Oseltamivir

Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071).

Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Production capacity is limited, and governments are stockpiling the drug.

Technical information

Indications and dosage

Roche recommendations in the United States

Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. According to prescription information by Roche for the United States[1], Tamiflu usage is indicated for both the treatment and prophylaxis of influenza at the following dosages.

  • Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Dosage for children is by weight.
  • Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual. Standard dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. Safety and efficacy for prophylaxis has not been established for patients under 13 years old.

The above treatment regimes are based upon studies of normal human influenza.

Dosage for avian flu

Peter Hobby (of the World Health Organization) has suggested that Vietnam should investigate and test a higher dosage and longer treatment with Tamiflu for patients with avian influenza[2][3]. Doctors in Vietnam concur, noting that

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. (de Jong et al. 2005)

Co-administration with probenecid

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. Probenecid reduces excretion of oseltamivir's active metabolite. 500 mg of probenecid given every six hours doubles oseltamivir's maximum blood concentration and also doubles the time that oseltamivir stays in the blood, multiplying a patient's overall exposure to the drug 2.5-fold. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. The evidence for this interaction comes from a 2002 study by Roche (Hill et al. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

Side effects

Information from Roche

The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States).

In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported. Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo.

According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:

  • General: Rash, swelling of face or tongue, toxic epidermal necrolysis
  • Digestive: Hepatitis, liver function tests abnormal
  • Cardiac: Arrhythmia
  • Neurologic: Seizure, confusion
  • Metabolic: Aggravation of diabetes

Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document.

Information from Japan: neurological effects and teen deaths

In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations. According to Japan's Pharmaceuticals and Medical Devices Agency, there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. In February 2005, a 14-year-old male died after falling nine stories from his condominium building. A third teen reportedly attempted to jump from the window of a building. The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche, which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005). Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety.

On November 18, 2005, a previously-scheduled Advisory Committee to the United States Food and Drug Administration (FDA) met to reconsider the pediatric safety of Tamiflu; a six-page report was issued: Pediatric Safety Update for Tamiflu. The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems). They did recommend adding a warning to prescription information regarding possible rashes.

The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].

Chemical synthesis

The reported azide-free Roche synthesis of tamiflu is summarized graphically below:

The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

Resistance

As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005).

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children (Ward et al., 2005). Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Third, the dosage regimen in Japan is different from that of other nations, and some children may have been given a suboptimal dosage of oseltamivir.

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005).

de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.

Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. First, these drugs work on a broader spectrum of influenza strains. Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission.

Production shortage/shikimic acid

In early-2005, Roche announced a production shortage. (See Pandemic Fears, below). According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid, which cannot be economically synthesized and is only effectively isolated from Chinese star anise, an ancient cooking spice; although most autotrophic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Star anise is grown in four provinces in China and harvested between March and May. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Ninety percent of the harvest is already used by Roche in making Tamiflu.

The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Other potential sources of shikimic acid include the ginko tree. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir.

Other actions

Tamiflu appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. Veterinary investigation of its use for canine parvo [8] and canine flu [9]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.

Pandemic fears

Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. In response to the epidemic, various governments – including those of the United Kingdom, Canada, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.

Wikinews has news related to this article: Taiwan to violate Tamiflu patent in order to compensate for vaccine shortage

In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Most patent laws allow governments to authorize supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies, although Roche has annouced its intention to remain the sole supplier of the drug. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production.

In late-October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. It said that, when distribution resumes in Canada, the remaining available drug will be saved for use in high-risk settings like long-term care facilities and hospitals. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Roche said it would instead send all supplies to China's health ministry[13].

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15].

U.S. Government policy and oseltamivir

In November, 2005, U.S. president George W. Bush requested Congress to fund $7.1 billion in emergency spending for flu pandemic prepardness (the Senate had already passed an $8.1 billion bill)[16]. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17].

Some commentators (e.g., [18]) question the motives of the U.S. government's endorsement and planned purchase of oseltamivir, noting Secretary of State Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the Tamiflu patent. Rumsfeld is a former chairman of Gilead, and federal disclosure forms indicate that he owns between $5 million and $25 million in Gilead stock (Schwartz 2005 [19]). The rise in Gilead's share prices from $35 to $57 per share will have added between $2.5 million to $15.5 million to Rumsfeld's net worth. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20].

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21].

Personal stockpiling of Tamiflu

The short supply of Tamiflu has prompted some individuals to stockpile the drug. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice.

One argument against individual stockpiling is that limited drugs should be kept for more strategic or ethical deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Ethical arguments are sometimes made: Why should affluent people (or nations) have preferred access to antiviral medications? Illegal importation may divert the drug from poorer countries where the risk of avian influenza is actually higher.

