratories Symmetrel - 100 MG - Capsule, Liquid Filled Endo Laboratories Symmetrel - 100 MG - Capsule Novartis Symmetrel - 100 MG - Oral Tablet Endo Laboratories

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Symmetrel (FM) Ciba-Geigy, Austria Symmetrel (FM) Ciba-Geigy, Swed. Symmetrel (FM) Geigy, Ger. Symmetrel (FM) Geigy, Norw. Symmetrel (FM) Novartis, Hong Kong Symmetrel (FM) Novartis, Israel Symmetrel (FM) Novartis, Venez. Symmetrel Alliance, UK Symmetrel BMS, Canad. Symmetrel Endo, USA Symmetrel Novartis, Austral. Symmetrel Novartis, Gr. Symmetrel Novartis, Irl. Symmetrel Novartis, Neth. Symmetrel Novartis, NZ Symmetrel Novartis, S.Afr. Symmetrel Novartis, Singapore Symmetrel Novartis, Switz. tregor Hormosan, Ger. Viregyt (FM) Thiemann, Ger. Viregyt EGIS, Hung. Viregyt-K Egis, Cz. Viregyt K Egis, Pol. Virofral (FM) Ferrosan, Swed. Virofral (FM) Novo Nordisk, Denm. Virucid (DI) Hofmann, Austria

Table A.1.2 Rimantadine Trade Name List103

Name, Form & Strength Contact Flumadine - 50 MG/5 ML - Oral Syrup Forest Pharmaceuticals Flumadine - 100 MG - coated tablet Forest Pharmaceuticals Flumadine (FM) Forest, Israel Flumadine Forest Pharmaceuticals, USA Gabirol Chinoin, Mex. Rimantadine Hydrochloride - 100 MG - Tablet Geneva Generics Rimantadine Hydrochloride - 100 MG - Tablet Global Pharmaceutical Rimantadine Hydrochloride Tablets USP 29 Roflual - 200 MG - Capsule Hoffmann-La Roche Roflual - 400 MG - Capsule Hoffmann-La Roche Roflual (FM) Roche, Fr.

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Appendix 2: Case Series Table A.2 Cases of H5N1 infection treated with amantadine in Hong Kong in 19974 5 Age/sex Medical History Amantadine

begun* Symptoms and outcome*

13 F NR Day 7† Persistent MODS; died on day 25 54 M Old myocardial

infarction Day 1 Persistent MODS; died on day 7

5 F NR Day 1 Fever, URTI symptoms; recovered 24 F NR Day 3

Severe pneumonia requiring ventilatory support; recovered

2 M Glucose-6-phosphate dehydrogenase

deficiency

On admission Fever, URTI symptoms; recovered

60 F Malignant thymoma treated 10 years ago

Day 5 Progressive MODS; died on day 6

25 F NR Day 3 Persistent MODS; died on day 24 16 F NR Day 3 Severe pneumonia requiring ventilatory support;

recovered NR = none relevant; MODS = multiple organ dysfunction syndrome; URTI = upper respiratory tract infection * Days counted from hospital admission † Also begun on IV ribavirin at the same time

Appendix 3: Proportions of adamantane resistance in influenza A strains 2000-2007

Table A.3.1 Adamantane resistant variants among H1 influenza A viruses: number resistant/number tested (proportion resistant) Country Literature Source 2000 2001 2002 2003 2004 2005 2006 2007

Deyde 2007104 * 1/3 (33.3%) Reyes 2007a6 1 * 2/102 (2%)

Canada

Reyes 2007b6 2 * 167 (0%)MMWR 2006105 * 0/3 Bright 20066 0 * 2/8 (25%)

United States

Deyde 2007 * 0/13 6/147 (4.1%)South America Deyde 2007 * 0/5 0/39 Russia Shevchenko 2005106 * 32 (9.%)Europe Deyde 2007 * 0/37 13/29 (44.8%)

Suzuki 2003107 * 5/22 (22.7%) 4/23 (17.4%) Saito 2003108 * 5/22 (22.7%) 4/23 (17.4%) Deyde 2007 * 0/1 0/2

Japan

Saito 2007109 * (0%) 0/61 China Deyde 2007 * 8/29 (27.6%) 33/46 (71.7%) Hong Kong Deyde 2007 * 0/3 7/22 (31.9%)

Barr 2007a6 6 1/5 (20)%Taiwan Deyde 2007 * 0/7 4/17 (23.5%)

Thailand Barr 2007a 1/10 (10)%Cambodia Barr 2007a 0/3 South Korea Deyde 2007 * 1/60 (1.7%)Malaysia Barr 2007a 0/10 Philippines Barr 2007a 0/14Singapore Barr 2007a 1/10 (10)%Macau (SAR) Barr 2007a 9/11 (82)%New Caledonia Barr 2007a 0/5Solomon Is Barr 2007a 0/3Australia Barr 2007a 8/20 (40)%New Zealand Barr 2007a 1/7 (14)%Oceania Deyde 2007 * 0/1 1/1 (100%)Africa Deyde 2007 * 0/1 0/6South Africa Barr 2007a 1/3 (33)%Note: Isolates collected in seasons spanning consecutive years are placed in the cell of the most recent year. * Denotes strains identified as H1N1, all others only identified as H1

