Zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza virus in patients who have been symptomatic for up to 2 days. Zanamivir has been thoroughly studied in children as well as adults. With proven efficacy in children and its favorable tolerability profile, zanamivir is the only neuraminidase inhibitor to be approved for patients as young as 7 years of age. Zanamivir is also being evaluated for the prevention of influenza.

Nonsystemic administration of influenza medication is desirable because influenza is not a systemic infection; the virus is confined to the respiratory tract.3 Systemic influenza symptoms such as fever and myalgia arise from the activity of inflammatory mediators (cytokines) that respiratory cells release into the bloodstream.₁₆ To maximize its antiviral potency and tolerability, zanamivir was developed for administration by oral inhalation. The topical mode of delivery of zanamivir via the Diskhaler(r) device allows the medication to be delivered directly to the site of infection in the respiratory tract with minimal systemic drug exposure. The extremely low systemic exposure with zanamivir contributes to its favorable tolerability (see below).

Data from a survey₁₇ of more than 1400 patients using zanamivir during the 1999-2000 influenza season demonstrate that topical administration of zanamivir via the Diskhaler(r) device is well accepted and does not deter them from using the medication. Ninety percent (90%) of patients indicated that they found the instructions for using the device easy to understand; the same proportion found the device easy or very easy to use.

The recommended dose of zanamivir for the treatment of influenza is two inhalations for a total dose of 10mg twice daily for 5 days. Patients should be advised to complete the 5-day course of therapy even if they begin to improve within 5 days. The finding that the compliance rate across the zanamivir treatment studies exceeded 90%₁₈ suggests that the length of the recommended regimen does not hinder completion of the course of treatment.

Zanamivir is the first antiviral specifically developed to combat both influenza A and influenza B viruses, responsible for approximately 65% and 35% of influenza infections, respectively.₁₉ This activity against both virus types differentiates zanamivir from the only other class of anti-influenza medicines, the M2 inhibitors, which are only active against influenza A. Whereas zanamivir inhibits viral replication and proliferation by inhibiting neuraminidase, an enzyme present in both influenza A and influenza B viruses, the M2 inhibitors inhibit viral replication and proliferation by blocking an M2 ion channel present only on influenza A viruses. Thus, while the M2 inhibitors are ineffective in inhibiting influenza B viruses, zanamivir potently inhibits their growth in vitro. In addition, zanamivir was more potent than the M2 inhibitors amantadine and rimantadine at inhibiting growth of influenza A virus in in vitro tests.₂₀

Zanamivir’s dual activity against influenza A and B is particularly important from the practical standpoint that the viral pathogens responsible for illness attributed to influenza are often unknown when antivirals are prescribed for a patient. Because of the time and high cost requirements of rapid diagnostic tests, influenza is nearly always diagnosed clinically on the basis of symptoms, a necessary practice if antiviral therapy is to be initiated early enough to be helpful. Influenza A and B cannot be distinguished clinically, and they often co-circulate. When influenza is clinically diagnosed and the responsible pathogens have not been isolated, it is most prudent to prescribe zanamivir to ensure coverage against influenza B as well as influenza A.

Although neuraminidases are found in other viruses such as parainfluenza or mumps, zanamivir is selective for the neuraminidase of influenza A and B.15,20 Also, zanamivir does not affect viruses such as rhinovirus and adenovirus, devoid of neuraminidase.15,20

In clinical trials involving more than 4000 patients and in normal clinical practice involving tens of thousands more, no zanamivir-resistant viruses have been isolated after use of inhaled zanamivir.₂₁This finding is attributed to zanamivir’s selective action at a site on viral neuraminidase that, unlike many other portions of influenza viruses, is highly conserved. A resistant strain of influenza B virus was identified in the atypical case of an immunocompromised 18-month female after a course of zanamivir treatment (16mg to 32mg every 6 hours for 2 weeks) with an investigational nebulized solution.₂₂

The lack of association of zanamivir with the development of viral resistance distinguishes it from the M2 inhibitors, which act at portions of the influenza virus that readily mutate to engender resistant viral strains.₂₃ Cross-resistance occurs, so that viruses resistant to one M2 inhibitor are resistant to the other. Across studies, one-quarter to one-half of patients treated with rimantadine shed resistant virus as early as 2 days after initiation of therapy.23 One study conducted in a nursing home₂₄ determined that amantadine-resistant viruses were found in all patients from whom viral isolates could be obtained who had received amantadine at the onset of influenza symptoms. Three individuals residing in adjacent rooms who had not received amantadine also became infected with identical resistant viruses, a finding that suggests that amantadine-resistant viruses are contagious. Similar transmission of resistant viruses to family members has also been observed with rimantadine.23

The efficacy of inhaled zanamivir (10mg inhaled twice daily for 5 days) was established in a series of double-blind, placebo-controlled trials25,26,₂₇,28,29 conducted at study sites throughout the world (Table 1). Most studies enrolled patients as young as 12 years of age, and some enrolled patients at high risk of developing complications of influenza (Table 1). Patients participating in the studies were required to be feverish or to have a fever and to be suffering from at least two symptoms including headache, myalgia, cough, or sore throat.

Figure 1

Table 1. Phase II and III Parallel-Group, Placebo-Controlled Trials with Inhaled Zanamivir

*p<0.05 vs placebo

^Numbers are for the intent-to-treat population.

