Drugs

, Volume 62, Issue 1, pp 71–106 | Cite as

Zanamivir

An Update of its Use in Influenza
Adis Drug Evaluation

Summary

Abstract

Zanamivir is a potent competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza A and B viruses.

Zanamivir (10mg by inhalation via the Diskhaler® twice daily, or 10mg inhaled plus 6.4mg intranasally two or four times daily, for 5 days) reduced the median time to alleviation of major influenza symptoms by up to 2.5 days compared with placebo. Significant reductions of 1 to 2.5 days versus placebo were observed with inhaled zanamivir in phase III trials involving otherwise healthy adults, high-risk patients or children aged 5 to 12 years. Accelerated return to normal activities, and reduced interference with sleep, consumption of relief medication and incidence of complications leading to antibacterial use were also observed with zanamivir.

When used for prophylaxis, inhaled zanamivir 10 to 20 mg/day for 10 days to 4 weeks (plus 6.4 mg/day intranasally in one trial) prevented influenza A in 67% of recipients in a university community, significantly reduced the number of families with new cases of influenza compared with placebo or prevented new cases of influenza in long-term care facilities.

The tolerability of inhaled or intranasal zanamivir was similar to that of placebo in otherwise healthy adults, high-risk and elderly patients, and children. Recommended dosages of zanamivir did not adversely affect pulmonary function in patients with respiratory disorders in a well-controlled trial, although there have been rare reports of bronchospasm and/or a decline in respiratory function.

Conclusion: Zanamivir (used within 48 hours of symptom development) reduces the duration of symptomatic illness, causes accelerated return to normal activities or reduces complications requiring antibacterial use in adults, high-risk individuals and children with influenza. Vaccination remains the intervention of choice for prophylaxis in selected populations. However, the efficacy, good tolerability profile and lack of resistance with zanamivir make it a useful option, particularly in those not covered or inadequately protected by vaccination, who are able to use the inhalation device. The use of zanamivir in patients with respiratory disorders remains unclear because of concerns regarding its potential for bronchospasm. Prospective cost-effectiveness analyses and investigations of efficacy in preventing serious complications of influenza, particularly in high-risk patients, are required. Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households.

Overview of Pharmacodynamic Properties

Zanamivir is a potent competitive inhibitor of viral neuraminidase, and inhibits a wide range of influenza A and B types in vitro. The drug is selective for the viral form of the neuraminidase enzyme and does not interact to any significant extent with its human lysosomal equivalent.

The concentrations of zanamivir required to inhibit in vitro plaque formation of influenza A and B viruses by 50% in Madin-Darby canine kidney cells (MDCK) were 0.004 to 0.014 μ mol/L in laboratory-passaged strains of influenza A and B and 0.002 to 16 μ mol/L in assays of clinical isolates. Higher concentrations of amantadine, rimantadine and ribavirin than zanamivir were needed to inhibit replication of all influenza virus strains tested. Zanamivir was also effective in the inhibition of influenza A and B strains in yield reduction assays in human respiratory epithelium; concentrations required for 90% inhibition of viral replication were s<0.03 μ mol/L for two strains of influenza A [A/Virginia/88 (H3N2) and A/Texas/36/91 (H1N1)] virus and0.75 μ mol/L for influenzaB/Hong-Kong/5/72 virus.

The antiviral activity of zanamivir against influenza A and B strains appeared similar to that of oseltamivir carboxylate, with the drug concentration required to inhibit plaque formation or viral replication being 0.4 to 60.0 μ mol/L and 0.2 to 26.0 μ mol/L, respectively, in MDCK cell cultures and 0.0003 to 0.0046 μ mol/L and 0.0003 to 0.002 μ mol/L, respectively, in influenza neuraminidase enzymatic assays.

Intranasal administration of the drug results in inhibition of viral replication in mouse and ferret models, with doses as low as 0.05 mg/kg having antiviral activity in ferrets. Zanamivir was 100 to 1000 times more active against influenza A and B than amantadine and ribavirin in animal studies.

