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Relenza (Zanamivir): antiviral agent for the treatment of influenza

Development and Pharmacology

Influenza, commonly called “the flu,“ is caused by viruses that infect the respiratory tract. Compared with most other viral respiratory infections, such as the common cold, influenza infection often causes a more severe illness. The typical symptoms of influenza include fever, cough, sore throat, runny or stuffy nose, headache, muscle aches, and often fatigue. Although nausea, vomiting, and diarrhea can accompany influenza infection, especially in children, gastrointestinal symptoms are rarely prominent. For most people the symptoms of influenza last 6-10 days, but some develop serious and potentially life-threatening medical complications, such as pneumonia. In an average year, influenza is associated with about 20,000 deaths in the United States and many more hospitalizations.

Zanamivir

Flu-related complications can occur at any age; however, the elderly and people with chronic health problems are much more likely to develop serious complications after influenza infection than younger, healthier people.

Influenza viruses are divided into three types, designated A, B, and C. Influenza types A and B are responsible for epidemics of respiratory illnesses that occur almost every winter and are often associated with increased rates of hospitalization and death. Influenza type C usually causes either a very mild respiratory illness or no symptoms at all. Thus, type C typically does not cause epidemics and does not have the severe public health impact associated with influenza types A and B.

Influenza viruses continually change over time, usually by mutation. Thus, while a person infected with specific influenza viral strain develops antibodies to that virus, a new influenza strain may evade detection by the immune system, allowing reinfection to occur. At present three different influenza strains circulate worldwide: two type A viruses and one type B. Type A viruses are divided into subtypes based on differences in two key viral proteins called hemagglutinin (H) and neuraminidase (N). The current subtypes of influenza A are designated A(H1N1) and A(H3N2).

The control of influenza focuses on the prevention of severe disease and death from influenza and its complications. To accomplish this, annual administration of an inactivated vaccine is recommended for people at high risk (the elderly and those with chronic disease) and for healthcare providers in contact with high-risk patients. The vaccine is 70%-90% effective in preventing influenza in adults, but is less so among young children and the elderly.

Naturally, efficacy depends on how closely the vaccine is matched to the strain of influenza. Also, despite its availability for decades and the fact that its use has approximately tripled in recent years, the vaccine is still not optimally employed in the United States. There is considerable room for increased use of current vaccines and for the development of new vaccines to reduce the number of deaths and to prevent annual epidemics.

Seasonal prophylaxis with antiviral drugs represents an alternative method to prevent influenza epidemics. Two agents, amantidine and rimantidine, are available for this purpose. These drugs are structurally similar and have similar mechanisms of action. When started early, these drugs may shorten the duration of influenza by about one day. Unfortunately, amantidine and rimantidine are effective only for influenza A, and their utility is further limited by adverse reactions and the development of viral resistance. Thus, there remains considerable interest in the development of novel agents for the treatment and prevention of influenza.

Zanamivir (Relenza), a new antiviral agent with a novel mechanism of action, was approved in July 1999 for the treatment of uncomplicated influenza in adults and adolescents over the age of 12. Zanamivir was designed and synthesized using knowledge of the crystal structure of the key influenza virus surface protein, neuraminidase. Specifically, zanamivir is designed to function as an inhibitor of this enzyme, which is present in both influenza types A and B. Neuraminidases are enzymes that break the bond holding virus particles to the infected cell. This enzyme is essential for viral replication since it allows for the release of virus from infected cells, prevents virus aggregation, and also may decrease virus inactivation by respiratory mucus. By inhibiting neuraminidase, zanamivir (Relenza) is capable of blocking the release of newly formed virus from the surface of infected cells and alters virus particle aggregation and release. These actions prevent the spread of virus through the respiratory tract and thereby limit the duration of influenza infection.

Based on clinical trials to date, zanamivir appears to be safe and modestly effective. It may offer some advantages over existing antiviral agents based on its unique mechanism of action and broader spectrum of activity (influenza A and B); however, this remains to be demonstrated in controlled studies.

Although neuraminidase resistance to zanamivir has not been reported in trials to date, insufficient information is available to characterize the risk of emergence of zanamivir resistance with more widespread use. Influenza viruses with reduced susceptibility to zanamivir have been recovered in vitro by passage of the virus in the presence of increasing concentrations of the drug.

Genetic analysis of these viruses showed that the reduced susceptibility is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with nebulized zanamivir 16-32 mg every 6 hours for 2 weeks. Analysis of this variant showed a hemagglutinin mutation, which resulted in a reduced affinity for human cell receptors.

There was also a mutation in the neuraminidase active site, which reduced the enzyme’s activity to zanamivir by 1,000-fold.

Zanamivir (Relenza): Therapeutics

Zanamivir is indicated for the treatment of uncomplicated influenza in adults and adolescents greater than or equal to 12 years of age who have been symptomatic for less than or equal to 2 days. This indication is based on studies involving 6,000 patients worldwide in which the predominant infections were with influenza A. The principal study enrolled nearly 1600 adults and adolescents over the age of 12 with uncomplicated influenza of onset within two days. The presence of influenza virus was confirmed by culture, hemagglutination inhibition antibodies, or direct investigational tests.

