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[e-drug] Oseltamivir expiry date (3)

  • From: "Andy Gray" <Graya1@ukzn.ac.za>
  • Date: Tue, 12 May 2009 09:43:17 +0200

E-DRUG: Oseltamivir expiry date (3)

Hi all

Previous postings have raised the issue of the expiry date
determination for oseltamivir - the EMEA has issued a statement in this
regard; not all links are provided, but the Q&A is included). Another
issue raised has been the restriction to use in children aged 1 year and
older - the MHRA has also ruled on that issue. Both are examples of how
regulatory and public health authorities are having to deal with
uncertainty n the face of a major potential threat.

I've appended two stories from the UK Guardian - copied as "fair use" - that underline how the authorities are dealing with that uncertainty. One of the greatest sources of uncertainty is the timing of this outbreak - the Northern Hemisphere may escape this wave, but the Southern Hemisphere is entering winter, when the chances for human-to-human spread may be increased.



European Medicines Agency
Press office
7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 09
E-mail: mail@emea.europa.eu http://www.emea.europa.eu London, 8 May 2009 Doc. Ref. EMEA/284971/2009 PRESS RELEASE

European Medicines Agency recommendations on extension of shelf life for Tamiflu

The European Medicines Agency has recommended that the shelf life of Tamiflu capsules should be extended from five to seven years. Once formally approved by the European Commission, this will apply to all newly manufactured Tamiflu capsules.

In view of the recent outbreak of the novel influenza A/H1N1 virus, the European Medicines Agency has also reviewed ways to use Tamiflu capsules in case of a shortage. The Agency???s Committee for Medicinal Products for Human Use (CHMP) recommended that Tamiflu capsules that are already on the market may be used for up to two more years after their current five-year expiry date during a declared pandemic. Patients who have Tamiflu capsules that have recently expired should not dispose of them because they might be needed during a novel influenza A/H1N1 pandemic.

The recommendations are made by the Committee as part of a wider request from Agency???s Executive Director Thomas L??nngren to look into ways to prevent shortages of antiviral medicines and to ensure that the medicines are available to those who might need them. These recommendations will only apply if a pandemic has been declared by the World Health Organization (WHO).

Antiviral medicines such as Tamiflu play an important role in the management of an influenza pandemic. Unlike vaccines, which are normally not available during the early stages of a pandemic, antivirals can be used right from the onset of the pandemic. Governments worldwide have been stockpiling these medicines, including Tamiflu, to make them available to the public, in accordance with national preparedness plans.


1. More information is available in a question-and-answer document.
2. Tamiflu is a centrally authorised medicine for the treatment and prevention of influenza in adults and children over the age of one year.
The European public assessment report for Tamiflu is available here.
3. The assessment report of the CHMP with recommendations on the usability of expired Tamiflu in the event of a pandemic is available here.
4. A separate press release with information on the Agency???s guidance on use of antiviral medicines in case of a novel influenza A/H1N1 pandemic is available here.
5. An EMEA review of influenza antiviral medicinal products for use in pandemics is available here.
6. More information on the work of the European Medicines Agency in relation to pandemic influenza vaccines is available here.
7. The European Commission and the European Centre for Disease Prevention and Control (ECDC) are responsible for the coordination of the European response to the public health threats posed by the influenza outbreak. The European Medicines Agency is working closely with them to support their work. An overview of the activities of the European Commission can be found at:
Information about the work of the ECDC can be found at:
8. Information about the work of the WHO can be found at:
9. This press release, together with other information about the work of the EMEA, is available on the EMEA website:

Media enquiries only to:
Martin Harvey Allchurch or Monika Benstetter Tel. (44-20) 74 18 84 27, E-mail press@emea.europa.eu ~~~ http://www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/27353509en.pdf
European Medicines Agency
7 Westferry Circus, Canary Wharf, London E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16
E-mail: mail@emea.europa.eu http://www.emea.europa.eu ?? European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.
London, 8 May 2009
Doc. Ref. EMEA/273535/2009

Questions and answers on the use of antiviral medicines in case of novel influenza A/H1N1 pandemic

In view of the recent outbreak of the novel influenza virus A/H1N1, the European Medicines Agency has reviewed the use of the antiviral medicines Tamiflu (oseltamivir) and Relenza (zanamivir). The Agency???s Committee for Medicinal Products for Human Use (CHMP) has recommended that during a declared pandemic:
??? Tamiflu can be used in children younger than one year of age; ??? Tamiflu and Relenza can be used in women who are pregnant or breastfeeding; ??? Tamiflu capsules that have already been distributed may be used for an additional two years after the current expiry dates.

This review was carried out under an Article 5(3) procedure1. (1.
Article 5(3) of Regulation (EC) No 726/2004, opinion on any scientific matter concerning the evaluation of medicinal products for human use).

