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Stefan Gravenstein - One of the best experts on this subject based on the ideXlab platform.
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Inhaled Zanamivir Versus Rimantadine for the Control of Influenza in a Highly Vaccinated Long-term Care Population
Journal of the American Medical Directors Association, 2005Co-Authors: Stefan Gravenstein, Paul J. Drinka, Dan Osterweil, Margo Schilling, Peggy Krause, Michael J. Elliott, Peter Shult, Arvydas Ambrozaitis, Ruth Kandel, Ellen F. BinderAbstract:Background Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of Zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. Methods This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled Zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. Results Of 482 randomizations (238 Zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. 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%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. Conclusions This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly.
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Inhaled Zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
Journal of the American Medical Directors Association, 2005Co-Authors: Arvydas Ambrozaitis, Stefan Gravenstein, Michael J. Elliott, Gerrit A Van Essen, Ethan Rubinstein, Ligita Balciuniene, Ausra Stikleryte, Catriona Crawford, Peter ShultAbstract:Background Antiviral chemoprophylaxis effectiveness for influenza control has not been prospectively established for unvaccinated residents of long-term care facilities. This study evaluated the efficacy and tolerability of Zanamivir against the standard of care (no intervention, ie, placebo) for influenza outbreak control in a largely unvaccinated institutionalized population. Objective To evaluate the efficacy and tolerability of Zanamivir versus placebo for influenza outbreak control in long-term care facilities. Methods This double-blind, randomized, placebo-controlled study prospectively enrolled/followed residents of long-term care facilities (LTCF) at 12 centers for 1 to 3 influenza seasons (1997 to 2000). Following influenza outbreak declaration, asymptomatic subjects were randomized for prophylaxis to inhaled Zanamivir 10 mg or inhaled placebo given once daily for 14 days. The proportion of randomized subjects who during prophylaxis developed symptomatic, laboratory-confirmed influenza (SLCI) was the primary end point. Results Influenza outbreaks were explosive. The attack rates varied from 9.5 to 14.8 per 100 residents. Of 1763 consents given and resulting in 494 randomizations, 49% received Zanamivir and 51% placebo; 66% were elderly and 9% were vaccinated. SLCI occurred in 6% of Zanamivir and 9% of placebo subjects ( P = .355; protective efficacy for Zanamivir = 29%, 95% confidence interval 31% to 62%), and symptomatic influenza confirmed by culture in 2% and 6%, respectively ( P = .052; protective efficacy = 65%, 95% confidence interval 8.5% to 86%). Zanamivir use was also associated with a 70% (95% confidence interval 13% to 89%) reduction in laboratory-confirmed influenza with fever (2% vs 6%, P = .043). Influenza B was not detected. Zanamivir was well tolerated. No virus isolate demonstrated Zanamivir resistance. Conclusions The protective efficacy of Zanamivir versus placebo for SLCI was marginal, for all laboratory confirmed illnesses, but significant against culture proven and febrile influenza, suggesting Zanamivir can be effective for outbreak control and symptom reduction of unvaccinated institutionalized residents. Zanamivir had an acceptable safety profile in elderly, high-risk LTCF residents and was not associated with the emergence of resistant strains.
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Zanamivir
Drug Safety, 2001Co-Authors: Stefan Gravenstein, Sebastian L. Johnston, Elke Loeschel, Alison WebsterAbstract:Post-marketing experience shows Zanamivir to be well tolerated in the general population for the treatment and prophylaxis of influenza type A and B infections. Individuals at high-risk of influenza have potentially more to gain from Zanamivir therapy. We assessed safety and tolerability findings from treatment and prophylaxis studies in over 982 high-risk subjects. Eight treatment studies involving high-risk subjects have been conducted with Zanamivir 10mg twice daily for 5 days. The incidence and pattern of adverse events was similar in Zanamivir and placebo recipients. Lower respiratory adverse events reported by recipients receiving Zanamivir occurred at similar or lower frequencies to those receiving placebo. In one treatment study involving 525 patients with asthma or chronic obstructive pulmonary disease, Zanamivir recipients had a small but significantly increased mean morning peak expiratory flow rate (PEFR) and evening PEFR compared with placebo during the treatment period (days 1 to 5). Eight prophylaxis studies have been conducted, five in family or community settings and three in nursing homes. Data from these studies demonstrate that Zanamivir is well tolerated for prophylaxis. In nursing home studies, where 90% of participants were high risk, the pattern and incidence of adverse events were similar to that reported in otherwise healthy individuals, and similar to both placebo and rimantadine, a comparator in one study. In treatment and prophylaxis studies the incidence and pattern of adverse events in participants ≥65 years or with chronic underlying respiratory disorders was similar for Zanamivir or placebo recipients. Overall, Zanamivir was well tolerated and study drug discontinuations were low. A small number of deaths have been reported in studies of high-risk elderly individuals, but none were considered to be related to Zanamivir. Thus clinical studies have demonstrated that Zanamivir has a comparable safety profile in high-risk and otherwise healthy recipients. Approximately 1.72 million treatment courses of Zanamivir were prescribed up to the end of January 2001. Many spontaneous adverse event reports received since marketing, a third of these from non-healthcare professionals, reflect the underlying condition being treated. However, a number of events have resulted in changes to the Zanamivir prescribing information, including rare reports of bronchospasm, dyspnoea, rash, urticaria and allergic type reactions including facial and oropharyngeal oedema. The reported safety profile of Zanamivir, for treatment and prophylaxis of high risk subjects with influenza type A and B infections supports its continued use in these individuals who are likely to benefit most.
