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Oseltamivir, sold under the brand name Tamiflu among others, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu.<ref name=AHFS2017/> Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection.<ref name=CDC2014up /> They recommend it to prevent infection in those at high risk, but not the general population.<ref name=CDC2014up /> The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection.<ref name=CDC2014up>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=ECDC2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=NICE2009>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is taken by mouth, either as a pill or liquid.<ref name=AHFS2017>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations.<ref name=CDC2014up /><ref name=IDSA2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Brownlee2013>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Butler2014 /> A 2014 Cochrane Review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza.<ref name=Butler2014>Template:Cite journal</ref> Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.<ref name=Mich2013>Template:Cite journal</ref><ref name=Ebe2013 /> They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.<ref name=Mich2013/><ref name=Ebe2013>Template:Cite journal</ref> However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels.<ref>Template:Cite journal</ref>
Common side effects include vomiting, diarrhea, headache, and trouble sleeping.<ref name=AHFS2017/> Other side effects may include psychiatric symptoms and seizures.<ref name=AHFS2017/><ref name=Cochrane2012>Template:Cite journal</ref><ref name=Jeff2014>Template:Cite journal</ref> In the United States it is recommended for influenza infection during pregnancy.<ref name=Preg2017/> It has been taken by a small number of pregnant women without signs of problems.<ref name=Preg2017>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Dose adjustment may be needed in those with kidney problems.<ref name=AHFS2017/>
Oseltamivir was approved for medical use in the US in 1999.<ref name=AHFS2017/> It was the first neuraminidase inhibitor available by mouth.<ref>Template:Cite journal</ref> It is on the World Health Organization's List of Essential Medicines but was downgraded to "complementary" status in 2017.<ref name="WHO TRS 1006" /><ref>Template:Cite journal</ref><ref name="WHO21st"/> A generic version was approved in the US in 2016.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, it was the 205th most commonly prescribed medication in the United States, with more than 1Template:Nbspmillion prescriptions.<ref name="Top 300 of 2022">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Medical useEdit
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Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.<ref name=AHFS2017 /><ref name="Tamiflu Label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st"/> The WHO supports its use for severe illness due to confirmed or suspected influenza virus infection in critically ill people who have been hospitalized.<ref name="WHO21st">Template:Cite book</ref> Oseltamivir's risk-benefit ratio is controversial.<ref name=Brownlee2013 /><ref name=Butler2014 /> In 2017, it was moved from the core to the complementary list based on its lower cost-effectiveness.<ref>Template:Cite journal</ref> The Expert Committee did not recommend the deletion of oseltamivir from the EML and EMLc, recognizing that it is the only medicine included on the Model Lists for critically ill patients with influenza and for influenza pandemic preparedness.<ref name="WHO TRS 1006" /> However, the Committee noted that, since the inclusion of oseltamivir on the Model List in 2009, new evidence in seasonal and pandemic influenza has lowered earlier estimates of the magnitude of effect of oseltamivir on relevant clinical outcomes.<ref name="WHO TRS 1006" /> The Committee recommended that the listing of oseltamivir be amended, moving the medicine from the core to the Complementary List, and that its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients.<ref name="WHO TRS 1006" /> The Expert Committee noted that WHO guidelines for pharmacological management of pandemic and seasonal influenza would be updated in 2017: unless new information is provided to support the use of oseltamivir in seasonal and pandemic outbreaks, the next Expert Committee might consider oseltamivir for deletion.<ref name="WHO TRS 1006">Template:Cite book</ref>
High-risk peopleEdit
The US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), Public Health England and the American Academy of Pediatrics (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications.<ref name=CDC2014up /><ref name=ECDC2014/><ref name=CDC2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="AAP" /><ref name=PHE /> This includes 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.<ref name=CDC2014 /> The Infectious Disease Society of America takes the same position as the CDC.<ref name=IDSA2014 />
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",<ref name=Mich2013/> as did a 2014 Cochrane Review.<ref name=Cochrane2014 /> The Cochrane Review further 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."<ref name=Cochrane2014 /> That is not utilizing NIs for prevention or treatment "Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks."<ref name="Cochrane2014" />