Viral shedding and seroconversion were inhibited by intranasal zanamivir 7.2 to 96 mg/day as drops or spray given prophylactically [4 hours prior to viral inoculation with influenza A/Texas/91 (H1N1)] for 5 days to healthy volunteers in a pooled analysis of data from four randomised, double-blind placebo-controlled studies. Relative to placebo, the protective efficacy of intranasal zanamivir was 96% for viral shedding and 82% for infection (both p < 0.001). Duration of influenza A viral shedding and viral titres were also reduced significantly by early (beginning 26 or 32 hours after inoculation) or late (beginning 50 hours after inoculation) treatment with zanamivir for 4 days. Statistically significant reductions in incidences of febrile illness, median total symptom score, median weight of nasal secretions and percentage of patients using paracetamol (acetaminophen) were also observed with early treatment. In addition, intranasal administration of the drug (up to 6.4mg twice daily) for 5 days (starting 4 hours before inoculation of influenza B/Yamagata/88) significantly reduced viral shedding in healthy volunteers, although there were no significant effects on seroconversion or infection rates for this subtype.

There have been no reports of clinically significant viral resistance to zanamivir. The drug (10mg inhaled two and then four times daily) did not cause any clinically significant reductions in pulmonary function or airway responsiveness compared with placebo in 11 volunteers with mild or moderate asthma in a randomised, double-blind, crossover trial.

Overview of Pharmacokinetic Properties

Lung scintigraphy indicated that 13.2% of an inhaled 10mg dose of zanamivir was deposited in the bronchi and lungs in healthy adult volunteers; 77.6% of the dose was deposited in the oropharynx. Concentrations exceeding those required to inhibit influenza virus neuraminidases were retained in tracheal and bronchial epithelia for up to 24 hours after zanamivir administration.

Zanamivir exhibits linear pharmacokinetics. In adult volunteers, peak serum drug concentrations (Cmax) [approximately 47 and 97 μg/L] were attained within 1 to 2 hours after inhalation of zanamivir powder administered as single doses (5 and 10mg, respectively) via Diskhaler®; serum elimination half-life values were 5.05 and 4.14 hours, respectively. After multiple doses (10mg four times daily), Cmax (39 and 54 μg/L on days 1 and 7, respectively) occurred within 1 hour of administration. Approximately 12% (day 1) and 17% (day 7) of the administered dose was recovered in the urine as unchanged drug, with respective median renal clearance (CLr) values being 6.45 and 10.87 L/h.

Similarly, in children aged 3 months to 12 years, median Cmax values (40 to 47 μg/L) were observed ≤1 hour after administration of a single dose of zanamivir 10mg by nebuliser or Diskhaler®; area under the plasma concentration-time curve to infinity (AUC∞) was 167 to 192 μg/L · h. Less than 8% of the inhaled dose was excreted unchanged in the urine, with CLr values being <0.1 L/kg/h. The pharmacokinetics of zanamivir did not alter with age (3 months to <5 years, 5 to <9 years and 9 to 12 years).

Values for Cmax or time to Cmax were not significantly altered, although those for AUC∞ were increased, in patients with renal impairment. Current data indicate that clinically significant drug interactions with zanamivir are unlikely.

Therapeutic Efficacy

Treatment of Influenza: Overall, compared with placebo, zanamivir (10mg by inhalation only twice daily for 5 days, or inhalation plus nasal spray 6.4mg two or four times daily for 5 days) reduced the median time to alleviation of major symptoms [defined as no fever (temperature <37.8°C) and/or a feverishness score of zero, and the absence of or only mild headache, myalgia, cough and sore throat for 24 hours] by up to 2.5 (median 1) days in patients with laboratory-confirmed influenza and in intent-to-treat populations in well controlled phase II or III trials. In phase III trials, the difference from placebo was statistically significant for patients who were influenza positive (p ≤ 0.05 to p < 0.001 vs placebo) and in intent-to-treat populations (p ≤ 0.05 and p < 0.001). Various pooled analyses of trials in the zanamivir clinical programme confirm the benefit of zanamivir in terms of a reduction in median time to alleviation of symptoms. The drug is useful in the treatment of both influenza A and B. In addition, zanamivir demonstrated a greater effect against influenza in patients who were febrile at study entry than in those who were nonfebrile in phase II or III studies and pooled analyses.

Treatment with zanamivir resulted in an accelerated return to normal activities, significantly reduced the interference of influenza with sleep and reduced patients’ consumption of cough suppressants and/or paracetamol in some trials. In addition, pooled analyses of phase II and/or III trials indicate that zanamivir relative to placebo significantly reduces the incidence of complications associated with influenza (p < 0.001), and of respiratory events (p < 0.001) or complications (p = 0.047) leading to antibacterial use.