In the New England Journal of Medicine, Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1 (de Jong 2005).

Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. The packages were labeled Generic Tamiflu. Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly-labeled pills found in Holland, which contained only Vitamin C and lactose. However, sophisticated criminals could produce convincing fake packaging in the future. [22][23]

A fourth purported problem is that the H5N1 virus can be reliably diagnosed only in a small number of labs around the world; therefore, there is no way for home users to know whether flu-like symptoms are the result of avian flu or a more benign ailment. This argument lacks face validity, since treatment must begin before such tests results would be available anyway.

A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu.

References

  • Schwartz, Nelson . Oct 31, 2005. Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes)
  • Pollack, Andrew. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html)
  • Butler, D. Wartime tactic doubles power of scarce bird-flu drug [News article]. Nature 2005;438(7064):6. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html)
  • de Jong, Menno D.; Thanh, Tran Tan; Khanh, Truong Huu; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Nguyen Vinh; Cam, Bach Van; Qui, Phan Tu; Ha, Do Quang; Guan, Yi; Peiris, J.S. Malik; Hien, Tran Tinh; and Farrar, Jeremy. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. New England Journal of Medicine 2005;353(25):2667-2672. (Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1)
  • Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Drug Metabolism and Disposition 2002;30(1):13-19. (Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13)
  • Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759-65. PMID 15337401
  • Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H L, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. Avian flu: Isolation of drug-resistant H5N1 virus. Nature 2005;437(7062):1108.
  • Moscona, Anne. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective]. New England Journal of Medicine 2005;353(25):2633-2636.
  • Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. PMID 15709056
  • World Health Organization. WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.)
  • J. Org. Chem. 1998, 63, 4545-4550. Synthesis of Tamiflu.
  • J. Org. Chem. 2001, 66, 2044-2051. Synthesis of Tamiflu.
  • Chimia 2004, 58, 621.

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A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. MAD Magazine ran a parody of The Onion called "The Bunion" in one issue. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. Another popular send-up of the news that pre-dates The Onion is the Weekend Update segment on Saturday Night Live. A fourth purported problem is that the H5N1 virus can be reliably diagnosed only in a small number of labs around the world; therefore, there is no way for home users to know whether flu-like symptoms are the result of avian flu or a more benign ailment. Also, the National Lampoon crew has had a lasting influence on most American humorists, so it is not unlikely that The Onion's founders and staff had been influenced by them (considering that National Lampoon grew out of the college humor publication Harvard Lampoon and that The Onion also began as a college humor magazine.). [22][23]. While it is unknown if this book directly inspired/influenced The Onion's founders, it certainly shares similarities.

However, sophisticated criminals could produce convincing fake packaging in the future. The paper contained all the usual sections found in most major newspapers (classified ads, Sunday magazines, sports, local news, comics) satirized with the anarchistic Lampoon sense of humor. Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly-labeled pills found in Holland, which contained only Vitamin C and lactose. The book was an issue of the fictional "Ohio Republican-Democrat," a tabloid style newspaper. The packages were labeled Generic Tamiflu. O'Rourke and John Hughes. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. In 1978 National Lampoon released the book "National Lampoon's Sunday Newspaper Parody" which was edited by P.J.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. sponsorship or approval' by the president," referring to Title 18, 713, but then went on to ask that the letter be considered a formal application asking for permission to use the seal. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Klaskin, the Onion's lawyer, is quoted in the New York Times as saying "It is inconceivable that anyone would think that, by using the seal, The Onion intends to 'convey.. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1 (de Jong 2005). The letter written by Rochelle H. In the New England Journal of Medicine, Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains. The Onion has responded with a letter asking for formal use of the Seal in accordance with the Executive Order, while still declaring that the use is legitimate under Title 18, 713.