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Zanamivir: a review of clinical safety in individuals at high risk of developing influenza-related complications.
Drug safety, 2001Co-Authors: Stefan Gravenstein, Sebastian L. Johnston, Elke Loeschel, Alison WebsterAbstract:Post-marketing experience shows Zanamivir to be well tolerated in the general population for the treatment and prophylaxis of influenza type A and B infections. Individuals at high-risk of influenza have potentially more to gain from Zanamivir therapy. We assessed safety and tolerability findings from treatment and prophylaxis studies in over 982 high-risk subjects. Eight treatment studies involving high-risk subjects have been conducted with Zanamivir 10 mg twice daily for 5 days. The incidence and pattern of adverse events was similar in Zanamivir and placebo recipients. Lower respiratory adverse events reported by recipients receiving Zanamivir occurred at similar or lower frequencies to those receiving placebo. In one treatment study involving 525 patients with asthma or chronic obstructive pulmonary disease, Zanamivir recipients had a small but significantly increased mean morning peak expiratory flow rate (PEFR) and evening PEFR compared with placebo during the treatment period (days 1 to 5). Eight prophylaxis studies have been conducted, five in family or community settings and three in nursing homes. Data from these studies demonstrate that Zanamivir is well tolerated for prophylaxis. In nursing home studies, where 90% of participants were high risk, the pattern and incidence of adverse events were similar to that reported in otherwise healthy individuals, and similar to both placebo and rimantadine, a comparator in one study. In treatment and prophylaxis studies the incidence and pattern of adverse events in participants > or =65 years or with chronic underlying respiratory disorders was similar for Zanamivir or placebo recipients. Overall, Zanamivir was well tolerated and study drug discontinuations were low. A small number of deaths have been reported in studies of high-risk elderly individuals, but none were considered to be related to Zanamivir. Thus clinical studies have demonstrated that Zanamivir has a comparable safety profile in high-risk and otherwise healthy recipients. Approximately 1.72 million treatment courses of Zanamivir were prescribed up to the end of January 2001. Many spontaneous adverse event reports received since marketing, a third of these from non-healthcare professionals, reflect the underlying condition being treated. However, a number of events have resulted in changes to the Zanamivir prescribing information, including rare reports of bronchospasm, dyspnoea, rash, urticaria and allergic type reactions including facial and oropharyngeal oedema. The reported safety profile of Zanamivir, for treatment and prophylaxis of high risk subjects with influenza type A and B infections supports its continued use in these individuals who are likely to benefit most.
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Zanamivir
Drug Safety, 1999Co-Authors: Barbara Freund, Stefan Gravenstein, Michael Elliott, Irene MillerAbstract:Preclinical and clinical studies have clearly demonstrated that Zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequenciesand was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received Zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of Zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received Zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in Zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that Zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of Zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of Zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of Zanamivir supports its use in the management of influenza.
Frederick G Hayden - One of the best experts on this subject based on the ideXlab platform.