The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, 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.<ref name=CDC2014up/><ref name=ECDC2014/><ref name=IDSA2014/><ref name="AAP">Template:Cite journal</ref><ref name=PHE>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The EMA did not change its labeling of the drug in response to the Cochrane study.<ref name=ReutersEMA>Template:Cite news</ref>
A 2014 review recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of community-acquired pneumonia receive oseltamivir until the absence of influenza infection is established by polymerase chain reaction (PCR) testing.<ref>Template:Cite journal</ref>
A 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of otitis media. The same review found that oseltamivir did not significantly increase the risk of adverse events.<ref>Template:Cite journal</ref> A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of "nausea, vomiting, [and] psychiatric events in adults and vomiting in children."<ref>Template:Cite journal</ref> The decrease in duration of sickness was about 18 hours.<ref>Template:Cite journal</ref>
Otherwise healthy peopleEdit
In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours.<ref name=CDC2014 /> A German clinical practice guideline recommends against its use.<ref>Template:Cite journal</ref>
Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.<ref name=Mich2013/><ref name=Ebe2013/> When the analysis was restricted to people with confirmed infection, the same 2014 Cochrane Review (see above) found unclear evidence of change in the risk of complications such as pneumonia,<ref name=Cochrane2014>Template:Cite journal</ref> while three other reviews found a decreased risk.<ref name=Ebe2013 /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day.<ref name=Burch2009>Template:Cite journal</ref> Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.<ref name=Jeff2014 />
The 2014 Cochrane Collaboration review 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.<ref name=Cochrane2014 /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
The US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), the Public Health England (PHE), the Infectious Disease Society of America (IDSA), the American Academy of Pediatrics (AAP), and Roche (the originator) rejected the recommendations of the 2014 Cochrane Review to urgently change treatment guidelines and drug labels.<ref name=CDC2014up /><ref name=ECDC2014/><ref name=IDSA2014 /><ref name="AAP" /><ref name=PHE /><ref name=ReutersEMA />
PreventionEdit
Template:As of, the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development.<ref name=CDC2014 /> They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated.<ref name=CDC2014 /> They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed.<ref name=CDC2014 />
Template:As of, reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease.<ref name=Cochrane2014 /><ref>Template:Cite journal</ref> 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%).<ref name=Mich2013/> It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated high risk persons.<ref name=Mich2013/>
Side effectsEdit
According to the FDA, the two most common adverse drug reactions associated with oseltamivir therapy are nausea (10% vs 6% placebo) and vomiting (9% vs 3% placebo).<ref name="fda">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 nausea was 19. So, for every 19 children on oseltamivir one experienced vomiting. When used as a prophylactic there were more headaches, kidney, and psychiatric events.Template:Citation-needed Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious arrhythmias.<ref name=Cochrane2014 />
Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, abnormal heart rhythms, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome.<ref name="rocheinfo">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="rossi 2006">Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.</ref> Neuropsychiatric symptoms and body pain, followed by skin problems, were identified as the side effects most significantly reducing patient satisfaction on a drug review platform.<ref name="Antipov 2019">Template:Cite journal</ref>
The US and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.<ref name="Cohen 2014" /><ref name=FDApedsafe>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The frequency of these appears to be low and a causative role for oseltamivir has not been established.<ref name=FDApedsafe/><ref name="Medscape">Template:Cite news</ref> 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.<ref name=Cochrane2014 /> Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.<ref name="Cohen 2014">Template:Cite journal</ref>
It is pregnancy 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.<ref name="Australian Government">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Dose adjustment may be needed in those with kidney problems.<ref name=AHFS2017 />
Mechanism of actionEdit
Oseltamivir is a neuraminidase inhibitor, a competitive inhibitor of influenza's neuraminidase enzyme. The neuraminidase enzyme binds to the sialic acid which is found on glycoproteins on the surface of human cells. Then it cleaves the sialic acid, which helps new virions to exit the cell. As Oseltamivir is an analogue of the sialic acid, the enzyme can bind to Oseltamivir instead, in which case the enzyme will not bind to sialic acid, so it will not cleave it and new virons will not exit the cell.<ref name="Tamiflu Label" />
ResistanceEdit
Template:Flu The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.<ref name=ResistanceRev2011 /> A 2011 meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher rates among influenza A patients, especially the H1N1 subtype. 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.<ref name=ResistanceRev2011>Template:Cite journal</ref> In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.<ref name=CDC2014up />
