Zanamivir for Inhalation (Relenza—Glaxo Wellcome)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Just in time for the 1999 flu season, the fda has approved Glaxo Wellcome’s zanamivir (Relenza) for the treatment of influenza A and B. Zanamivir is the first of a new class of antiviral drugs, the sialic acid analogs, which were developed through computer-assisted design. These drugs are believed to inhibit viral replication by inhibiting the viral surface enzyme, neuraminidase.1 Zanamivir is formulated as an inhaled product that is delivered through a breath activated device.

Indications

Zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza virus (A and B) in adults and adolescents (³ 12 years of age). Patients should be symptomatic for two days or less.2

Dosage

The recommended dose is two inhalations at 5 mg each twice daily, about 12 hours apart, for five days. Two doses should be administered on the first day of treatment (at least 2 hours apart). Treatment should be initiated within two days after onset of symptoms. Patients should be instructed in the proper use of the delivery device and advised to complete the five-day course.1

Zanamivir is supplied as powder for inhalation. Each foil pack contains four blisters—each contain 5 mg of zanamivir and 20 mg of lactose. The contents of each blister is inhaled using a Diskhaler.

Potential Advantages

In contrast to amantadine and rimantadine, which are effective against influenza A only, zanamivir is active against influenza A and B although in the clinical trials patients were predominately infected with influenza A.1 The drug is well tolerated and is generally free of systemic side effects.2-4 One placebo-controlled study (n = 455) conducted in Australia, New Zealand, and South Africa reported a significant reduction in median time to the symptom relief of 1.5 days (6.0-4.5 days) in patients who initiated therapy within 36 hours of onset based on intent-to-treat analysis. In patients who were influenza positive and febrile, the median reduction was two days (6.5-4.5 days).3 A small number of high-risk patients (n = 79) had a statistically significant reduction in median time to alleviation of symptoms of 2.5 days (8.0-5.5 days).3 In influenza-positive patients, zanamivir-treated patients also reported less sleep disturbance and earlier return to normal activity.3

Potential Disadvantages

The administration of the drug requires two inhalations of zanamivir powder twice daily. The FDA had some concerns that this delivery system may be cumbersome for some patients and may require some initial training. Patients with underlying respiratory disease may experience bronchospasm and/or decline in pulmonary function after use of the drug.2 These patients should have a short-acting beta agonist available when treated with zanamivir.2 Therapy should be initiated within 48 hours after onset of influenza symptoms, and preferably within 36 hours.

Comments

Zanamivir is the first of a new class of antivirals, the selective neuraminidase inhibitors. Neuraminidase, also referred to as sialidase, is a surface glycoprotein essential for the replication of both influenza A and B viruses.5 The speculated roles of this enzyme include promotion of the release of virions from infected host cells, prevention of viral inactivation by respiratory mucus, and inducing the elaboration of certain cytokines (e.g., tissue necrosis factor).5 Animal models indicated that zanamivir reduces viral replication.1 The clinical benefit of zanamivir is modest. In a study conducted in the Southern Hemisphere (n = 455), zanamivir reduced the median time to symptom relief by 1.5 days when patients initiated treatment within 36 hours.3 However, in studies conducted in North America (n = > 600), zanamivir reduced the median time to symptom relief by only one day when patients initiated treatment within 48 hours and statistical significance was not achieved.2 Time-to-symptom improvement was defined as improvement in major symptoms: resolution of fever, headache, myalgia, cough, and sore throat.2 Findings from clinical trials did not show any difference in the rate of development of complications between treatment groups.

The drug has not been adequately studied in patients with high-risk underlying medical conditions. Zanamivir is currently FDA approved for the treatment of uncomplicated acute illness due in influenza. It is not approved for the prevention of illness, although a recent randomized, controlled trial showed the drug to be efficacious in healthy young adults.4

Zanamivir-resistant strains have been isolated in vitro; however they have been reported to be less infectious.1,2,7 The wholesale cost for a treatment course of zanamivir (5 days) is $44.

Clinical Implications

Prior to the approval of zanamivir, only amantadine and rimantadine have been approved for the treatment of influenza. The use of these agents was limited by inactivity against influenza B, rapid development of resistance, and CNS and gastrointestinal side effects. In contrast, zanamivir is active against influenza A and influenza B. It is well tolerated but should be used with caution in patients with underlying respiratory disease. Drug-resistant viruses can appear in about one-third of patients treated with amantadine or rimantadine.6 In clinical trials of zanamivir, drug-resistant strains have not been a problem.1,4

The benefit of zanamivir is modest. North American data showed that initiation of therapy within 48 hours failed to produce a statistically different reduction in median time to symptom improvement. Initiation of therapy within 36 hours may improve the efficacy, although it is unlikely that most adults will seek medical care or receive a definative diagnosis of influenza within 36 hours of onset of symptoms. The delivery system may also represent an obstacle to appropriate use in early stages of the illness. An orally active neuraminidase inhibitor is currently in the FDA pipeline.

There are no indications that the drug can reduce complications of influenza illness in patients at risk for these events. Vaccination remains the primary prophylactic means of controlling influenza and preventing sequelae. Patients should not eschew vaccination in favor of treatment after infection. The chemoprophylactic use of zanamivir has not been FDA approved, but neuraminidase inhibitors, especially orally active ones, may eventually have a role in managing influenza outbreaks particularly involving variant strains not covered by the vaccine.

References

1. Waghorn SL, et al. Drugs 1998;55(5):721-725.

2. Relenza Product Information. Glaxo Wellcome Inc. July 1999.

3. MIST Study Group. Lancet 1998;352:1877-1881.

4. Monto AS, et al. JAMA 1999;282(1):31-35.

5. Calfee DP, et al. Drugs 1998;56(4):537-553.

6. MMWR Morb Mortal Wkly Rep 1999;48:15-23.

7. Tai CY, et al. Antimicrob Agents Chemother 1998; 42:3232-3241.