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comparison of the activities of Zanamivir oseltamivir and rwj 270201 against clinical isolates of influenza virus and neuraminidase inhibitor resistant variants
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Larisa V Gubareva, Robert G Webster, Frederick G HaydenAbstract:RWJ-270201 is a novel cyclopentane inhibitor of influenza A and B virus neuraminidases (NAs). We compared the ability of RWJ-270201 to inhibit NA activity of clinical influenza isolates and viruses with defined resistance mutations with that of Zanamivir and oseltamivir carboxylate. In NA inhibition assays with influenza A viruses, the median 50% inhibitory concentration (IC50) of RWJ-270201 (approximately 0.34 nM) was comparable to that of oseltamivir carboxylate (0.45 nM) but lower than that of Zanamivir (0.95 nM). For influenza B virus isolates, the IC50 of RWJ-270201 (1.36 nM) was comparable to that of Zanamivir (2.7 nM) and less than that of oseltamivir carboxylate (8.5 nM). A Zanamivir-resistant variant bearing a Glu119-to-Gly (Glu119→Gly) or Glu119→Ala substitution in an NA (N2) remained susceptible to RWJ-270201 and oseltamivir carboxylate. However, a Zanamivir-selected variant with an Arg292→Lys substitution in an NA (N2) showed a moderate level of resistance to RWJ-270201 (IC50 = 30 nM) and Zanamivir (IC50 = 20 nM) and a high level of resistance to oseltamivir carboxylate (IC50 > 3,000 nM). The Zanamivir-resistant influenza B virus variant bearing an Arg152→Lys substitution was resistant to each NA inhibitor (IC50 = 100 to 750 nM). The oseltamivir-selected variant (N1) with the His274→Tyr substitution exhibited resistance to oseltamivir carboxylate (IC50 = 400 nM) and to RWJ-270201 (IC50 = 40 nM) but retained full susceptibility to Zanamivir (IC50 = 1.5 nM). Thus, drug-resistant variants with substitutions in framework residues 119 or 274 can retain susceptibility to other NA inhibitors, whereas replacement of functional residue 152 or 292 leads to variable levels of cross-resistance. We conclude that RWJ-270201 is a potent inhibitor of NAs of wild-type and some Zanamivir-resistant or oseltamivir-resistant influenza A and B virus variants.
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impact of Zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults
JAMA Internal Medicine, 2000Co-Authors: Laurent Kaiser, Oliver N. Keene, Michael R. Elliott, Janet Hammond, Frederick G HaydenAbstract:Background Influenza infections commonly lead to respiratory tract complications that result in antibiotic treatment. Objectives To determine frequency of respiratory events leading to antibiotic use following influenza illness in adolescents and adults, and to assess whether treatment with topical Zanamivir prevents these complications. Methods Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal Zanamivir, inhaled Zanamivir, or corresponding placebos. Twelve percent of enrolled subjects were high-risk patients. The main outcome was the incidence of respiratory events leading to antibiotic prescriptions in patients with proven influenza. Results Influenza infections were laboratory confirmed in 2499 (66%) of 3815 patients (influenza A in 88% and B in 12%). Placebo recipients developed a respiratory event leading to antibiotic use in 17% of cases, mainly for acute bronchitis or acute sinusitis. Among Zanamivir-treated patients (n = 1494%) the incidence of respiratory events leading to the use of antimicrobials was 11% (relative risk [RR] compared with placebo, 0.69; 95% confidence interval [CI], 0.57-0.84). Intranasal and inhaled Zanamivir seemed to reduce the number of upper (RR, 0.59; 95% CI, 0.36-0.97) and lower respiratory tract events (RR, 0.64; 95% CI, 0.38-1.08). Inhaled Zanamivir reduced the number of lower respiratory tract events (RR, 0.60; 95% CI, 0.42-0.85), but the reduction in the number of upper respiratory tract events was not statistically significant (RR, 0.90; 95% CI, 0.63-1.27). Conclusions Respiratory complications or worsening of symptoms leading to antibiotic use occurred in about 17% of adolescents or adults with influenza infection. Early treatment of influenza illness with Zanamivir reduced the number of these antibiotic prescriptions.