Study 1,₂₅ which enrolled 455 patients within 36 hours of onset of influenza symptoms, was conducted in the Southern hemisphere during the 1997-1998 flu season. Zanamivir alleviated symptoms of influenza a median 1.5 days sooner than placebo in both the intent-to-treat population and in patients with laboratory-confirmed influenza in this trial (Table 2). The response to zanamivir was similarly robust regardless of whether patients were infected with influenza A or influenza B (Table 2). The benefits of zanamivir were most pronounced in high-risk patients (for example, those older than 65 years), whose symptoms were alleviated a median 2.5 days earlier than with placebo (Table 2). High-risk patients treated with zanamivir compared with placebo patients experienced significantly fewer complications (14% vs 46% of patients; p<0.01) and used significantly fewer antibiotics for complications (14% vs 38% of patients; p<0.05).

Figure 2

Table 2. Symptom Alleviation Data from Study 125

*p<0.05 zanamivir vs placebo

These data are corroborated by results of a European study (Study 5),₂₈ which enrolled 356 patients within 48 hours of onset of symptoms. Zanamivir alleviated symptoms of influenza a median 2.5 days sooner than placebo in both the intent-to-treat population and in patients with laboratory-confirmed influenza (Table 3). Zanamivir relieved the range of influenza symptoms in this study: median symptom scores over 2 weeks were reduced with zanamivir compared with placebo for headache (33%), sore throat (33%), feverishness (20%), myalgia (25%), cough (44%), and weakness (25%). Statistically significant (p<0.05) benefits of zanamivir over placebo were observed beginning 24 hours after initiation of therapy for cough, feverishness, and myalgia. Data from the four other placebo-controlled studies, including one conducted in Japan, are consistent with those from Studies 1 and 5 (Table 1).

Figure 3

Table 3. Median Time to Alleviation of Influenza Symptoms in Study 528

*p<0.05 zanamivir vs placebo

Zanamivir rapidly and effectively alleviated the symptoms of influenza regardless of patients’ age or clinical characteristics, but a pooled analysis18 across the six placebo-controlled trials demonstrates that its benefits were especially evident in older patients and in patients with more severe illness (Table 4). In addition, although zanamivir administered as late as 2 days after onset of influenza symptoms was effective, it was most effective in patients administering it within 30 to 36 hours of symptom onset. Patients using zanamivir in Studies 2 and 3₂₆ had their symptoms alleviated in about half the time of placebo patients (median 4 days versus 7 days), an advantage that was less robust among patients using zanamivir more than 30 hours after symptom onset. The latter data underscore the importance of efficient clinical diagnosis of influenza, so that therapy can be initiated promptly for maximum benefit.

Figure 4

Table 4. Median Time to Alleviation of Influenza Symptoms Across Six Placebo-Controlled Studies18

*p<0.05 zanamivir vs placebo

Zanamivir has also been shown to be effective in the prevention of influenza although the drug has not been approved for this indication. Zanamivir (10mg once daily for 10 days) given as prophylaxis to families in which one member had developed influenza showed significant protective efficacy versus placebo in one recent study.₃₀ While 1 in 5 (19%) of families treated with placebo developed symptomatic, laboratory-confirmed influenza, only 1 in 25 (4%) of families treated with zanamivir developed influenza.

Zanamivir also protects against community-borne influenza. A short, 5-day course of zanamivir prophylaxis reduced the risk of development of influenza after close contact with individuals with influenza-like illness by a third compared with placebo in one study.₃₁ A 28-day course of zanamivir prophylaxis had a protective efficacy compared with placebo of 67% and 84% for laboratory-confirmed influenza and laboratory-confirmed influenza with fever, respectively, in a study32 conducted in a community setting during an influenza outbreak.

Adverse event data collected during Phase II and Phase III clinical trials of zanamivir in the treatment of influenza show that it has favorable tolerability, a feature that distinguishes it from other antiviral therapies for influenza. Unlike the M2 inhibitors, which may cause side effects such as jitteriness, nervousness, and anxiety in approximately 10% of patients,3,10 zanamivir is not associated with significant neurological side effects. Furthermore, zanamivir does not provoke nausea and vomiting, which are common side effects (10% to 20% incidence) of the neuraminidase tablet oseltamivir, the only other marketed neuraminidase inhibitor.₃₃ Even during long-term therapy in the 28-day prophylaxis study described above,₃₂ zanamivir’s tolerability profile was similar to that of placebo.

The most common adverse events reported with zanamivir and placebo in the influenza treatment studies are listed in Table 5. Most of these adverse events, such as headache, cough, and nasal signs and symptoms, probably occurred as symptoms of influenza rather than side effects of study medication. Adverse events were reported in zanamivir clinical trials regardless of their suspected cause.

Figure 5

Table 5. Adverse Events* in Phase II and Phase III Placebo-Controlled Clinical Trials with Inhaled Zanamivir

*Adverse events were reported regardless of their suspected cause.

Zanamivir should be prescribed cautiously in patients with chronic obstructive pulmonary disease or asthma because of the potential for bronchospasm or decline in lung function. Although not observed in clinical trials, bronchospasm has been noted in clinical practice in zanamivir-treated patients, the majority of whom had underlying respiratory disease.₃₄ The CDC recommends caution in using zanamivir in this population and states that patients with chronic obstructive pulmonary disease or asthma should have a fast-acting inhaled bronchodilator available when using the drug.₃₅

Zanamivir appears on the basis of in vitro and in vivo studies conducted and clinical experience accumulated to date to be devoid of drug interactions.₃₆ This advantage of zanamivir is attributed to its topical route of administration, which delivers the drug directly to the site of viral replication and minimizes systemic exposure. This lack of interaction with other medications is an especially important advantage of zanamivir because anti-influenza therapies are likely to be used in patient groups using other concomitant medications.