Ethical arguments are sometimes made: Why should affluent people (or nations) have preferred access to antiviral medications? Illegal importation may divert the drug from poorer countries where the risk of avian influenza is actually higher. 11649), but which allows for exceptions to be granted upon formal request. One argument against individual stockpiling is that limited drugs should be kept for more strategic or ethical deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. No. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. Ord. The short supply of Tamiflu has prompted some individuals to stockpile the drug. However, by Executive Order President Richard Nixon specifically enumerated the allowed uses of the Presidential Seal which is more restictive than the above title (Ex.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. This section would seem to allow the use of the presidential seal by The Onion. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Whoever knowingly displays any printed or other likeness of the great seal of the United States, or of the seals of the President or the Vice President of the United States, or the seal of the United States Senate, or the seal of the United States House of Representatives, or the seal of the United States Congress, or any facsimile thereof, in, or in connection with, any advertisement, poster, circular, book, pamphlet, or other publication, public meeting, play, motion picture, telecast, or other production, or on any building, monument, or stationery, for the purpose of conveying, or in a manner reasonably calculated to convey, a false impression of sponsorship or approval by the Government of the United States or by any department, agency, or instrumentality thereof, shall be fined under this title or imprisoned not more than six months, or both. (emphasis added). The rise in Gilead's share prices from $35 to $57 per share will have added between $2.5 million to $15.5 million to Rumsfeld's net worth. The law governing the Presidential Seal is contained in TITLE 18, 713 and contains the section:. Rumsfeld is a former chairman of Gilead, and federal disclosure forms indicate that he owns between $5 million and $25 million in Gilead stock (Schwartz 2005 [19]). Dixton, wrote a cease and desist letter to The Onion, asking the paper to stop using the presidential seal, which is used in an online segment poking fun at the President through parodies of his weekly radio address.

government's endorsement and planned purchase of oseltamivir, noting Secretary of State Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the Tamiflu patent. Bush, Grant M. Some commentators (e.g., [18]) question the motives of the U.S. In September 2005, the assistant counsel to President George W. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. Recently, an article from The Onion appeared on the 2005 Advanced Placement English Language and Composition test, in which students were asked to write an essay analyzing its use of satire.[4]. Bush requested Congress to fund $7.1 billion in emergency spending for flu pandemic prepardness (the Senate had already passed an $8.1 billion bill)[16]. [2] [3].

president George W. Columnist Ellen Makkai and others who believe the Harry Potter books recruit children to Satanism have also been taken in by The Onion's satire, using quotes from an Onion article as evidence for their claims. In November, 2005, U.S. [1]. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Exercise Televised. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. In late March 2004, Deborah Norville of MSNBC presented as genuine an article entitled Study: 58 Percent Of U.S.

Roche said it would instead send all supplies to China's health ministry[13]. The Evening News is Beijing's most popular newspaper, claiming a circulation of 1.25 million. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. sports franchises' threats to leave their home city unless new stadiums are built for them. It said that, when distribution resumes in Canada, the remaining available drug will be saved for use in high-risk settings like long-term care facilities and hospitals. The article is a parody of U.S. In late-October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. Congress's threats to leave Washington for Memphis, Tennessee or Charlotte, North Carolina unless Washington, DC built them a new Capitol building with a retractable dome.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. The story discusses the U.S. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Unless New Capitol Is Built (they were apparently unaware of The Onion's satirical nature). Most patent laws allow governments to authorize supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies, although Roche has annouced its intention to remain the sole supplier of the drug. On June 7, 2002, Reuters reported that the Beijing Evening News republished, in the international news page of its June 3 edition, translated portions of Congress Threatens To Leave D.C. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. to introduce democracy and protect their interests in the region, Bill Clinton declared himself "President for life.", Bob Dole was shot, and Tipper Gore was being held hostage.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. As the recount process unfolded, the Onion published a satirical issue reporting chaos in America, in which Serbia sent peacekeepers to the U.S. In response to the epidemic, various governments – including those of the United Kingdom, Canada, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Gore. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. The noteworthiness of this story was largely a matter of luck: the paper went to press election night, before the contested election results which led to Bush v. Veterinary investigation of its use for canine parvo [8] and canine flu [9]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses. Presidential election, when the future President remained undetermined, the Onion published a story titled Bush or Gore: "A New Era Dawns" which parodied the similarities between the two politicians.

Tamiflu appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. Just after the 2000 U.S. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir. In 1998, controversial minister Fred Phelps posted the Onion article '98 Homosexual-recruitment drive nearing goal on his God Hates Fags website as proof that homosexuals were indeed actively trying to get straight people to join their ranks. Other potential sources of shikimic acid include the ginko tree. Upon occasion the straight-faced manner in which the Onion reports non-existent happenings has resulted in outside parties mistakenly citing Onion stories as real news. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. The Onion's coverage of the September 11, 2001 attacks less than two weeks following the attacks was one of the earliest satirical reactions to those attacks, and was considered for a Pulitzer Prize.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. This brings The Onion back to the open state it was in prior to April 2004 when the restrictive move towards a Premium Service was first initiated. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Simultaneously The Onion discontinued their Premium Service which charged readers a substantial fee for additional content and vintage archives. Ninety percent of the harvest is already used by Roche in making Tamiflu. Club relaunched in a new design which presents the content as almost entirely discrete from The Onion itself. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. In late August 2005, The Onion's companion website The Onion A.V.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. As of 2004 the paper's founders are publishers of other weeklies: Keck of the Seattle weekly The Stranger and Johnson of Albuquerque's Weekly Alibi. Star anise is grown in four provinces in China and harvested between March and May. In early 2001, the company relocated its offices to New York City. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). A possible origin for its name is a mispronunciation of "The Union", which is a fairly common name for a legitimate paper. According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid, which cannot be economically synthesized and is only effectively isolated from Chinese star anise, an ancient cooking spice; although most autotrophic organisms produce shikimic acid, the isolation yield is low. The Onion remained a regional success until it began its website in 1996.