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Short-Term Treatment with Zanamivir to Prevent Influenza: Results of a Placebo-Controlled Study
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2000Co-Authors: Laurent Kaiser, Oliver N. Keene, Dan Henry, Nancy Flack, Frederick G HaydenAbstract:We explored the prophylactic activity of Zanamivir after presumed exposure to influenza in the community. After close contacts with index cases of influenza-like illnesses, 575 subjects were randomized in 4 treatment groups: 144 received placebo, 141 received intranasal Zanamivir, 144 received inhaled Zanamivir, and 146 received inhaled plus intranasal Zanamivir for 5 days. Of 25 subjects (4%) who developed symptomatic influenza during the 5 days of prophylaxis, 9 (36%) were in the placebo group, 8 (32%) were in the intranasal Zanamivir group (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.30‐2.72; ), 3 (12%) were in the P= .855 inhaled Zanamivir group (OR, 0.27; 95% CI, 0.07‐1.05; ), and 5 (20%) were in the P= .058 inhaled plus intranasal Zanamivir group (OR, 0.52; 95% CI, 0.17‐1.58; ). Short-term P= .247 treatment with intranasal Zanamivir was ineffective. However, inhaled Zanamivir treatment reduced the rate of influenza, which was 2%‐3% among Zanamivir recipients versus 6% among placebo recipients. Additional studies assessing a longer duration of postcontact prophylaxis are warranted. Zanamivir is a neuraminidase inhibitor with potent activity against both influenza A and B viruses and has been shown to be effective in treating influenza in adults [1, 2]. In adults challenged intranasally with influenza A virus, treatment with Zanamivir by nasal spray or drops was also 82% effective in preventing laboratory evidence of infection and 95% effective in preventing febrile illness [3]. However, the prophylactic activity of Zanamivir after presumed exposure to influenza, when influenza is circulating in the community, has not been fully investigated. In addition, uncertainty exists about the main site of influenza virus acquisition and replication in naturally occurring influenza. Some observations suggest that the lower respiratory tract is the predominant site rather than the upper respiratory tract. If this suggestion is correct, treatment with inhaled Zanamivir should be more effective than that with nasal sprays in preventing influenza. We conducted a study comparing a short course of treatment with intranasal and/or inhaled Zanamivir to prevent influenza in persons presumably exposed to influenza in the community.
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safety and efficacy of intravenous Zanamivir in preventing experimental human influenza a virus infection
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: David P. Calfee, Amy W. Peng, Lindsey Cass, Monica Lobo, Frederick G HaydenAbstract:Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered Zanamivir. Susceptible volunteers were randomized to receive either saline or Zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with approximately 10(5) 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50. day/ml in placebo, P < 0.005) were observed in the Zanamivir group, as were reductions in fever (14% versus 88% in placebo, P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered Zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.
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Safety and efficacy of once daily intranasal Zanamivir in preventing experimental human influenza A infection.
Antiviral therapy, 1999Co-Authors: David P. Calfee, Elizabeth K Hussey, Amy W. Peng, Monica C. Lobo, Frederick G HaydenAbstract:Zanamivir, a potent inhibitor of influenza A and B virus neuraminidases, is protective against experimental human influenza when given intranasally twice daily. We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical Zanamivir. In the first study, 36 uninfected volunteers received a single dose of Zanamivir by intranasal spray (6.4 mg), intranasal drops (16 mg) or dry powder oral inhalation (10 mg). At 4 h, median nasal wash concentrations were 50-fold higher after intranasal dosing than after inhalation. Substantial levels (spray group, median 4,596 ng/ml; drop group, 1,239 ng/ml) were detected in nasal wash 48 h after intranasal dosing. In the double-blinded efficacy study, 47 sero-susceptible volunteers were randomized to receive either placebo or Zanamivir intranasal spray (6.4 mg). Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of Zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge. In the group given three daily doses, reductions were seen in viral shedding and infection. In the two regimens providing Zanamivir 4 h prior to inoculation, significant reductions in nasal mucus weight were observed. Decreases in total symptom scores and the incidence of upper respiratory illness also occurred, but they did not reach statistical significance. The efficacy of a single dose of Zanamivir given 4 h prior to inoculation supports the hypothesis that influenza virus neuraminidase is essential for initial virus spread through respiratory secretions. These findings indicate that once daily dosing of Zanamivir is protective against experimental influenza A infection.
Oliver N. Keene - One of the best experts on this subject based on the ideXlab platform.
