Influenza World Health Care Professionals

The neuraminidase inhibitors (NAIs), oseltamivir (Tamiflu®) and zanamivir (Relenza®) are potent and selective drugs that have activity against both influenza A and B viruses. These agents inhibit neuraminidase, an enzyme that promotes the release of influenza virus from infected cells and facilitates viral spread within the respiratory tract. [1, 2] By inhibiting neuraminidase activity, NAIs prevent the influenza virus from spreading to and infecting other cells in the body, thereby greatly reducing the impact of the disease. 

To view a short film about the mode of action of neuraminidase inhibitors, please follow the link.

NAIs offer effective protection against influenza for individuals who have been in close contact with the virus by:

• decreasing viral shedding
• reducing the duration of influenza symptoms
• reducing the incidence of influenza-related complications. [3]

Because replication of influenza virus in the respiratory tract peaks 1–3 days after disease onset, NAIs are most effective when taken early on in the illness. [2] Therefore for maximum benefit, these agents should be taken as soon as possible after the onset of the disease, ideally within 48 hours of symptoms starting.

Oseltamivir (Tamiflu®)  

Oseltamivir (Tamiflu) is the prodrug of the active metabolite oseltamivir carboxylate, a potent, selective inhibitor of influenza virus neuraminidase. [4, 5] The neuraminidase enzyme, which is present on the surface of both influenza A and B viral particles, cleaves cellular-receptor sialic acid residues. Newly formed viral particles attached themselves to these residues, which are essential for the release of the replicated virus from the host cell to invade new cells. [2] Without neuraminidase, influenza infections are limited to one round of replication, rarely enough to cause disease. The mode of action of Tamiflu can be viewed by selecting this link: http://www.pharmasquare.org/flash/Tamiflu.html#Start

As with other antivirals, the efficacy of Tamiflu is maximal during the viral replication phase, or as soon as possible after the onset of symptoms. Clinical benefits are therefore highly dependent on how soon treatment is initiated: the sooner the better. [6, 7]

Tamiflu is the only approved antiviral for both adults and children older than 1 year that is effective against all common strains of influenza types A and B. Tamiflu has demonstrated in vitro activity against all clinically relevant influenza viruses, including H5N1 and Avian H7 and H9 strains. [8] Consequently, Tamiflu has an important role to play in both the management of seasonal influenza and potentially in a pandemic situation, including avian influenza.

Indications and dosage

Tamiflu is currently indicated for the treatment of acute illness due to influenza A or B in children (age ≥1 year), adolescents and adults who have been symptomatic for no more than 2 days. Tamiflu is available as capsules and a syrup suspension for paediatric use. For treatment of influenza, Tamiflu should be initiated as soon as possible within the first 48 hours of symptoms and continued for 5 days. As prophylaxis, Tamiflu should be initiated within 2 days of close contact with an infected individual and continued for 10 days (recommended in the European Union and the USA).

	Dose	Duration
Treatment
Adults and adolescents (≥13 years) Children (≥1 year) ≤15 kg >15–23 kg >23–40 kg >40 kg	75 mg twice daily 30 mg twice daily 45 mg twice daily 60 mg twice daily 75 mg twice daily	5 days 5 days 5 days 5 days 5 days
Post-exposure prophylaxis* [9]
On close contact with an infected individual Adults and adolescents (≥13 years) Children (≥1 year) ≤15 kg  >15–23 kg  >23–40 kg  >40 kg	75 mg once daily 30 mg once daily 45 mg once daily 60 mg once daily 75 mg once daily	10 days 10 days 10 days 10 days 10 days

*dosage adjustment of Tamiflu is necessary for patients with severe renal impairment (creatinine clearance <30 mL/min).

Efficacy
Tamiflu has been shown to be clinically effective for the treatment and prevention of influenza in adults and in children aged 1 year or older. Compared with placebo, Tamiflu reduces:

• severity of symptoms by 38% [4]
• median duration of influenza illness by 29–35% [4, 6]
• secondary complications such as bronchitis, pneumonia, sinusitis and otitis media by 50% [4]
• incidence of influenza-confirmed cases by 89% in individuals and 84% in affected households. [10]

Reduces the risk of complications
Influenza causes a variety of secondary complications, especially lower respiratory tract infections, bronchitis and pneumonia. In large controlled clinical trials Tamiflu has been shown to reduce the incidence of secondary complications: in healthy adults and adolescents lower respiratory tract complications were reduced by 67%, while in at-risk individuals Tamiflu led to a 34% reduction in lower respiratory tract complications. [3] In children aged 1–12 years, the incidence of physician-diagnosed complications requiring antibiotic therapy was reduced by 40% in the Tamiflu group. [11] Likewise, in the same study, the incidence of otitis media was almost halved in those children who had received Tamiflu (44%). [11]

People get better faster
In a clinical study involving more than 60 primary care and university health centres in the USA, duration of illness with Tamiflu treatment was reduced by 30% compared with placebo, while the severity of illness was reduced by 38% versus placebo. [4] This decreased the time to resume normal daily activities compared with placebo by more than 2 days. [4]
The clinical results in children are similar to those seen in adult patients. In a placebo-controlled trial in children aged 1–12 years Tamiflu significantly reduced the median duration of illness by 26% (36 hours; P<0.0001), from 137 hours in the placebo group to 101 hours. [11] In the same study, the median symptom score was reduced by 29%, from 1358 to 960. [11]