Of the patients with confirmed influenza, 89% had influenza A, and 11% had influenza B. The study participants received 10 mg inhaled zanamivir twice daily for 5 days. Time to improvement in major symptoms of influenza was defined as no fever and self-assessment of “none“ or “mild“ for headache, myalgia, cough, sore throat and loss of appetite. In these studies, zanamivir reduced the severity and duration of flu symptoms from 1 to 2.5 days faster than placebo, even among high-risk patients (defined primarily as the elderly and those with respiratory and cardiovascular disease).

Results from these studies also showed that those who used zanamivir returned to normal activities two days earlier and reported less interference with work and recreational activities in the period following treatment than those receiving placebo. In these studies there was no consistent difference in treatment effect in patients with influenza A compared with influenza B; however, these trials enrolled smaller numbers of patients with influenza B and thus provided less evidence in support of efficacy in influenza B. In general, patients with lower temperature (101°F or less) or those having less severe symptoms at entry appeared to derive less benefit from therapy.

However, the high-risk patients using zanamivir reported a significant reduction in the use of additional prescription flu medicines.

Because currrent zanamivir formulations require aerosol delivery, concerns remain about the ability of patients to reliably administer effective drug levels to the respiratory tract. Questions concerning the safety and efficacy of zanamivir in pediatric patients (<12 years of age), in adult patients with underlying chronic pulmonary disease (severe or decompensated chronic obstructive pulmonary disease or asthma) or in other patients with high-risk underlying medical conditions also remain. FDA advises the vaccine should be used under careful supervision and with fast-acting bronchodilators readily available.

Also, at present there are no adequate and well-controlled studies in pregnant women or during breast-feeding, but animal studies indicate that zanamivir crosses the placenta and is excreted in milk. Thus caution should be exercised in pregnant or breast-feeding patients.

Adverse Reactions

No serious adverse events have been directly attributed to zanamivir. In trials to date, the overall incidence of respiratory, gastrointestinal and other adverse effects did not differ significantly from placebo. It should be noted, however, that symptoms noted in the trials (malaise, fatigue, fever, abdominal pain, myalgia, arthralgia) were often difficult to distinguish from influenza illness. Elevations of liver enzymes and CPK, lymphopenia, and neutropenia were reported, but these occurred in similar proportions of zanamivir and lactose-vehicle placebo recipients with acute influenza-like illness.

There are several reports of bronchospasm or decline of pulmonary function in patients with chronic obstructive pulmonary disease when treated with zanamivir (Relenza). The significance of these reports remains to be established by controlled trials. Doses of zanamivir up to 64 mg/day have been administered by nebulizer, and there have been no reports of overdosage. Additionally, when doses of up to 1,200 mg/day for 5 days have been administered IV, adverse effects were similar to those seen in clinical studies at the recommended dose.

Zanamivir (Relenza): Drug Interactions

Relenza (Zanamivir) is not a substrate for, nor does it induce or inhibit human cytochrome (CYP) isoenzymes including CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4. An interaction study involving 138 patients was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers.

There was no clear difference in hemagglutination inhibition antibody titers at 2 and 4 weeks after vaccine administration between zanamivir and placebo recipients. Thus the use of zanamivir should not affect the evaluation of individuals for annual influenza vaccination in accordance with guidelines of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

Pharmacokinetics

Zanamivir has low oral bioavailability and essentially no antiviral activity after systemic administration, presumably as a result of poor penetration into respiratory secretions. Approximately 4%-17% of the inhaled dose is absorbed systemically. Peak serum concentrations range from 17 to 142 ng/mL within 1 to 2 hours after a 10 mg dose. The drug displays linear pharmacokinetics, not altered with multiple doses. Relenza (Zanamivir) has limited plasma protein binding (<10%) and a volume of distribution of 16 L. The serum half-life of zanamivir following inhalation ranges from 2.5 to 5.1 hours. It

is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. No zanamivir metabolites have been detected. Total clearance ranges from 2.5 to 10.9 L/hr. In limited studies in patients with mild to moderate or severe renal impairment, significant decreases in renal clearance (total clearance: normal 5.3 L/hr, mild/moderate 2.7 L/hr, and severe 0.8 L/hr; median values) and significant increases in half-life (normal 3.1 hr, mild/moderate 4.7 hr, and severe 18.5 hr) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency.

Administration, Dosage and Patient Information

Relenza is available as Rotadisk blisters of 5 mg of white powder for inhalation using the hand-held, breath-activated device provided called a Diskhaler. The drug product may be stored at room temperature and should not be opened until use. Patients should be instructed on the proper use of this device. For maximum benefit, treatment must begin within 48 hours of onset of flu symptoms.

The recommended dose of Relenza (Zanamivir) for the treatment of influenza in patients greater than or equal to 12 years of age is two inhalations (one 5 mg blister per inhalation for a total dose of 10 mg) twice daily, approximately 12 hours apart, for 5 days.

Two doses should be taken on the first day of treatment whenever possible, provided there is at least 2 hours between doses. On subsequent days, doses should be about 12 hours apart at approximately the same time each day.

Patients should be advised to finish the entire 5-day course of treatment even if they start to feel better sooner. Also advise patients that the use of zanamivir for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others.

Patients with asthma or COPD should be instructed to use their bronchodilators before taking zanamivir, and should be warned of the potential risk of bronchospasm with zanamivir (Relenza). These patients should have a fast-acting inhaled bronchodilator available and should stop zanamivir and contact their physician promptly if they experience worsening respiratory symptoms.

The safety and efficacy of repeated treatment courses of Relenza (Zanamivir) have not been studied and the safety in pregnancy and breast-feeding has not been established.

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