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Zanamivir for the treatment of influenza a and b infection in high risk patients a pooled analysis of randomized controlled trials
JAMA Internal Medicine, 2001Co-Authors: Jacob Lalezari, Oliver N. Keene, Katrina Campion, Chris SilagyAbstract:Background Influenza can cause significant morbidity and mortality, particularly in patients considered to be at high risk (such as the elderly and those with chronic disease) of developing influenza-related complications. Data on the efficacy of Zanamivir in high-risk patients are lacking because individual studies recruited a limited number of these patients. Methods A retrospective pooled analysis of data from high-risk patients in studies completed before or during the 1998–1999 winter season was performed to investigate the efficacy and safety of inhaled Zanamivir (10 mg twice daily for 5 days) for the treatment of confirmed influenza. All studies were randomized, double-blind, and placebo-controlled with 21- to 28-day follow-up. A total of 2751 patients was recruited. Of these, 321 (12%) were considered high risk and 154 were randomized to Zanamivir. The median time to alleviation of influenza symptoms and time to return to normal activities were the main outcome measures. Results Zanamivir-treated high-risk patients had a treatment benefit of 2.5 days compared with those given placebo ( P = .015). Patients treated with Zanamivir returned to normal activities 3.0 days earlier ( P = .022) and had an 11% reduction ( P = .039) in the median total symptom score over 1 to 5 days relative to those taking placebo. In addition, Zanamivir reduced the incidence of complications requiring antibiotic use by 43% relative to placebo users ( P = .045). Adverse events reported were of a similar nature and frequency between the two groups. Conclusion This pooled analysis shows that Zanamivir is an effective and well-tolerated treatment for influenza in patients considered at high-risk of developing influenza-related complications.
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impact of Zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults
JAMA Internal Medicine, 2000Co-Authors: Laurent Kaiser, Oliver N. Keene, Michael R. Elliott, Janet Hammond, Frederick G HaydenAbstract:Background Influenza infections commonly lead to respiratory tract complications that result in antibiotic treatment. Objectives To determine frequency of respiratory events leading to antibiotic use following influenza illness in adolescents and adults, and to assess whether treatment with topical Zanamivir prevents these complications. Methods Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal Zanamivir, inhaled Zanamivir, or corresponding placebos. Twelve percent of enrolled subjects were high-risk patients. The main outcome was the incidence of respiratory events leading to antibiotic prescriptions in patients with proven influenza. Results Influenza infections were laboratory confirmed in 2499 (66%) of 3815 patients (influenza A in 88% and B in 12%). Placebo recipients developed a respiratory event leading to antibiotic use in 17% of cases, mainly for acute bronchitis or acute sinusitis. Among Zanamivir-treated patients (n = 1494%) the incidence of respiratory events leading to the use of antimicrobials was 11% (relative risk [RR] compared with placebo, 0.69; 95% confidence interval [CI], 0.57-0.84). Intranasal and inhaled Zanamivir seemed to reduce the number of upper (RR, 0.59; 95% CI, 0.36-0.97) and lower respiratory tract events (RR, 0.64; 95% CI, 0.38-1.08). Inhaled Zanamivir reduced the number of lower respiratory tract events (RR, 0.60; 95% CI, 0.42-0.85), but the reduction in the number of upper respiratory tract events was not statistically significant (RR, 0.90; 95% CI, 0.63-1.27). Conclusions Respiratory complications or worsening of symptoms leading to antibiotic use occurred in about 17% of adolescents or adults with influenza infection. Early treatment of influenza illness with Zanamivir reduced the number of these antibiotic prescriptions.
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Clinical Efficacy of Inhaled Zanamivir for the Treatment of Patients with Influenza B Virus Infection
Clinical Drug Investigation, 2000Co-Authors: Albert D. M. E. Osterhaus, Alison Webster, Mika J Makela, James A. Hedrick, Kelly J. Henrickson, Oliver N. KeeneAbstract:Objective: To evaluate the efficacy of Zanamivir, a neuraminidase inhibitor, for the treatment of patients with influenza B. Design and Settings: This was a pooled analysis of phase II and III randomised, double-blind, placebo-controlled studies completed before or during the 1998 to 1999 winter season that investigated the efficacy of inhaled Zanamivir 10mg twice daily in patients with influenza. Results: A total of 2065 patients were enrolled in eight studies; 394 (19%) of these patients were influenza B-positive. Patients with influenza B had a similar illness to those with influenza A. Influenza B-positive patients were alleviated of their symptoms 2.0 days faster (4.0 days vs 6.0 days; p < 0.001) and returned to normal activities 1.5 days quicker (5.5 days vs 7.0 days; p < 0.001) when treated with Zanamivir compared with placebo. A similar efficacy was observed in Zanamivir-treated patients with influenza A infection. Conclusions: This analysis confirms that Zanamivir is effective for the treatment of patients with influenza B virus infection.
