Tamiflu the preferred option for pandemic stockpiling, says EMEA (European Medicines Agency)

by Scrip News,
SCRIP World Pharmaceutical News

Europe, 03 Nov 2005 - Roche's Tamiflu (oseltamivir) is the preferred antiviral for large-scale use in the event of a flu pandemic, because it is marketed in two different formulations and can also be made available as a magistral preparation. Nonetheless, smaller amounts of other antivirals should be stockpiled for use in specific circumstances such as drug resistance, says the European Medicines Agency (EMEA).

Antivirals will form the first line of defence against a pandemic if one does break out, as vaccines against the pandemic strain will not be ready for several months after the strain is identified. Moreover, antivirals will probably be more useful as prophylactic agents than as treatments, the EMEA says.

The agency has conducted a study into which antivirals will be of most use for both prophylaxis and treatment before a pandemic vaccine becomes available. Estimates of how effective antivirals will be in a pandemic situation are largely based on their use in the treatment and prophylaxis of seasonal flu epidemics, and the pattern and severity of a pandemic may well be different, it says.

Moreover, the usefulness of antivirals is restricted by the need to begin treatment within two days of the onset of clinical flu symptoms, and even then the effect is modest. Their efficacy against pandemic strains is uncertain.

The EMEA therefore recommends a twofold approach, starting with long-term prophylaxis of certain key groups such as healthcare workers, decision-makers and police in the early stages of a pandemic. Then, for the general population, prompt treatment of infected people (index cases) combined with post-exposure prophylaxis of their close contacts could slow down the progress of the pandemic.

four antivirals
The four antivirals examined by the EMEA are the M2 inhibitors, rimantadine (Forest's Flumadine) and amantadine (Alliance Pharmaceuticals' Lysovir), and the neuraminidase inhibitors, oseltamivir and zanamivir (GlaxoSmithKline's Relenza). All of them, says the agency, are potentially useful in a pandemic but no single one is the ideal solution, so it would be useful to have more than one agent available to cope with special and unexpected circumstances, such as the emergence of resistant strains.

Rimantadine and amantadine appear to have similar efficacy against flu, although resistance can be a problem, and analysis of some 2004 H5N1 viruses (the type thought most likely to cause a pandemic) isolated from poultry and humans in Asia showed them to be resistant to both drugs. The increasing use of amantadine in China raises further concerns about the emergence of amantadine-resistant variants, the EMEA says.

neuraminidase inhibitors
The prospects for the neuraminidase inhibitors are more promising. Treatment with oseltamivir has been shown to result in a significant shortening of the period to cessation of virus shedding, and therefore the duration of illness. While there are no data on the use of oseltamivir in a pandemic situation, in vitro studies suggest that it is likely to be effective against the current strains of H5N1 viruses and other avian viruses with pandemic potential (such as H9N2 and H7N7).

As for prophylaxis, oseltamivir is indicated for the prevention of flu in adults and children aged over 13 in the EU (approval for paediatric use is pending). Again, there are no data on prophylactic use of oseltamivir in a real pandemic situation, and no properly controlled clinical trials with respect to the current avian flu strains, the EMEA notes.

However, when the product was recently tested against a 2004 clinical isolate of the current avian flu strain in a mouse model, it significantly reduced mortality against a lethal challenge at a dosage equivalent to the approved human dose. It has also been shown to inhibit the 1918 avian flu strain as well as other pandemic strains. For the time being at least, the clinical significance of oseltamivir-resistant strains of flu appears to be limited, although this will be monitored by the global Neuraminidase Inhibitor Susceptibility Network, the EMEA observes.

The major advantage of oseltamivir over zanamivir is that it is available as 75mg capsules (shelf life of five years) and as powder for reconstitution (shelf life of two years). Moreover, Roche has produced a user guide on how to prepare a magistral solution of the product by dissolving the active substance in water. This bulk formulation has a number of advantages over the commercial forms: a longer shelf life, a shorter manufacturing cycle and wider availability. This method of preparation is simple and can be done in a pharmacy, hospital or suitable laboratory, the EMEA points out.

Zanamivir

As for zanamivir, in vitro studies have shown that it is effective against the H5N1 virus that caused fatal illness in Hong Kong in 1997. In a mouse model using avian H5N1, H6N1 and H9N2 strains, intranasal zanamivir significantly reduced viral titres in the lungs and completely blocked the spread of virus to the brain, suggesting that systemic spread may be related to the level of viral replication in the lungs.

The drawbacks of using zanamivir are that it is available only as an inhaled powder and it is not approved everywhere for prophylactic use (it does not have this indication in the EU, for example). "In a pandemic situation, zanamivir may not be the preferred agent due to its mode of administration," the EMEA says.

Estimating stock levels

Estimating the quantity of antivirals needed to cope with a pandemic depends on the pandemic strategy and the availability of vaccine against the pandemic strain, the agency says. The optimal duration of prophylaxis during a pandemic is not known, but it is possible that periods exceeding the recommended duration of normal seasonal prophylaxis (six to eight weeks) will be needed.

As oseltamivir is the antiviral of choice for large-scale stockpiling, the agency suggests that it would be useful to explore the use of magistral formulations of the product in the interpandemic period, in order to rotate stocks and test and improve the distribution system.

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