What is Tamiflu?

Tamiflu is currently authorised to treat or prevent influenza in adults and children over the age of one year. Tamiflu has been authorised in all countries of the European Union (EU) since June 2002. The company that makes Tamiflu is Roche Registration Limited.

The active substance in Tamiflu, oseltamivir, is a ???neuramidase inhibitor???. It acts specifically on the influenza virus, blocking some of the enzymes on its surface, known as neuramidases. When the neuramidases are blocked, the virus cannot spread.

What is Relenza?

Relenza is another neuramidase inhibitor currently authorised to treat or prevent influenza in adults and children from the age of five years.
Relenza was first authorised in Sweden in 1999 and is currently authorised in all countries of the EU. The company that makes Relenza is GlaxoSmithKline.

How can antiviral medicines be used in case of an influenza pandemic?

In case of an influenza pandemic, the use of antiviral medicines, such as Tamiflu and Relenza, should be based on official recommendations. If an influenza pandemic is declared by the World Health Organization (WHO), antiviral medicines will be supplied through governmental organisations in accordance with national pandemic plans, together with instructions on when and how to use the medicines. In preparation for this, governments worldwide have been stockpiling antiviral medicines, such as Tamiflu.

Why is the EMEA reviewing Tamiflu and Relenza?

The current outbreak of novel influenza virus A/H1N1 has been classified by the WHO as being able to trigger a pandemic. The WHO also stated that the neuramidase inhibitors such as oseltamivir and zanamivir have shown effectiveness against the novel virus. In preparation for an influenza pandemic, the European Medicines Agency has been looking at a number of ways to ensure that antiviral medicines are available to those who might need them.

On 30 April 2009, the Executive Director of the Agency requested that the CHMP give its scientific opinion on the following issues:
??? the possible use of Tamiflu capsules already on the market for two additional years after the current expiry dates, considering that the shelf life for newly manufactured Tamiflu capsules is being extended from five to seven years; ??? the use of Tamiflu in children under the age of one year to prevent or treat the novel influenza A/H1N1; ??? the use of Tamiflu and Relenza in women who are pregnant or breastfeeding to prevent or treat the novel influenza A/H1N1.

Which data has the CHMP reviewed?

To make a recommendation on the use of Tamiflu capsules beyond five years, the Committee looked at data on the condition of the capsules after seven years, in particular the impurities and degradation products that may develop during storage.

For the use of Tamiflu in infants below the age of one, the Committee looked at the interim results of an ongoing study in children under one year, two previous studies and a retrospective analysis in children.
Regarding the use of Tamiflu in pregnant women, the CHMP reviewed evidence from the published literature and data provided by the company on 232 cases of women who took the medicine during pregnancy.
For Relenza, the CHMP reviewed data previously provided by the company on women who took the medicine during pregnancy or while breastfeeding.

What are the conclusions of the CHMP?

Based on the data submitted by the company, the CHMP recommended an extension of the shelf life of Tamiflu capsules from five to seven years. During a novel influenza A/H1N1 pandemic, this extension will also apply to the capsules already distributed, including those that have already expired provided that they have been kept in appropriate conditions (at room temperature). This might help to prevent shortages.

In case of a pandemic, the Committee agreed that there is enough evidence to support the use of the Tamiflu for the treatment in children younger than one year of age. The Committee noted that there is less evidence to support the use of Tamiflu for the prevention of influenza.
Therefore doctors should carefully consider the benefits and risks for each infant. Should Tamiflu be prescribed to children under the age of one, the recommended dosage is 2 to 3 mg per kg body weight.

In case of a pandemic, the Committee agreed that there is enough evidence to support the use of Tamiflu and Relenza in pregnant and breastfeeding women.

What are the recommendations for patients?
??? Patients who have expired Tamiflu capsules should not dispose of them as they might be asked to use them in case of the A/H1N1pandemic; ??? Patients must not take Tamiflu capsules unless they receive clear instructions from their doctor or health authorities; ??? Patients who have any further questions should speak to their doctor or pharmacist.

What are the recommendations for prescribers?
??? Doctors should follow official recommendation when prescribing antiviral medicines such as Tamiflu and Relenza during a pandemic; ??? The current CHMP recommendation on the extended use of Tamiflu and Relenza will only apply in case of a influenza A/H1N1 pandemic; ??? Doctors should continue to prescribe Tamiflu and Relenza for seasonal influenza according to the current prescribing information.

What will happen next?

The CHMP opinion will be communicated to the Member States, so that they act accordingly. For further information, see the scientific opinion adopted by the CHMP on 7 May 2009.