(See Pandemic Fears, below). The Onion was founded in 1988 and originally published in Madison, Wisconsin by two juniors at the University of Wisconsin-Madison, Tim Keck and Christopher Johnson; they sold it to colleagues the following year. In early-2005, Roche announced a production shortage. The regular contributors include:. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Each issue features columns by (fictional) regular and guest writers. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. Past writers have included Max Cannon, Rich Dahm, Tim Harrod, David Javerbaum, Ben Karlin, Carol Kolb, Robert Siegel, and Jack Szwergold.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Herman Zweibel (Zwiebel is German for onion), who has "held the position since 1901" and is rather insane; the real editor is currently Scott Dikkers, the managing editor is Peter Koechley, and the current writing staff comprises Todd Hanson, Maria Schneider, John Krewson, Joe Garden, and Chris Karwowski, as well as the graphics work of Mike Loew and Chad Nackers. First, these drugs work on a broader spectrum of influenza strains. The Onion's fictional editor is T. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. . This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. Both print and online editions of The Onion are published on Wednesdays.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. The staff of the Onion have also produced numerous books, including Our Dumb Century, Finest News Reporting, and Dispatches from the Tenth Circle. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. As well:. Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. The newspaper was revamped on August 31, 2005, which changed the layout of the website homepage. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1. Regular features of The Onion include:.

They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Club blogs and reader forums, and presents itself as an almost-separate entity from The Onion itself. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Club has its own domain, includes its own regular features (including weekly sex advice column Savage Love), A.V. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. The online incarnation of The A.V. de Jong et al. The print edition also contains previews of upcoming live entertainment specific to cities where a print edition is published.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). Club that features interviews, reviews of various newly-released media, and other weekly features. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. The second half of the newspaper is a non-satirical — but still often humorous — entertainment section called The A.V. Third, the dosage regimen in Japan is different from that of other nations, and some children may have been given a suboptimal dosage of oseltamivir. Obsession with fame and celebrity are frequently satirized, as well as the general credulousness of the public. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. The paper often reports on everyday events in a sensationalistic manner ("Area Man Confounded by Buffet Procedure").

First, children typically have a longer infection period, giving a longer time for resistance to develop. It parodies traditional newspaper features and styles. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. The Onion's articles comment on current events, both real and imagined (an example of the latter: "All Americans Issued Life Jackets for Some Reason"). This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children (Ward et al., 2005). Paul, Denver/Boulder, and San Francisco. Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). As of May 2005 its print editions are distributed in Madison, Milwaukee, New York City, Chicago, Minneapolis-St.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). It contains satirical articles as well as a general entertainment section. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. The Onion is a parody newspaper published weekly in print and on the Internet. As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. "Embedded in America": The Onion Ad Nauseam Complete News Archives Volume 16 (2005, ISBN 1400054567). Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization. "Fanfare for the Area Man": The Onion Ad Nauseam Complete News Archives Volume 15 (2004, ISBN 1400054559).

It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. and Them": The Onion Ad Nauseam: Complete News Archives Volume 14 (2003, ISBN 140004961X). The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. "Relations Break Down Between U.S. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The Onion Ad Nauseam: Complete News Archives Volume 13 (2002, ISBN 1400047242). Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Dispatches from the Tenth Circle: The Best of The Onion (2001, ISBN 0609808346).