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Short-Term Treatment with Zanamivir to Prevent Influenza: Results of a Placebo-Controlled Study
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2000Co-Authors: Laurent Kaiser, Oliver N. Keene, Dan Henry, Nancy Flack, Frederick G HaydenAbstract:We explored the prophylactic activity of Zanamivir after presumed exposure to influenza in the community. After close contacts with index cases of influenza-like illnesses, 575 subjects were randomized in 4 treatment groups: 144 received placebo, 141 received intranasal Zanamivir, 144 received inhaled Zanamivir, and 146 received inhaled plus intranasal Zanamivir for 5 days. Of 25 subjects (4%) who developed symptomatic influenza during the 5 days of prophylaxis, 9 (36%) were in the placebo group, 8 (32%) were in the intranasal Zanamivir group (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.30‐2.72; ), 3 (12%) were in the P= .855 inhaled Zanamivir group (OR, 0.27; 95% CI, 0.07‐1.05; ), and 5 (20%) were in the P= .058 inhaled plus intranasal Zanamivir group (OR, 0.52; 95% CI, 0.17‐1.58; ). Short-term P= .247 treatment with intranasal Zanamivir was ineffective. However, inhaled Zanamivir treatment reduced the rate of influenza, which was 2%‐3% among Zanamivir recipients versus 6% among placebo recipients. Additional studies assessing a longer duration of postcontact prophylaxis are warranted. Zanamivir is a neuraminidase inhibitor with potent activity against both influenza A and B viruses and has been shown to be effective in treating influenza in adults [1, 2]. In adults challenged intranasally with influenza A virus, treatment with Zanamivir by nasal spray or drops was also 82% effective in preventing laboratory evidence of infection and 95% effective in preventing febrile illness [3]. However, the prophylactic activity of Zanamivir after presumed exposure to influenza, when influenza is circulating in the community, has not been fully investigated. In addition, uncertainty exists about the main site of influenza virus acquisition and replication in naturally occurring influenza. Some observations suggest that the lower respiratory tract is the predominant site rather than the upper respiratory tract. If this suggestion is correct, treatment with inhaled Zanamivir should be more effective than that with nasal sprays in preventing influenza. We conducted a study comparing a short course of treatment with intranasal and/or inhaled Zanamivir to prevent influenza in persons presumably exposed to influenza in the community.
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clinical efficacy and safety of the orally inhaled neuraminidase inhibitor Zanamivir in the treatment of influenza a randomized double blind placebo controlled european study
Journal of Infection, 2000Co-Authors: Mika J Makela, D M Fleming, Oliver N. Keene, K Pauksens, T Rostila, Alison WebsterAbstract:TM twice daily for 5 days or matching placebo. Influenza symptoms and temperature were recorded daily for 14 days. The primary endpoint was time to alleviation of clinically significant symptoms of influenza. Other endpoints included symptom severity, use of relief medications, time to return to normal activities, complications and investigator’s assessment of symptoms. Results: A total of 356 patients were recruited; 277 (78%) had laboratory-confirmed influenza and 32 (9%) were considered high-risk (i.e. elderly or with underlying medical conditions). Zanamivir significantly reduced the time to alleviation of symptoms versus placebo (median 5 days versus 7.5 days, P < 0.001), a 33% reduction in duration of illness. Zanamivir significantly reduced the severity of several symptoms; improvements versus placebo were discernible after approximately 24 h. The proportion of patients who were afebrile after 24 h increased by 46% versus placebo. Similar treatment benefits were observed in the high-risk patients. Zanamivir was well tolerated, with an adverse event profile similar to that of placebo. Conclusions: Zanamivir is effective in reducing the duration and severity of influenza illness and is well tolerated. Zanamivir should therefore be a clinically valuable intervention in the management of influenza. © 2000 The British Infection Society
Arnold S. Monto - One of the best experts on this subject based on the ideXlab platform.
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Zanamivir prophylaxis an effective strategy for the prevention of influenza types a and b within households
The Journal of Infectious Diseases, 2002Co-Authors: Arnold S. Monto, D M Fleming, Michael E. Pichichero, Steve J. Blanckenberg, Olli Ruuskanen, Chris Cooper, Caron KerrAbstract:A double-blind, randomized study of inhaled Zanamivir for the prevention of influenza in families was conducted. Once a person with a suspected case of influenza was identified (index patient), treatment of all other household members (contacts) > or =5 years old was initiated. Contacts received either 10 mg Zanamivir or placebo inhaled once daily for 10 days. Index patients received relief medication only. In total, 487 households (242 placebo and 245 Zanamivir) were enrolled, with 1291 contacts randomly assigned to receive prophylaxis. Four percent of Zanamivir versus 19% of placebo households (P<.001) had at least 1 contact who developed symptomatic, laboratory-confirmed influenza, representing 81% protective efficacy (95% confidence interval, 64%-90%). Protective efficacy was similarly high for individuals (82%) and against both influenza types A and B (78% and 85%, respectively, for households). Zanamivir was well tolerated and was effective in preventing influenza types A and B within households where the index patient was not treated.
