Oseltamivir

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Oseltamivir
Oseltamivir.svg
Oseltamivir-3D-balls.png
Systematic (IUPAC) name
ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
Clinical data
Trade names Tamiflu
AHFS/Drugs.com monograph
MedlinePlus a699040
Licence data US Daily Med:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability >80%[1]
Protein binding 42% (parent drug), 3% (active metabolite)[1]
Metabolism Hepatic, to oseltamivir carboxylate[1]
Half-life 1-3 hours, 6-10 hours (active metabolite)[1]
Excretion Urine (>90% as oseltamivir carboxylate), faeces[1]
Identifiers
CAS number 196618-13-0 N
ATC code J05AH02
PubChem CID 65028
DrugBank DB00198
ChemSpider 58540 YesY
UNII 20O93L6F9H YesY
KEGG D08306 YesY
ChEBI CHEBI:7798 YesY
ChEMBL CHEMBL1229 YesY
Chemical data
Formula C16H28N2O8P 
Mol. mass 312.4 g/mol
 N (what is this?)  (verify)

Oseltamivir INN /ɒsəlˈtæmɨvɪər/, marketed under the trade name Tamiflu, is an antiviral medication used to prevent and treat influenza A and influenza B (flu).[2] The medication is taken orally.[3]

The Infectious Disease Society of America, the United States' Centers for Disease Control and Prevention (CDC), and the UK National Institute for Health and Care Excellence recommend the use of oseltamavir for people who have complications or are at high risk for complications who present within 48 hours of first symptoms of infection.[4] They recommend its use to prevent infection in at-risk people but not the general population.[4] Some recommend that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection.[4][5][6][7][8][9] However, these recommendations are controversial[4] as are criticisms of the recommendations.[8][10][11] A Cochrane review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus.[11] Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[12][13] They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.[12][13]

Side effects include psychiatric symptoms, increased rates of vomiting, and headaches.[3][14][15] 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.[16][17] Dose adjustment may be needed in those with kidney problems.[3]

It was the first orally administered neuraminidase inhibitor commercially developed.[18] It was discovered and developed by US-based Gilead Sciences, which licensed the exclusive rights to Roche in 1996.[19] 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[edit]

Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.[3][16] It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[20] Oseltamivir's risk-benefit ratio is controversial.[10][11]

High risk[edit]

The United States Centers for Disease Control (CDC), European Centers for Disease Control (ECDC), Public Health England and American Academy of Pediatrics recommend the use of oseltamavir for people who have complications or are at high risk for complications.[4][5][6][7][21] This include those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and Indigenous peoples of the Americas among others.[5] The Infectious Disease Society of America takes the same position as the CDC.[8]

A systematic review of systematic reviews in PLoS One did not find evidence for benefits in people who are at risk, noting that "the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality", [12] as did a 2014 Cochrane review.[22] The Cochrane review nonetheless recommended: "On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza."[22]

The United States and European Centers for Disease Control (CDC), Public Health England, Infectious Disease Society of America, and the American Academy of Pediatrics, and Roche (the originator) reject the conclusions of the Cochrane review, arguing in part 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 people not infected with influenza.[4][6][7][8][21] The EMA did not change its labelling of the drug in response to the Cochrane study.[23]

Otherwise healthy[edit]

In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours.[5] A German clinical practice guideline recommends against it use.[24]

Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[12][13] 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,[22] while two other reviews found a decreased risk.[13][25] Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day.[2] Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.[26]

A 2014 Cochrane Collaboration concluded that oseltamivir did not affect the need for 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. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms.[22][27]

The United States and European Centers for Disease Control (CDC), Public Health England, Infectious Disease Society of America, and the American Academy of Pediatrics, and Roche (the originator) rejected the recommendations of the 2014 Cochrane review to urgently change treatment guidelines and drug labels.[4][6][7][8][21][23]

Prevention[edit]

The CDC does not recommend the general use of oseltamivir for prevention due to concerns that widespread use will encourage resistance development.[5] They recommend that it be considered in those at high risk who have been exposed to the disease within 48 hours but have not received or only recently received the flu shot.[5] They also recommended it during outbreaks in long term care homes and in those who are significantly immunosuppressed.[5]

Reviews conclude that when used for prevention oseltamivir decreases the risk of people exposed developing symptomatic disease.[22][28] A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1% to 12% (a relative decrease of 64 to 92%).[12] It recommended against its use in healthy, low risk persons due to cost, the risk of resistance development, and side effects.[12] It concluded it might be useful for prevention in high risk persons who had not been vaccinated.[12]

Side effects[edit]

A package of capsules

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.[22]

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.[29][30] 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.[31][32] The frequency of these appears to be low and a causative role for oseltamivir has not been established.[32][33][34] 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.[22] Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.[31]

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.[16][35][36] Dose adjustment may be needed in those with kidney problems.[3]

Resistance[edit]

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[37] 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.[37] In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.[4]

H1N1 flu or "Swine flu"[edit]

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.[38]

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.[4]

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.[39]

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.[40]

Seasonal flu[edit]

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.[41] In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance.[42] 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.[43] As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all seasonal flu samples tested since October 2011.[44][45] 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.[46]

H3N2[edit]

Three studies have found resistance in 0%, 3.3%, and 18% of subjects.[37] In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations.[47]

Influenza B[edit]

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.[48] 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"[edit]

H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt.[49]

H7N9 Avian influenza[edit]

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.[50]

Mechanism of action[edit]

The prodrug oseltamivir is itself not virally effective; however, once in the liver it is hydrolysed to its active metabolite - the free oseltamivir carboxylate.[1]

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.[29]

Pharmacokinetics[edit]

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

History[edit]

Plate from François-Pierre Chaumeton's 1833 "Flore Medicale"

Oseltamivir was discovered by scientists at Gilead using shikimic acid as a starting point for synthesis; shikimic acid was originally available only as an extract of Chinese star anise but by 2006 30% of the supply was manufactured recombinantly in E. coli.[51][52] Gilead exclusively rights to their patents to Roche in 1996.[19] The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia, and several other countries.[19] The patents for oseltamivir begin to expire in 2016.[19]

In 1999 the FDA approved oseltamivir for treatment of influenza in adults[53] based on two double-blinded, randomized, placebo-controlled clinical trials.[54] In June 2002 EMA approved oseltamivir for prophylaxis and treatment of influenza. In 2003 a 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.[55]

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[56] and there were worldwide shortages of the drug, driven by the high demand for stockpiling.[51] 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.[57]

In 2006 a Cochrane review raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness.[58]

In December 2008, the Indian drug company, Cipla won ia 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.[59]

Marketing display used at festivals features a person living in a hermetically sealed environment

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”.[60] NICE, the CDC, WHO, and the European Centre for Disease Prevention maintained their recommendation to use oseltamivir, which again caused governments around the world to stockpile the drugs in case of a pandemic.[61][62]

From 2010 to 2012 Cochrane requested the full clinical study reports of their trials from Roche, which did not provide them, but in 2011 a freedom of information request to the European Medicines Agency provided Cochrane 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.[citation needed] 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.[60] 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.[63]

Veterinary use[edit]

There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection.[64] 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.[65]

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]