MHRA authorises temporary distribution of unlicensed medicine

In accordance with Article 5(2) of Directive 2001/83/EC on the Community Code relating to Medicinal Products for Human Use, in response to the confirmed spread of influenza virus the Secretary of State for Health has temporarily authorised the distribution of unlicensed oseltamivir powder and an unlicensed oral liquid formulation of oseltamivir for administration to infants under 1 year of age in the prevention or treatment of influenza. The Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994 and the Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous
Amendments) Regulations 2005 have been amended.

The lessons of swine flu
We must accept the uncertainty surrounding potential pandemics and prepare for surprises if we are to respond effectively Ian Scoones guardian.co.uk, Sunday 10 May 2009 11.00 BST

As the swine flu outbreak backstory seeps out, there are some vitally important lessons that can be learned. Huge investment in pandemic preparedness and contingency plans, improvements in surveillance and response systems and stockpiling of drugs and vaccines have followed recent avian influenza outbreaks. But do we have effective global disease surveillance and control systems that can prevent a disaster?

In the face of a potential pandemic, huge numbers of potential deaths are bandied about, based on highly suspect data and assumptions and resulting in wild speculation and panic. The counter move is to keep quiet, cover up and assure the populace. Neither approach helps, as we don't know what will happen, when and to whom. This acceptance of uncertainty and ignorance in a public debate is tough. But it is also vital. Otherwise inappropriate public policy arises and misguided signals are given.

Preparing for a pandemic means preparing for surprises - and being ready to respond rapidly and flexibly under conditions of uncertainty requires a new set of skills, bureaucratic routines and incentive systems in the public agencies charged with protecting the world from emerging infectious diseases.

As Emery Roe and Paul Schulman argue in their recent book High Reliability Management, reliability must be a feature of any system operating in a complex, uncertain world. This requires, they argue, high reliability professionals who can track between local understandings of what is happening on the ground and the broader policy situation, liaising between agencies and across scales.

These professionals are currently absent from the international effort
- creating a vacuum at the heart of the response - because authoritative knowledge consists of accepted expertise that does not acknowledge uncertainty, ignorance or complexity.

In a potentially global pandemic situation, global assessments are also based on global statistics, but in reality major structural inequalities affect the likely outcomes of rapid disease spread. We don't know why disease virulence and mortalities are high in Mexico, but apparently lower elsewhere. This may have a complex medical, viral cause. But it also may be to do with access to healthcare and effectiveness of response.

In the UK there is much brash talk of being "the best prepared" country in the world. But being prepared means having stockpiles of drugs, an effective surveillance system and a functioning national health system.
Such conditions do not exist everywhere; other diseases and poverty affect people's health and ability to resist new viruses.
Underdevelopment and inequality play a big part in the dynamics of diseases, and should not be forgotten in the rush to construct a global public response to a potential pandemic.

The swine flu story is also revealing how poor surveillance and reporting systems mean an outbreak can quickly get out of control - there were big gaps in detection and reporting that date back to February. But local people knew of the disease, and have strong hypotheses about its origins. Anselma Amador from La Gloria, the village where the first known case of swine flu occurred told the Guardian: "We are not doctors, but it is hard for us not to think the pig farms around here don't have something to do with it ???The flu has pig material in it and we are humans, not pigs." La Gloria residents say local hills prevent the farm's fetid air from moving on past their village.

These explanations are dismissed by the health minister and pig farming company, but why are such leads not being followed up? And why are such early-warning approaches, based on local knowledge about disease incidence and its dynamics, not part of the standard surveillance system? Why is such knowledge of the "not doctors" so easily dismissed?

In south-east Asia local understandings of avian flu and its spread have been vitally important. Medical doctors, epidemiologists, virologists, veterinarians and other specialists need to work hand in hand with local people for surveillance to be effective.

The naming of "swine flu" is also now being fiercely debated, revealing much about the politics of a disease. An Israeli health minister and a number of Muslim groups have objected on religious grounds. World animal health organisation the OIE has also argued that the flu should be relabelled "North American influenza", as the virus had not been isolated in animals, "no current information on influenza-like animal disease in Mexico or the US could support a link between human cases and possible animal cases including swine", it says.

While religious sensibilities might be understandable, what does the OIE's position tell us about a co-ordinated international response? Made up of chief veterinary officers from around the world, the OIE, as the WTO-recognised body dealing with trade in animals and their products, has enormous influence on - and is enormously influenced by - the international livestock and meat trade. Within countries, pressures not to declare an animal disease outbreak can be immense, and slow reporting and a commitment to facilitating certain types of trade, for certain countries and certain business interests, may be part of the political economy of decision-making.

Another strong lesson from the avian flu experience is that attention to the changing structure of the livestock industry is essential to understanding how diseases emerge and spread. While it is easy to blame big agribusiness and industrial farming techniques, the situation is more complex.