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Zanamivir Prophylaxis: An Effective Strategy for the Prevention of Influenza Types A and B within Households
The Journal of infectious diseases, 2002Co-Authors: Arnold S. Monto, Michael E. Pichichero, Steve J. Blanckenberg, Olli Ruuskanen, Chris Cooper, Douglas M. Fleming, Caron KerrAbstract:A double-blind, randomized study of inhaled Zanamivir for the prevention of influenza in families was conducted. Once a person with a suspected case of influenza was identified (index patient), treatment of all other household members (contacts) > or =5 years old was initiated. Contacts received either 10 mg Zanamivir or placebo inhaled once daily for 10 days. Index patients received relief medication only. In total, 487 households (242 placebo and 245 Zanamivir) were enrolled, with 1291 contacts randomly assigned to receive prophylaxis. Four percent of Zanamivir versus 19% of placebo households (P
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Influenza resistance to Zanamivir generated in ferrets
International Congress Series, 2001Co-Authors: M. Louise Herlocher, Rob J. Fenton, Andrew C. Merry, Stephanie Elias, Arnold S. MontoAbstract:Abstract Zanamivir (4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid), an anti-neuraminidase drug, is highly effective in the treatment of influenza. Influenza resistance to Zanamivir has proved difficult to raise. Two neuraminidase mutations leading to resistance in vitro have been identified in several viruses—glu 119 gly and arg 292 lys. Only one resistant virus (an influenza B clone) has been observed in vivo in an immunocompromised child. This series of experiments sought to develop A/LA/1/87 (H3N2) influenza clones resistant to Zanamivir in a ferret model. Using this model resistance to amantadine was easily developed within 6 days of treatment. Although most ferrets treated with Zanamivir shed virus in the nasal wash, all ferrets were protected from fever and illness when treated with Zanamivir. When ferrets were infected with nasal wash from ferrets previously infected with A/LA/1/87 (H3N2) and treated with Zanamivir, 20 clones from their nasal wash grew on MDCK cells in the presence of 1 μM Zanamivir. Sequencing of the NA genes of these clones revealed no mutations at positions 119 or 292. However, a nucleotide mutation at position 685 was observed in five of the clones. Sequencing of HA1 and HA2 for all genes is underway. Although characterization of the 20 clones is not complete, we can say that resistance to Zanamivir will not arise as quickly or with the same frequency as does resistance to amantadine.
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randomized placebo controlled studies of inhaled Zanamivir in the treatment of influenza a and b pooled efficacy analysis
Journal of Antimicrobial Chemotherapy, 1999Co-Authors: Arnold S. Monto, Alison Webster, Oliver N. KeeneAbstract:Zanamivir, a potent, highly selective inhibitor of influenza virus A and B neuraminidase, has been evaluated in seven, similarly designed, placebo-controlled studies of the treatment of influenza. Patients with typical influenza symptoms were recruited when influenza was known to be circulating in the community. Six of these studies included a Zanamivir 10 mg inhaled bd (for 5 days) treatment arm, the dose regimen submitted to regulatory agencies. Pooled analyses were conducted to evaluate efficacy more precisely in terms of the alleviation of symptoms in population subgroups and for secondary endpoints. Median time to alleviation of symptoms, the primary endpoint, was reduced from 6.0 days in the placebo group (n = 1,102) to 5.0 days in the Zanamivir group (n = 1,133), P 50 years (n = 263), compared with 1 day (P < 0.001) in patients aged <50 years. In 'high-risk' IP patients (recruited into all treatment studies), there was a treatment benefit of 2.5 days (n = 305, P = 0.006). Pooled analyses of secondary endpoints showed statistically significant reductions in antibiotic use, time to return to normal activities and use of relief medication. In addition, reductions in symptom scores were apparent shortly after commencing Zanamivir treatment. By the evening of the second day of treatment, the median total symptom score had fallen by 44% in Zanamivir recipients compared with 33% in placebo recipients (P < 0.001). These results highlight the groups likely to show greatest benefit from Zanamivir treatment, and confirm the clinical relevance of the treatment benefit.