33

Table A.3.2 Adamantane resistant variants among H3 influenza A viruses* number resistant/number tested (proportion resistant) Country Literature

Source 2000 2001 2002 2003 2004 2005 2006 2007

Bright 20056 4 * 0/9 0/3 0/8 0/11 6/20 (30.0%)Reyes 2007a6 1 * 463/506 (91.5%) Reyes 2007b6 2 * Deyde 20071 0 4 * 1/20 (5.0%) 8/8 (100%)

Canada

Pabbaraju 2008110 * 74% 38%Bright 2005 * 4/252 (6%) 0/31 4/290 (1.4%) 3/174 (1.7%) 9/466 ( 1.9) 92/636 (14.5%) Bright 20066 0 * 193/209 (92.3%)MMWR 20061 0 5 * 109/120 (91%).

United States

Deyde 2007 * 140/1310 (10.7%) 761/789 (96.4%) Bright 2005 * 0/4 0/24 5/26 (19.2%) Mexico Deyde 2007 * 5/16 (31.2%) 70/72 (97.2%) Bright 2005 * 0/20 0/22 0/9 0/25 9/209 (4·3%) South

America Deyde 2007 * 18/248 (7.2%) 73/76 (96.0%) Shevchenko 20051 06 * 84 (10%) 84 (14%)Russia Ivanova 2006111 * 12/101 (14%)Bright 2005 * 2/56 (3·6%) 0/5 0/10 0/31 4/85 (4·7%) Europe Deyde 2007 * 10/73 (13.7%) 32/75 (42.7%) Saito 2003a1 0 8 * 19/59 (32.2%) 3/7 (42.9%) Bright 2005 * 0/28 0/6 0/28 0/37 2/47 (4·3%) Kitarhori 2006112 * 1/35 (2.8) 3/53 (5.3) 1/32 (3.1) 0/25 (0)) Deyde 2007 * 3/20 (15.0%) 7/7 (100%)Hata 2007113 * 3/8 (37.5%) 0/23 (87.0%)

Japan

Saito 2007114 * 231/354 (65.3%)Bright 2005 * 1/16 (6·3%) 1/13 (7·7%) 5/61 (8·2%) 50/87 (57·5%) 93/126 (73·8%) Xu 2006115 30/40 (75%)

China

Deyde 2007 * 71/76 (93.4%) 8/8 (100%)Bright 2005 * 0/18 0/21 0/13 17/93 (18·3%) 16/23 (69·6%) Deyde 2007 * 38/52 (73.1%) 7/7 (100%)

Hong Kong

Tang 2008116 * 0/30 (0%) 0/29 (0%) 0/30 (0%) 6/30 (20%) 16/30 (53.3%) 25/30 (83.3%) 10/12 (83.3%) Bright 2005 * 0/5 1/10 (10·0%) 0/5 6/10 (60·0%) 5/22 (22·7%) Deyde 2007 * 1/5 (20.0%) 8/8 (100%)Barr 2007a6 6 1/2 (50%)

Taiwan

Barr 2007b6 7 2/2 (100%)Barr 2007a * 3/13 (23%)Thailand Barr 2007b 6/10 (60%)

Table A.3.2 (cont.)

34

35

Country LiteratureSource

2000 2001 2002 2003 2004 2005 2006 2007

Cambodia Barr 2007a * 2/2 (100%)Bright 2005 * 0/5 0/30 0/13 3/40 (7·5%) 8/53 (15·1%)South Korea Deyde 2007 * 9/26 (34.6%) 41/41 (100%)

Sri Lanka Barr 2007a * 1/1 (100%) Barr 2007a * 8/10 (80%)Malaysia Barr 2007b 2/9 (22%)Barr 2007a * 2/10 (20%)Philippines Barr 2007b 1/1 (100%)Barr 2007a * 6/12 (50%) Singapore Barr 2007b 0/1 (0%)Barr 2007a * 10/10 (100%)Macau (SAR) Barr 2007b 1/1 (100%)

Indonesia Barr 2007a 0/3 (0%) New Caledonia Barr 2007b 0/1 (0%)

Barr 2007a * 7/22 (32%) Australia Barr 2007b 20/40 (50%) Simonsen 2007117 * 0% 20/46 (43%) Barr 2007a * 3/12 (25%)

New Zealand

Barr 2007b 9/12 (75%)Bright 2005 * 0/11 0/9 0/8 0/8 0/19Oceania Deyde 2007 * 1/8 (12.5%) 2/3 (66.7%)Bright 2005 * 1/10 (10·0%) 0/6 0/9 0/8 Africa Deyde 2007 * 0/4 0/2Barr 2007a * 1/5 (20%)South Africa Barr 2007b 10/10 (100%)

Note: Isolates collected in seasons spanning consecutive years are placed in the cell of the most recent year. * Denotes strains identified as H3N2, all others identified only as H3

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