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Oseltamivir

Clinical data
Trade names	Tamiflu
AHFS/Drugs.com	Monograph
MedlinePlus	a699040
License data	US DailyMed: 48517 US FDA: Oseltamivir
Pregnancy category	AU: B1
Routes of administration	oral
ATC code	J05AH02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	>80%
Protein binding	42% (parent drug), 3% (active metabolite)
Metabolism	Hepatic, to oseltamivir carboxylate
Elimination half-life	1-3 hours, 6-10 hours (active metabolite)
Excretion	Urine (>90% as oseltamivir carboxylate), faeces
Identifiers
IUPAC name ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
CAS Number	196618-13-0
PubChem CID	65028
DrugBank	DB00198
ChemSpider	58540
UNII	20O93L6F9H
KEGG	D08306
ChEBI	CHEBI:7798
ChEMBL	ChEMBL1229
CompTox Dashboard (EPA)	DTXSID9044291
Chemical and physical data
Formula	C16H28N2O8P
Molar mass	312.4 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES O=C(OCC)/C1=C/(OC(CC)CC)(NC(=O)C)(N)C1
InChI InChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1 Key:VSZGPKBBMSAYNT-RRFJBIMHSA-N
(what is this?)  (verify)

Oseltamivir INN /ɒsəlˈtæmvɪər/, marketed under the trade name Tamiflu, is an antiviral medication used to prevent and treat influenza A and influenza B (flu). The drug is taken orally.

The world's leading medical bodies for infectious disease, including the Infectious Disease Society of America and the United States' Centers for Disease Control and Prevention recommend the use of oseltamavir for people at high risk for complications and those at lower risk who present within 48 hours of first symptoms of infection. However these recommendations are controversial. Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.

Side effects include psychiatric symptoms and increased rates of vomiting. It is pregnancy category C in the United States and category B in Australia meaning that it has been taken by a small number of women without signs of problems and in animal studies it looks safe.

It was the first orally active neuraminidase inhibitor commercially developed. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences, and is marketed by Genentech. Gilead licensed the exclusive rights to Roche in 1996. The starting material of the oseltamivir production process is shikimic acid. It is extracted from the pods of the Chinese star anise, grown in mountain provinces in the south west of China. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical use

Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.

The Infectious Disease Society of America, the United States' Centers for Disease Control and Prevention, the European Centers for Disease Control, and the American Academy of Pediatrics recommend the use of oseltamavir for people at high risk for complications and those at lower risk who present within 48 hours of first symptoms of infection.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Efficacy

Oseltamivir's risk-benefit ratio is controversial. Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. There is low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1% to 12% in those exposed. It is unclear whether it affects the risk of needing to be hospitalized or the risk of death. While it reduces the duration of symptoms by a little less than a day one review found that it does not reduce serious complications among people seeking care for flu-like symptoms, though pneumonia was reduced among those infected with influenza. No evidence was found regarding whether treatment changes the risk of hospitalization in the elderly or other high risk populations, and that it is unclear if it affects rates of death. When the analysis was restricted to people with confirmed infection, a Cochrane review found unclear evidence of change in the risk of complications such as pneumonia. A systematic review of systematic reviews found that it prevented influenza, but recommended against its use in healthy, low risk persons due to cost, the risk of resistance development, and side effects. This review concluded it might be useful for prevention in high risk persons who had not been vaccinated. No evidence was found to support the usefulness of oseltamivir for the prevention of serious complications of influenza, as the trials were designed to demonstrate the more trivial outcome of "reduction of duration of symptoms" and were not designed or powered to evaluate impact on more clinically relevant outcomes.

In 2014 Cochrane published an updated systematic review using all of the previously unreleased data, concluding that oseltamivir does not reduce hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. They concluded that guidance should be revised to take account of the evidence of small benefit and increased risk of harms. Moreover the authors stated that their conclusions are similar to those reached by the U.S. FDA at the time of approval; that randomized clinical trial data supported the use of oseltamivir for the prevention and treatment of flu symptoms only, and didn't support claims of prevention of infection, transmission, or complications. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection.

The United States and European Centers for Disease Control, Public Health England, Infectious Disease Society of America, and the American Academy of Pediatrics, and Roche (the originator) reject the Cochrane Collaboration conclusions, arguing that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from patients not infected with influenza. The EMA did not change its labelling of the drug in response to the Cochrane study.

Side effects

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the number needed to harm was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious heart rhythm problems.

Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome. The incidence of these adverse outcomes is unknown, and a causative role for oseltamivir has not been established.

The U.S. and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance. The frequency of these appears to be low and a causative role for oseltamivir has not been established. The 2014 Cochrane review found a dose-response effect on psychiatric events. In trials of prevention in adults one person was harmed for every 94 treated. Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.