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efficacy and safety of the neuraminidase inhibitor Zanamivir in the treatment of influenza a and b virus infections
The Journal of Infectious Diseases, 1999Co-Authors: Arnold S. Monto, D M Fleming, D Henry, R De Groot, Mika J Makela, T Klein, M Elliott, Oliver N. KeeneAbstract:Background The sialic acid analogue Zanamivir (GG167) is a selective inhibitor of influenza A and B virus neuraminidases. These viral enzymes are essential for the release of virus from infected cells, and they may also reduce the inactivation of virus by respiratory secretions. When administered experimentally directly to the respiratory tract, Zanamivir has potent antiviral effects. We assessed the therapeutic activity of Zanamivir in adults with acute influenza. Methods We conducted separate randomized, double-blind studies in 38 centers in North America and 32 centers in Europe during the influenza season of 1994–1995. A total of 417 adults with influenza-like illness of <48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of Zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of Zanamivir by inhalation plus placebo spray, or placebo by both routes. Treatments were self-administered twice daily for five days. Results Of 262 patients with confirmed influenzavirus infe...
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Inhaled Zanamivir Versus Rimantadine for the Control of Influenza in a Highly Vaccinated Long-term Care Population
Journal of the American Medical Directors Association, 2005Co-Authors: Stefan Gravenstein, Paul J. Drinka, Dan Osterweil, Margo Schilling, Peggy Krause, Michael J. Elliott, Peter Shult, Arvydas Ambrozaitis, Ruth Kandel, Ellen F. BinderAbstract:Background Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of Zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. Methods This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled Zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. Results Of 482 randomizations (238 Zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. 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%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. Conclusions This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly.
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Inhaled Zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
Journal of the American Medical Directors Association, 2005Co-Authors: Arvydas Ambrozaitis, Stefan Gravenstein, Michael J. Elliott, Gerrit A Van Essen, Ethan Rubinstein, Ligita Balciuniene, Ausra Stikleryte, Catriona Crawford, Peter ShultAbstract:Background Antiviral chemoprophylaxis effectiveness for influenza control has not been prospectively established for unvaccinated residents of long-term care facilities. This study evaluated the efficacy and tolerability of Zanamivir against the standard of care (no intervention, ie, placebo) for influenza outbreak control in a largely unvaccinated institutionalized population. Objective To evaluate the efficacy and tolerability of Zanamivir versus placebo for influenza outbreak control in long-term care facilities. Methods This double-blind, randomized, placebo-controlled study prospectively enrolled/followed residents of long-term care facilities (LTCF) at 12 centers for 1 to 3 influenza seasons (1997 to 2000). Following influenza outbreak declaration, asymptomatic subjects were randomized for prophylaxis to inhaled Zanamivir 10 mg or inhaled placebo given once daily for 14 days. The proportion of randomized subjects who during prophylaxis developed symptomatic, laboratory-confirmed influenza (SLCI) was the primary end point. Results Influenza outbreaks were explosive. The attack rates varied from 9.5 to 14.8 per 100 residents. Of 1763 consents given and resulting in 494 randomizations, 49% received Zanamivir and 51% placebo; 66% were elderly and 9% were vaccinated. SLCI occurred in 6% of Zanamivir and 9% of placebo subjects ( P = .355; protective efficacy for Zanamivir = 29%, 95% confidence interval 31% to 62%), and symptomatic influenza confirmed by culture in 2% and 6%, respectively ( P = .052; protective efficacy = 65%, 95% confidence interval 8.5% to 86%). Zanamivir use was also associated with a 70% (95% confidence interval 13% to 89%) reduction in laboratory-confirmed influenza with fever (2% vs 6%, P = .043). Influenza B was not detected. Zanamivir was well tolerated. No virus isolate demonstrated Zanamivir resistance. Conclusions The protective efficacy of Zanamivir versus placebo for SLCI was marginal, for all laboratory confirmed illnesses, but significant against culture proven and febrile influenza, suggesting Zanamivir can be effective for outbreak control and symptom reduction of unvaccinated institutionalized residents. Zanamivir had an acceptable safety profile in elderly, high-risk LTCF residents and was not associated with the emergence of resistant strains.