Zanamivir is effective in the treatment of influenza in high-risk patients [individuals aged ≥65 years, patients with cardiovascular conditions (excluding hypertension) or respiratory, endocrine or metabolic conditions, or those who are immunocompromised]; relative to placebo, the drug reduced median time to alleviation of major symptoms by 1.5 to 3.25 days, although results from early studies were often not statistically significant because of small sample sizes. In a pooled analysis involving 321 high-risk patients with laboratory-confirmed influenza, major symptoms were alleviated significantly earlier (2.5 days) with zanamivir (10mg inhaled twice daily for 5 days) than with placebo (p = 0.015); the difference was reduced to 1.5 days (p = 0.046) in the intent-to-treat population. Zanamivir also reduced the time until return to normal activities (by 3 and 2 days) and complications requiring antibacterial use (by 43 and 37%; p = 0.045 and 0.042, respectively) relative to placebo in patients considered at high risk with confirmed influenza or in the intent-to-treat population, respectively. In a randomised, double-blind, placebo-controlled phase III trial in patients with asthma or chronic obstructive pulmonary disease, zanamivir significantly shortened the median time to alleviation of symptoms (by 1.5 days, p = 0.009) in patients with laboratory-confirmed influenza; the difference (1 day) was not significant in the intent-to-treat population. The drug also significantly reduced sleep disturbance (from 3 to 2 nights, p = 0.042) and produced a small but statistically significant reduction in mean maximum daily temperature (p = 0.02).

In a pooled analysis of phase II and III trials, significantly more zanamivir than placebo recipients were rapid resolvers in the high-risk subgroup (74 vs 53%, p = 0.014) and in patients aged ≥50 years (70 vs 54%, p = 0.005). Furthermore, there was a greater reduction (by 6 days) in the time to alleviation of symptoms in zanamivir recipients aged ≥50 years who were not using relief medication than in placebo recipients (p < 0.001) in this analysis.

In children aged 5 to 12 years, zanamivir (10mg inhaled twice daily for 5 days) significantly reduced the median time to alleviation of symptoms in those with laboratory-confirmed influenza (by 1.25 days, p < 0.001) and in intent-to-treat populations (by 1 day, p < 0.001) relative to placebo. In each of these groups, patients who received zanamivir used significantly less relief medication (p = 0.005 and 0.016) and returned to normal activities significantly earlier (1 day, p = 0.022 and 0.019) than those using placebo.

Prophylaxis of Influenza: In a double-blind study of 4-weeks’ prophylaxis in two university communities, zanamivir 10mg inhaled once daily was 67% effective in preventing laboratory-confirmed influenza A (p ≤ 0.001 vs placebo).

In a post-contact prevention study, the number of families with at least one household member who developed influenza was significantly reduced with zanamivir (10mg once daily for 10 days) compared with placebo in an intent-to-treat analysis (4 vs 19%, p < 0.001) and in an analysis of families in which the index case had laboratory-confirmed influenza (8 vs 29%, p < 0.001).

Very few residents of long-term care facilities developed confirmed influenza or symptoms of disease after prophylactic treatment with zanamivir (10mg once daily for 14 days or until the outbreak was over) during outbreaks of influenza. Zanamivir 10mg once daily for 14 days was at least as effective as rimantadine 100mg once daily in the prophylaxis of influenza A in nursing homes; in a preliminary trial over three influenza seasons, laboratory-confirmed influenza A developed in 2.9% of 238 zanamivir recipients compared with 7.4% of 244 rimantadine recipients (p = 0.038).

Tolerability

Zanamivir (10mg by inhalation only twice daily for 5 days or inhalation plus nasal spray 6.4mg two or four times daily for 5 days) is well tolerated, with an adverse events profile similar to that of placebo. The most common adverse events for zanamivir (n = 2289) and placebo (n = 1520) in phase II and III trials included nasal signs and symptoms (3 and 3%, respectively), diarrhoea (3 and 4%), nausea (3 and 3%), headache (2 and 3%), bronchitis (2 and 3%), cough (2 and 3%) and sinusitis (2 and 2%). As was the case with adverse event rates in treatment trials, the rate of adverse events in studies of prophylaxis was similar in zanamivir recipients (n = 1063) to that in placebo recipients (n = 744), with the most common adverse events being headache (37 and 41 %, respectively), nasal signs and symptoms (33 and 36%), throat and tonsil discomfort (25 and 31 %), malaise and fatigue (21 and 24%) and cough (18 and 24%).