People can be protected from developing clinical influenza after exposure to virus
Several large controlled studies have demonstrated that Tamiflu is effective in preventing clinical influenza in healthy adults when used as prophylaxis after exposure to close contacts, such as household members, or as seasonal prophylaxis in the community [10, 12]. When used as post-exposure prophylaxis and treatment of index cases in the household, Tamiflu significantly reduces secondary spread of influenza in families by 80–90%. [13]

People can be protected against influenza throughout the influenza season
Tamiflu 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness during a community outbreak from 25/519 (4.8%) in the placebo group to 6/520 (1.2%) in the Tamiflu group – a 76% reduction (p=0.0006). [12]

Early intervention is key
Earlier intervention with Tamiflu is associated with significantly better clinical effect. Initiation of Tamiflu therapy within the first 12 hours after onset of fever reduced the total median illness duration by 41% (3.1 days) more than intervention at 48 hours. [7] Earlier intervention enhances the effects of treatment, resulting in faster recovery and resumption of normal activities.
Find out more about the efficacy of Tamiflu in the treatment and prevention of influenza, here.

Safety
Up to the end of 2006, over 43 million patients have received Tamiflu.
Tamiflu is generally well tolerated by patients. The most frequently reported side-effects are mild nausea, vomiting and abdominal pains, though these effects are usually self-limiting and some can be reduced by taking the medication with food. [9] 

The following adverse reactions have been reported during post-marketing use of Tamiflu: dermatitis, rash, eczema, urticaria, angioneurotic oedema, hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, as well as very rare reports of severe skin reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Additionally there are very rare reports of hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness.
More information about the safety of Tamiflu can be found here.

Resistance
The risk of emergence of drug resistance in clinical use in the treatment of influenza has been extensively examined. In clinical studies, viral samples from approximately 4,000 patients with influenza infection treated with Tamiflu showed 0.3% (4/1228) of adults and adolescents and 4.0% (17/421) of children aged 1–12 years to be transiently carrying influenza virus with decreased neuraminidase susceptibility to oseltamivir carboxylate. [14] The emergence of resistance may be higher in young children and in children who had immunosuppression or who were under-exposed to oseltamivir. Patients carrying resistant virus cleared it normally and showed no clinical deterioration. All resistant genotypes are disadvantaged compared to the corresponding wild-type isolate and are likely to be less contagious in humans.

Zanamivir (Relenza®)
Zanamivir (Relenza) was the first neuraminidase inhibitor to be developed and, like Tamiflu, is effective in the treatment and prevention of influenza [1].

Treatment of influenza in adults and adolescents
The efficacy of Relenza 10 mg inhaled twice daily for 5 days in the treatment of influenza has been evaluated in placebo-controlled studies conducted in North America, the southern hemisphere, and Europe during their respective influenza seasons. These studies showed a 1–1.5-day difference in median time to symptom improvement. No consistent differences in rate of development of complications were observed between treatment groups.

Paediatric patients
The efficacy of Relenza 10 mg inhaled twice daily for 5 days in the treatment of influenza in paediatric patients has been evaluated in a placebo-controlled study conducted in North America and Europe, enrolling 471 patients, aged 5 to 12 years (55% male, 90% Caucasian), within 36 hours of symptom onset. Median time to symptom improvement was 1 day shorter in patients receiving zanamivir compared with placebo. No consistent differences in rate of development of complications were observed between treatment groups.

Prophylaxis of influenza
The efficacy of Relenza in preventing naturally occurring influenza illness has been demonstrated in two post-exposure prophylaxis studies in households (10 mg inhaled once daily for 5 days) and two seasonal prophylaxis studies during community outbreaks of influenza (10 mg inhaled once daily for 28 days). In the post-exposure prophylaxis studies, the proportion of households with at least 1 new case of symptomatic laboratory-confirmed influenza was reduced from 19.0% (32 of 168 households) for the placebo group to 4.1% (7 of 169 households) for the group receiving Relenza in the first study, and 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the group receiving Relenza in the second study. In the seasonal prophylaxis studies, the incidence of symptomatic laboratory-confirmed influenza was reduced from 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the group receiving Relenza in the first study and from 1.4% (23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving Relenza in the second study.

While Tamiflu and Relenza are both NAIs, Relenza differs from Tamiflu in a number of key aspects.

• Low oral bioavailability means that Relenza is administered using a Diskhaler, which some patients, particularly the elderly, may find difficult to use, potentially affecting compliance. [15]
• Relenza is approved for the treatment and prevention of influenza in children older than 5 years, whereas Tamiflu is approved for both indications for all patients over 1 year of age.
• Delivery by inhalation has been associated with a risk of bronchospasm, even in patients without a history of respiratory disease. [16]
• As Relenza is inhaled, drug concentrations of Relenza outside of the respiratory tract are low, while Tamiflu is systemically absorbed and concentrations in tissues and organs outside of the respiratory tract reach antiviral efficacious levels. [17]

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