Resistance

Influenza (flu)
Types Avian A/H5N1 subtype Canine Equine Swine A/H1N1 subtype
Vaccines 2009 pandemic Pandemrix Live attenuated Seasonal flu vaccine brands
Treatment Amantadine Baloxavir marboxil Laninamivir Oseltamivir Peramivir Rimantadine Umifenovir Zanamivir
Pandemics 1889-1890 Russian flu 1918 Spanish flu 1957-1958 Asian flu 1968 Hong Kong flu 1977 Russian flu 2009 swine flu
Outbreaks 1976 swine flu 2006 H5N1 India 2007 Australian equine 2007 Bernard Matthews H5N1 2008 West Bengal 2015 United States H5N2 outbreak 2020–2022 H5N8 outbreak
See also Flu season Influenza evolution Influenza research Influenza-like illness Vaccine reformulations
v t e

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme. Meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date. In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.

H1N1 flu or "Swine flu"

As of December 15, 2010, the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.

The CDC found sporadic oseltamivir-resistant 2009 H1N1 virus infections had been identified, including with rare episodes of limited transmission, but the public health impact had been limited. Those sporadic cases of resistance were found in immunosuppressed patients during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis.

During 2011 a new influenza A(H1N1)2009 variant with mildly reduced oseltamivir (and zanamivir) sensitivity was detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia.

While there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013 widespread transmission of oseltamivir-resistant pH1N1 has not occurred.

Seasonal flu

Resistance to Oseltamivir was widespread in seasonal flu from 2007-2009. In the 2007-2008 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant. In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance. All Oseltamivir-resistant strains maintained sensitivity to zanamivir.

Resistance to Oseltamivir has been low in seasonal flu from 2009-2012. In the 2010-2011 flu season, the US CDC reported maintained Oseltamivir sensitivity in 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B. As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all seasonal flu samples tested since October 2011. In the US in the season 2013-2014 only 1% of 2009 H1N1 viruses have shown resistance to oseltamivir. No other influenza viruses have shown resistance to oseltamivir.

H3N2

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18 percent of a group of 50 Japanese children treated with oseltamivir in 2002-2003. 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. claim to have used more rigorous detection techniques than previous studies. Inadequate dosage may also have been an issue.

Influenza B

In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals having not been treated with these drugs. The prevalence was 1.7 percent. According to the CDC, as of October 3, 2009 no influenza B strains tested have shown any resistance to oseltamivir.

H5N1 Avian influenza "Bird flu"

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. 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 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 oseltamivir could lead to underdosage and, thus, the emergence of resistant strains of H5N1.

Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso et al. suggest "a higher prevalence of resistant viruses should be expected" during a pandemic. Resistant strains have also appeared in the EU.

Established markers of neuraminidase inhibitor resistance were found in 2.4% of human and 0.8% of avian isolates of H5N1 influenza.

H7N9 Avian influenza

There was emergence of oseltamivir-resistant virus with the Arg292Lys mutation in two patients among 14 adults infected with A(H7N9) during treatment with oseltamivir.

Mechanism of action

The prodrug oseltamivir is itself not virally effective; however, once in the liver it is hydrolysed to its active metabolite - the free oseltamivir carboxylate.

Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor of the activity of the viral neuraminidase (NA) enzyme upon sialic acid, found on glycoproteins on the surface of normal host cells. By blocking the activity of the enzyme, oseltamivir prevents new viral particles from being released through the cleaving of terminal sialic acid on glycosylated hemagglutinin and thus fail to facilitate virus release.

Pharmacokinetics

Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver. It has a volume of distribution of 23-26 litres. Its half-life is about 1–3 hours and its active metabolite has a half-life of 6–10 hours. It is predominantly eliminated in the urine as the active carboxylate metabolite (>90% of oral dose).

History

Around 40 Hoffman-LaRoche sponsored randomised clinical trials of oseltamivir were completed around the end of the nineties. In October 1999 and November 2000 FDA approved oseltamivir for treatment and profylaxis of influenza. In June 2002 EMA approved oseltamivir for prophylaxis and treatment of influenza. In 2003 the Kaiser pooled analysis of 10 randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults. From 2004 governments around the world began stockpiling oseltamivir by fears of avian influenza H5N1. In January 2006 a Cochrane review concluded that oseltamivir reduced complications such as pneumonia. The Kaiser 2003 paper drove the result in the meta-analysis. In 2009 a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009 WHO declared the A/H1N1 influenza a “pandemic”. The CDC, WHO, and the European Centre for Disease Prevention claimed the effectiveness of oseltamivir against complications, which caused governments around the world to stockpile these drugs in case of a pandemic. Also in 2009 NICE advised them to use in people at risk for complications. From 2010 to 2012 Cochrane in vain requested the full clinical study reports of their trials to Roche, but in 2011 a freedom of information request to the European Medicines Agency provided them with the clinical study reports from 16 Roche oseltamivir trials. In 2012 the Cochrane team published the interim version of the Cochrane review based on EMA’s incomplete clinical study reports, but in 2013 Roche released 77 full clinical study reports of oseltamivir trials, after GSK released the data on zanamivir studies. In 2014 Cochrane published an updated review based solely on full clinical study reports and regulatory documents. In the mean time buying a strategic reserve of Tamiflu the US has spent more than $1.3 billion. In 2013 the UK National Audit Office, said that the government spent £560m (€670; $930m) on antivirals for stockpiling between 2006 and 2013: £424m on oseltamivir and £136m on zanamivir.