Recent pooled analyses of participants considered to be at high risk (including those with chronic respiratory conditions and participants aged ≥65 years) [n = 982 in treatment trials and n = 1126 in trials of prophylaxis], indicate that the nature and incidence of adverse events is similar in zanamivir recipients to those in placebo recipients in both the prophylaxis and treatment indications. The adverse events profile in these patients also appears to be similar to that in patients not at high risk, with the most common adverse events in treatment studies including asthma, bronchitis, sinusitis, diarrhoea, nausea, headaches, nasal signs and symptoms, musculoskeletal pain, pneumonia, dizziness and abnormal liver function tests. The incidence of serious adverse events and discontinuation of treatment due to adverse events was generally low in high-risk patients.

Importantly, compared with placebo, zanamivir 10mg inhaled twice daily for 5 days did not appear to exacerbate lower respiratory tract symptoms in patients with chronic respiratory disease and did not adversely affect pulmonary function (assessed using forced expiratory volume in 1 second and peak expiratory flow rate), although there have been rare reports of bronchospasm and/or a decline in respiratory function during post-marketing surveillance.

Zanamivir is well tolerated in elderly (aged ≥65 years) and paediatric (aged 5 to 12 years) populations; the drug’s tolerability profile in these patient groups appears similar to that in the general population.

Pharmacoeconomic Considerations

From the perspective of a managed-care organisation, zanamivir (10mg inhaled twice daily for 5 days) appeared to be more cost effective than oseltamivir (75mg twice daily) in otherwise healthy patients with laboratory-confirmed influenza in a retrospective indirect comparison of data derived from randomised placebo-controlled trials. The incremental cost (currency year not given) per successfully treated patient was $US498 with zanamivir and $US677 with oseltamivir; the incremental costs per symptom-free day gained were $US22.58 and $US38.51, respectively.

From the perspective of the government health payer, incremental costs associated with zanamivir treatment (10mg inhaled twice daily for 5 days) compared with no active treatment were 17 to 28% lower per day of symptoms avoided and per quality of life-year (QALY) gained in high-risk individuals than in the general population. In addition, the cost effectiveness of zanamivir varied with the estimated prevalence of influenza in the population. When the diagnostic accuracy for influenza was low (14%) the incremental cost per symptom day avoided and per QALY gained was 59 to 60% higher in both the general population and high-risk individuals than when the diagnostic accuracy for influenza was high (34 or 35%, which reflects the situation when influenza is circulating within the community).

Results from various trials were sensitive to a number of parameters including the influenza-positive rate, the impact of zanamivir on days to alleviation of symptoms, the incidence of hospitalisation (especially in high-risk patients), health-related quality of life for influenza, the cost of zanamivir, death rates (high-risk patients only) and compliance rates (high-risk patients).

Dosage and Administration

In the US, zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza A and B virus infection in adults and paediatric patients aged ≥7 years whereas, in the UK, the drug is indicated for the treatment of influenza A and B in adults and adolescents aged ≥12 years who present with symptoms typical of influenza when the disease is circulating in the community. In both countries, the drug should be administered within 48 hours of the onset of symptoms at a recommended dosage of 10mg by oral inhalation twice daily for 5 days. There is currently no recommended regimen for the use of zanamivir in the prophylaxis of influenza.

Dosage modifications are not required in elderly patients or in those with renal or hepatic impairment. In the US, zanamivir is not generally recommended for the treatment of patients with underlying airways disease; however, if the drug is prescribed for these patients, respiratory function should be carefully monitored and a fast-acting bronchodilator made available. Similar precautions are advised in the UK prescribing information, which recommends informing patients with asthma or chronic obstructive pulmonary disease of the potential risk of broncho-spasm, monitoring patients closely during drug use, and making a fast-acting bronchodilator available. In both countries, the drug should be discontinued in any patient who develops bronchospasm or a decline in respiratory function. In addition, immediate treatment may be required.

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© Adis International Limited 2002

Authors and Affiliations

  1. 1.Adis International Limited, AucklandMairangi Bay, Auckland 10New Zealand

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