H1N1 flu or "swine flu"Edit
Template:As of, the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide showed resistance to oseltamivir.<ref name="Update on oseltamivir resistance to influenza H1N1 (2009) viruses">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>Template:Cite news</ref>
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, Template:As of, widespread transmission of oseltamivir-resistant pH1N1 has not occurred.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Seasonal fluEdit
From 2009 to 2014, oseltamivir resistance was very low in seasonal flu. In the 2010–11 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
H3N2Edit
Three studies have found resistance in 0%, 3.3%, and 18% of subjects.<ref name=ResistanceRev2011 /> In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza virus and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations.<ref name="ward et al. 2005">Template:Cite journal</ref>
Influenza BEdit
In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%.<ref>Template:Cite journal</ref> According to the CDC, Template:As of, transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
H5N1 avian influenza "bird flu"Edit
Template:As of, 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.<ref name="pmid23279894">Template:Cite journal</ref>
H7N9 avian influenzaEdit
Template:As of, two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation.<ref>Template:Cite journal</ref>
PharmacokineticsEdit
Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver, via esterases.<ref name = PK /> It does not interact with cytochrome P450 enzymes in the liver.<ref name="fda" /> It has a volume of distribution of 23–26 litres.<ref name = PK /> Its half-life is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours.<ref name = PK /> More than 90% of the oral dose is eliminated in the urine as the active metabolite.<ref name = PK />
HistoryEdit
Oseltamivir was discovered by scientists at Gilead Sciences 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.<ref name="TamifluSupply">Template:Cite journal</ref><ref name=Rawat>Template:Cite journal</ref> Gilead exclusively licensed their relevant patents to Roche in 1996.<ref name=WIPO>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The drug has not been patent-protected in Thailand, the Philippines, Indonesia, and several other countries.<ref name=WIPO />
In 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> based on two double-blind, randomized, placebo-controlled clinical trials.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In June 2002, the European Medicines Agency (EMA) approved oseltamivir phosphate for prophylaxis and treatment of influenza. In 2003, a pooled analysis of ten randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults.<ref name="kaiser meta analysis">Template:Cite journal</ref>
Oseltamivir (as Tamiflu) was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005.Template:Medcn 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<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and there were worldwide shortages of the drug, driven by the high demand for stockpiling.<ref name=TamifluSupply /> In November 2005, US 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 Donald Rumsfeld, who was a past chairman of Gilead Sciences, recused himself from all government decisions regarding the drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
In 2006, a Cochrane Review (since withdrawn) raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness.<ref>Template:Cite journalTemplate:Retracted</ref>
In December 2008, the Indian drug company Cipla won a 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 World Health Organization (WHO) certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.<ref>Template:Cite news</ref>
In 2009, a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009, the WHO declared the A/H1N1 influenza a pandemic.<ref name="jefferson bmj 2014">Template:Cite journal</ref> The National Institute for Health and Care Excellence (NICE), the CDC, the WHO, and the ECDC maintained their recommendation to use oseltamivir.<ref name=NICE2009/><ref name="WHO guidelines">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
From 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide.<ref name="BMJ Tamiflu">Template:Cite journal</ref> In 2011, a freedom of information request to the European Medicines Agency (EMA) provided Cochrane with reports from 16 Roche oseltamivir trials. In 2012, the Cochrane team published an interim review based on those reports. In 2013, Roche released 74 full clinical study reports of oseltamivir trials after GSK released the data on zanamivir studies.<ref>Template:Cite journal</ref> In 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents.<ref name=Cochrane2014 /><ref name="BMJ Tamiflu" /> In 2016, Roche's oseltamivir patents began to expire.<ref name=WIPO />
Veterinary useEdit
There have beenTemplate:When reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirus infection.<ref>Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
ResearchEdit
Oseltamivir has been deemed ineffective at treating COVID-19, consistent with the SARS-CoV-2 virus lacking influenza's neuraminidase enzyme.<ref>Template:Cite journal</ref>
ReferencesEdit
Further readingEdit
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External linksEdit
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