3 November 2006
Oseltamivir (Tamiflu) now produced in United States for Pandemic Flu Preparedness…Are we safer?
Amidst fears of a bird flu pandemic, the US Department of Health and Human Services (HHS) has been adamant that the US be self-reliant in the supply of the anti-influenza drug oseltemivir (“Tamifllu”) for the American public. Now through a working partnership with Roche AG, the Swiss manufacturer of Tamiflu, and its external contractors, the US is able to make the drug entirely on US soil. The US production facility is part of Roche’s worldwide global production network capable of producing 400 million treatment courses of Tamiflu annually by the end of 2006 (Roche Pharmaceuticals Press Release, 14 September 2006, [http://www.rocheusa.com/newsroom/current/2006/pr2006091401.html]).
Oseltamivir is the generic name for Tamiflu that is used in the treatment and prophylaxis of both Influenza virus A and Influenza virus B. Oseltamivir is a neuraminidase inhibitor which prevents new viral particles from being released by infected cells. Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of infected cells. This promotes the release of progeny viruses from infected cells (FDA Information on Tamiflu, [http://www.fda.gov/cder/drug/infopage/tamiflu/default.htm] and Roche Tamiflu Fact Sheet, [http://www.roche.com/med_mbtamiflu05e.pdf]).
Roche AG (http://www.roche.com/home.html) is the primary maker of Tamiflu and in early 2005, it announced a production shortage resulting from a bottleneck due to lack of shikimic acid. Shikimic acid is a critical ingredient that is isolated from star anise, which is an ancient cooking spice. Star anise is only grown in four provinces in China and harvested between March and May, and also in Lang Son province in Vietnam. The extraction process for the shikimic acid from star anise is long, complicated, and has a low yield. Therefore, Roche is now shifting production to a fermentation process using E. coli bacteria. This will decrease, if not eliminate, reliance on limited and unpredictable agricultural resources. Reports have indicated that this new fermentation production method of shikimic acid also produces much higher amounts of this critical ingredient.
Tamiflu is hoped to be effective in combating the next flu pandemic, assuming the virus causing the next pandemic is susceptible to this neuraminidase inhibitor. In preparing for this future pandemic, many countries and health organizations, including the US and the WHO, have begun stockpiles of oseltamivir (Roche Media News, 19 April 2006, [http://www.roche.com/med-cor-2006-04-19]). Along with the US, multiple countries have begun to produce oseltamivir. Prior to 2004 all production of this medication occurred in Switzerland at the Roche company production facility in Basel.
"The ability to produce Tamiflu from start to finish on US soil is a significant milestone that will help ensure access to Tamiflu when and where it is needed," said George Abercrombie, president and chief executive officer for Hoffman-La Roche, Inc., the company's US pharmaceutical division (Roche Press Release, 14 September 2006). He continues, “"This most recent expansion further demonstrates Roche's long term commitment to serving as a responsible and collaborative partner with the U.S. government on pandemic preparedness and response To date, HHS has ordered 21.3 million courses of Tamiflu for the U.S. Strategic National Stockpile, which will be delivered in full this year. The total targeted U.S. stockpile is 81 million antiviral treatment courses by the end of 2008; HHS plans to purchase 50 million treatment courses and subsidize by 25 percent the states' purchases of 31 million courses”.
Oseltamivir is the only oral neuraminidase inhibitor licensed by the FDA to prevent and treat influenza infection. The only other FDA-licensed neuraminidase inhibitor drug for influenza prevention and therapy, zanamivir (“Relenza”) is only available commercially as an inhaled drug and not as a pill or capsule. Of note, influenza viruses that are resistant to oseltamivir (Tamiflu) are still susceptible to zanamivir (Relenza). The US Department of Health and Human Services (see their pandemic flu website: www.pandemicflu.gov) is stockpiling both oseltamivir and, to a lesser extent, zanamivir.
If the next pandemic influenza virus is susceptible to these neuraminidase inhibitor medications, then we will be better prepared and safer than in the absence of this stockpile. At the same time it is important to remember that both oseltamivir (Tamiflu) and zanamivir (Relenza) have important caveats to their use and effectiveness. In addition, antiviral drugs are only one part of overall pandemic flu preparedness and response.
Shoshana Avertick, Jordan Kanter, Stephanie Hrycaj, Igor Fogelman, Pete Harlan, and Shannon Hibbard.
Graduate students, Georgetown University Master of Science (M.S.) Program in Biohazardous Threat Agents and Emerging Infectious Diseases. Biodefense Public Health Countermeasures MICB-523.Washington, DC. Course instructor and article editor: Daniel R. Lucey, MD, MPH. Adjunct Professor of Microbiology and Immunology. Director, Center for Biologic Counterterrorism and Emerging Diseases, EROne Institute, Washington Hospital Center, Washington, DC. Website for this posting: www.BePast.org. E-mail:Daniel.R.Lucey@Medstar.net