Acidic hydrolysis then removed the imine. The Onion's Finest News Reporting, Volume 1 (2000, ISBN 0609804634). With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Our Dumb Century: The Onion Presents 100 Years of Headlines from America's Finest News Source (1999, ISBN 0609804618). Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. Gorzo the Mighty, the Emperor of the Universe, villain in the style of 1930s science fiction. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Jackie Harvey, a ridiculously uninformed media critic who writes the column The Outside Scoop.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. Jean Teasdale, an overweight nerdish woman with kitsch tastes, whose constantly upbeat attitude always finds the bright side of her otherwise depressing white trash life. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Smoove B, a smooth talking ladies' man who insists on the best of everything for his dates. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. Herbert Kornfeld, Accounts Receivable Supervisor, a white man with a boring desk job who speaks in gangsta rap-isms and ebonics. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. He is similar to the Comic Book Guy from The Simpsons.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Larry Groznic, an overweight geek with an obsession for subcultural fandoms. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Jim Anchower, a slacker and stoner with a different job every few weeks, whose musical tastes are stuck in 1970s rock and roll. The synthesis commences from naturally available (−)-shikimic acid. Jackie Harvey was given his own blog. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. A daily fictional stock market analysis titled "Stock Watch", a web opinion poll titled "QuickPoll", and "National News Highlights" of three regional stories, were added.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. "In the News" was retitled "From the Print Edition". The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. "What Do You Think?" became "American Voices," with the question updated daily, and only three responders each day. They did recommend adding a warning to prescription information regarding possible rashes. Up until August 31, 2005, one of them was almost always a "systems analyst.". The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems). "What Do You Think?", a survey showing photos of the same six people, although their names and professions change every week.

On November 18, 2005, a previously-scheduled Advisory Committee to the United States Food and Drug Administration (FDA) met to reconsider the pediatric safety of Tamiflu; a six-page report was issued: Pediatric Safety Update for Tamiflu. "In the News" photograph and caption with no accompanying story (such as "Frederick's of Anchorage Debuts Crotchless Long Underwear", "National Association Advances Colored Person"). Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. "The ONION in History": a front page produced in the look of newspapers of an earlier era, satirizing that earlier style and content (these are all taken from the book "Our Dumb Century"). The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche, which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005). Cynical horoscopes. A third teen reportedly attempted to jump from the window of a building. Random and bizarre editorials.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. Point-Counterpoint. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. "Infographic"), with a bulleted list of items on a theme. According to Japan's Pharmaceuticals and Medical Devices Agency, there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004. The "Infograph" (a.k.a. In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations. "STATshot", an illustrated statistical snapshot which parodies "USA Today Snapshots".

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:.

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. 500 mg of probenecid given every six hours doubles oseltamivir's maximum blood concentration and also doubles the time that oseltamivir stays in the blood, multiplying a patient's overall exposure to the drug 2.5-fold. Probenecid reduces excretion of oseltamivir's active metabolite.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. 2005). (de Jong et al. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Doctors in Vietnam concur, noting that. Peter Hobby (of the World Health Organization) has suggested that Vietnam should investigate and test a higher dosage and longer treatment with Tamiflu for patients with avian influenza[2][3]. The above treatment regimes are based upon studies of normal human influenza.

According to prescription information by Roche for the United States[1], Tamiflu usage is indicated for both the treatment and prophylaxis of influenza at the following dosages. Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. . Production capacity is limited, and governments are stockpiling the drug.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Chimia 2004, 58, 621. Synthesis of Tamiflu.

Chem. 2001, 66, 2044-2051. Org. J. Synthesis of Tamiflu.

Chem. 1998, 63, 4545-4550. Org. J. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.).

WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. World Health Organization. PMID 15709056. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. Ward P, Small I, Smith J, Suter P, Dutkowski R. New England Journal of Medicine 2005;353(25):2633-2636. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective].

Moscona, Anne. Nature 2005;437(7062):1108. Avian flu: Isolation of drug-resistant H5N1 virus. Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H L, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y.

PMID 15337401. Lancet 2004;364(9436):759-65. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al.

(Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13). Drug Metabolism and Disposition 2002;30(1):13-19. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P.

(Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1). New England Journal of Medicine 2005;353(25):2667-2672. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. Malik; Hien, Tran Tinh; and Farrar, Jeremy.

de Jong, Menno D.; Thanh, Tran Tan; Khanh, Truong Huu; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Nguyen Vinh; Cam, Bach Van; Qui, Phan Tu; Ha, Do Quang; Guan, Yi; Peiris, J.S. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html). Nature 2005;438(7064):6. Wartime tactic doubles power of scarce bird-flu drug [News article].

Butler, D. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html). Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. Pollack, Andrew.

Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes). Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Oct 31, 2005. Schwartz, Nelson .

Metabolic: Aggravation of diabetes. Neurologic: Seizure, confusion. Cardiac: Arrhythmia. Digestive: Hepatitis, liver function tests abnormal.

General: Rash, swelling of face or tongue, toxic epidermal necrolysis. Safety and efficacy for prophylaxis has not been established for patients under 13 years old. Standard dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual.

Dosage for children is by weight. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days.

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