While the "livestock revolution" is celebrated as a source of economic growth in the developing world, rapid restructuring of the livestock sector has major downsides and implications for how industries are regulated and diseases managed. Backyard production of poultry or pigs can be replaced by poorly regulated industrial units aimed at maximising returns but with little attention to safety, animal welfare, disease control or environmental pollution. Independence, transparency and effective and timely information flows are essential for international efforts to control emerging diseases. As the details begin to emerge on the swine flu outbreaks, a more comprehensive assessment of the political economy of agriculture - and the pig industry in particular - in Mexico will be essential in learning lessons for the future.

Right now, of course, the spotlight is focused on the international public health response. Preparing for a pandemic means preparing for surprises - and being ready to respond rapidly and flexibly under conditions of uncertainty. As the experience with avian influenza has shown, this may require more than simply the top-down, "active and aggressive" technocratic responses being urged.


British scientists crack swine flu code as world tally rises to 2,384 ??? Mapping of genetic code will aid creation of vaccine ??? Five new cases diagnosed in the UK today David Batty guardian.co.uk, Friday 8 May 2009 16.29 BST

The World Health Organisation (WHO) today increased its global tally of confirmed swine flu cases to more than 2,300, as British scientists announced they had worked out the full genetic code for the virus.

Five new cases were diagnosed in the UK today - four schoolchildren and an adult linked to Alleyn's School in Dulwich, south London, which has been closed all week after six pupils were diagnosed with the illness.
There are now 39 confirmed cases in the UK.

Mexico remains the worst affected country, with more than 1,100 laboratory-confirmed human cases of H1N1 virus influenza, including 42 deaths. The United States has reported nearly 900 laboratory-confirmed human cases, including two deaths. Another 22 countries have confirmed cases but no deaths.

The latest figures came as the health secretary, Alan Johnson, said the Health Protection Agency, which monitors infectious diseases, had fully mapped the genetic code of the virus.

He said this would help scientists to understand how the virus operates and to identify the parts that can be used to manufacture a vaccine.

On a visit to a laboratory in Hertfordshire, he was told that researchers hope European manufacturers will be able to take delivery of prototypes in the coming months to enable mass production of a vaccine to begin.

Johnson said: "A significant step towards protecting the world's health against swine flu has been taken. We now look to the vaccine industry to produce the required quantities of vaccine as quickly as possible."

The entire genetic fingerprint and sequence of the swine flu virus will now be analysed to learn how the virus behaves as it infects individuals.

At a meeting of Asian health ministers in Bangkok today, the WHO director general, Dr Margaret Chan, said the world was "better prepared for an influenza pandemic than at any time in history", largely because of precautions taken over the threat of bird flu.

She said: "Years of alert and expectation mean that most countries now have preparedness plans. Vaccine manufacturing capacity has increased sharply. Large stocks of antiviral drugs have been produced and procured.

"Right now, treatment courses from the WHO stockpile are being shipped to more than 70 countries in the developing world."

Mexico's ambassador to the United Nations in Geneva said he would raise concerns at the WHO annual meeting later this month about "discriminatory" measures imposed against the country, its people, and its exports because of the flu. China has placed dozens of Mexicans in forced quarantine as a protective measure against the spread of the virus.

Around the world, public opinion seems to be shifting from fear of a pandemic to scepticism as to whether the virus poses a significant threat.

Half of 2,000 Britons surveyed yesterday said they believe the government over-hyped the threat of swine flu, and are now less worried about it spreading.

The research by online polling centre Toluna found two-thirds of respondents thought the government had coped well with the outbreak, while more than half (54%) thought the NHS was well prepared to cope with a possible pandemic.

The report noted a decline in public worry about the virus spreading, with 40% worried about the virus, compared with 50% last week.

Public health officials around the world acknowledge their worst fears about the new virus have yet to materialise. But many experts worry that people will become too complacent and fail to heed warnings if the virus returns in a more dangerous form in the autumn.

"People are taking a sigh of relief too soon," said Dr Richard Besser, acting director of the US Centres for Disease Control and Prevention.

"The measures we've been talking about - the importance of hand-washing, the importance of covering coughs, the real responsibility for staying home when you're sick and keeping your children home when you're sick - I'm afraid that people are going to say, 'Ah, we've dodged a bullet. We don't need to do that,'" he said.

Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Dept of Therapeutics and Medicines Management
* Consultant Pharmacist
Centre for the AIDS Programme of Research in South Africa (CAPRISA) Nelson R Mandela School of Medicine University of KwaZulu-Natal PBag 7 Congella 4013 South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@ukzn.ac.za or andy@gray.za.net

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