Commercial issues

The patent for oseltamivir is held by Gilead Sciences and is valid at least until 2016. Gilead licensed the exclusive rights to Roche in 1996. The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia, and several other countries.

Oseltamivir 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, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic.

In late October 2005, Roche announced 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. Sales were suspended in Hong Kong as well, and on November 8, 2005, also in China. Roche said it would instead send all supplies to China's health ministry.

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic oseltamivir was produced in February 2006, and was to have been available to the public in July 2006.

In November 2005, U.S. President George W. Bush requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Rumsfeld recused himself from all government decisions regarding the drug.

In December 2005, Roche signed a sublicense for complete oseltamivir production with China's Shanghai Pharmaceuticals, and by March 2006, a sublicense had also been granted to India's Hetero.

In May 2006, the WHO asked Roche to be ready to ship an emergency stockpile of oseltamivir to Indonesia if needed. The alert was in response to suspected human-to-human transmission within a family, and was planned to last for two weeks.

In December 2008, the Indian drug company, Cipla won its case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.

Production shortage/shikimic acid

In early 2005, Roche announced a production shortage. In 2006, however, Roche said production was about to reach 400-million treatment courses annually, that "capacity was well in excess of total government orders placed to date," and "the supply shortage no longer exists." Total government orders between 2005 and 2007 were estimated to be around 200 million treatment doses. In fact, Roche CEO William Burns said a shortage of orders could cause Roche to reduce production in the future. Roche attributes production increases in part to its agreements with 15 external contractors in 9 countries.

Personal stockpiling

A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states issued advisories strongly discouraging this practice.

In The New England Journal of Medicine, Anne 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 have only ten pills of 75 mg each (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.

Another argument against individual stockpiling is that limited drugs should be kept for more strategic 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 having come down with avian influenza. Ethical arguments are sometimes made as to whether affluent people or nations should have preferred access to antiviral medications. Illegal importation might divert the drug from poorer countries, where the risk of avian influenza is actually higher. A counter argument is that it is difficult to justify prohibition of individual stockpiling, when some of the same arguments are pertinent to corporate stockpiling, which is both allowed and encouraged.

A third argument is that it would be difficult for home users to determine whether illegally imported Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets 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 the appearance of counterfeit Tamiflu outside of the United States: incorrectly labeled tablets found in the Netherlands, which contained only vitamin C and lactose.

An argument in favour of individual stockpiling is that Roche is on the record as saying that, without more orders, they may have to actually curtail production. Individual stockpiling could bring market forces to play, maintaining production capacity and allowing the total supply on hand to be higher in case demand again outstrips production in the future, for instance, during a sudden influenza outbreak.

Veterinary use

There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection. The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production.

Manufacturing

Oseltamivir is marketed by Genentech under the trade name Tamiflu, as capsules (containing oseltamivir phosphate 98.5 mg equivalent to oseltamivir 75 mg) and as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir 6 mg/ml).

See also

• Amantadine and rimantadine — M2 inhibitors, other medications used for influenza treatment

References

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Further reading

• Pollack, Andrew (November 5, 2005). "Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu". The New York Times.
• Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16424427, please use {{cite journal}} with |pmid=16424427 instead.
• Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/jo980330q, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/jo980330q instead.
• Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/jo005702l, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/jo005702l instead.
• Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.2533/000942904777677605, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.2533/000942904777677605 instead.
• Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/ja0616433, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/ja0616433 instead.
• Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1951305, please use {{cite journal}} with |pmid=1951305 instead.

External links

• Official website
• MedlinePlus Drug Information: oseltamivir (systemic) –Last Revised - 05/01/2009 Advice for the Patient
• Pharmasquare – Tamiflu Mode of Action – Flash animation showing the mode of action of oseltamivir
• FDA information page on oseltamivir
• Flu Drugs FAQ – U.S. National Institute of Allergy and Infectious Diseases
• Reto U. Schneider: The race to develop GS4104 - A comprehensive feature story about the development of Tamiflu published in January 2004 in NZZ-Folio, the magazine of the daily Neue Zürcher Zeitung in Switzerland (translated from German).

• Ill-formatted IPAc-en transclusions
• Acetamides
• Ethyl esters
• Gilead Sciences
• Neuraminidase inhibitors