oseltamivir

File:A Tamiflu (oseltamivir) capsule.jpg

File:Tamiflu dry syrup.png

Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.{{cite web | title=Tamiflu- oseltamivir phosphate capsule Tamiflu- oseltamivir phosphate powder, for suspension | website=DailyMed | date=15 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee3c9555-60f2-4f82-a760-11983c86e97b | access-date=30 January 2020 | archive-date=28 October 2020 | archive-url=https://web.archive.org/web/20201028142110/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee3c9555-60f2-4f82-a760-11983c86e97b | url-status=live }} It is on the World Health Organization's List of Essential Medicines. The WHO supports its use for severe illness due to confirmed or suspected influenza virus infection in critically ill people who have been hospitalized.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} Oseltamivir's risk-benefit ratio is controversial. In 2017, it was moved from the core to the complementary list based on its lower cost-effectiveness.{{cite journal | vauthors = Kmietowicz Z | title = WHO downgrades oseltamivir on drugs list after reviewing evidence | journal = BMJ | volume = 357 | pages = j2841 | date = June 2017 | pmid = 28607038 | doi = 10.1136/bmj.j2841 | s2cid = 42931361 }} 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. 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. 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. 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.{{cite book | vauthors = ((World Health Organization)) | year = 2017 | title = The selection and use of essential medicines: report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th Model List of Essential Medicines for Children) | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/259481 | id = WHO technical report series;1006. License: CC BY-NC-SA 3.0 IGO | hdl-access=free | isbn=9789241210157 }}

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.{{cite web|title=Influenza Antiviral Medications: Summary for Clinicians|url=https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm|website=U.S. Centers for Disease Control and Prevention (CDC)|access-date=9 December 2014|date=3 December 2014|url-status=live|archive-url=https://web.archive.org/web/20141213041036/http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm|archive-date=13 December 2014}} 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. The Infectious Disease Society of America takes the same position as the CDC.

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", as did a 2014 Cochrane Review. 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." 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."

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.{{cite journal | title = Recommendations for prevention and control of influenza in children, 2014-2015 | journal = Pediatrics | volume = 134 | issue = 5 | pages = e1503-19 | date = November 2014 | pmid = 25246619 | doi = 10.1542/peds.2014-2413 | author1 = Committee On Infectious Diseases | doi-access = free }}{{cite web |author=Public Health England |url= https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/370673/AV_full_guidance.pdf |title=The use of antivirals for the treatment and prophylaxis of influenza: PHE summary of current guidance for healthcare professionals|date=November 2014|url-status=live|archive-url=https://web.archive.org/web/20141208203357/https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/370673/AV_full_guidance.pdf|archive-date=8 December 2014}} The EMA did not change its labeling of the drug in response to the Cochrane study.{{cite news|url=https://www.reuters.com/article/us-roche-hldg-tamiflu-idUSBREA3824K20140409|title=Researchers, regulators and Roche row over stockpiled drug Tamiflu |work= Reuters|date=9 April 2014 |url-status=live|archive-url=https://web.archive.org/web/20150924195709/http://www.reuters.com/article/2014/04/09/us-roche-hldg-tamiflu-idUSBREA3824K20140409|archive-date=24 September 2015}}

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.{{cite journal | vauthors = Musher DM, Thorner AR | title = Community-acquired pneumonia | journal = New England Journal of Medicine | volume = 371 | issue = 17 | pages = 1619–28 | date = October 2014 | pmid = 25337751 | doi = 10.1056/NEJMra1312885 }}

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.{{cite journal | vauthors = Qiu S, Shen Y, Pan H, Wang J, Zhang Q | title = Effectiveness and safety of oseltamivir for treating influenza: an updated meta-analysis of clinical trials | journal = Infectious Diseases | volume = 47 | issue = 11 | pages = 808–819 | date = 2015 | pmid = 26173991 | doi = 10.3109/23744235.2015.1067369 | s2cid = 207746253 }} 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."{{cite journal | vauthors = Heneghan CJ, Onakpoya I, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Mahtani KR, Nunan D, Howick J, Jefferson T | title = Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data | journal = Health Technology Assessment | volume = 20 | issue = 42 | pages = 1–242 | date = May 2016 | pmid = 27246259 | pmc = 4904189 | doi = 10.3310/hta20420 }} The decrease in duration of sickness was about 18 hours.{{cite journal | vauthors = Malosh RE, Martin ET, Heikkinen T, Brooks WA, Whitley RJ, Monto AS | title = Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials | journal = Clinical Infectious Diseases | volume = 66 | issue = 10 | pages = 1492–1500 | date = May 2018 | pmid = 29186364 | doi = 10.1093/cid/cix1040 | doi-access = free }}

In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours. A German clinical practice guideline recommends against its use.{{cite journal | vauthors = Holzinger F, Beck S, Dini L, Stöter C, Heintze C | title = The diagnosis and treatment of acute cough in adults | journal = Deutsches Ärzteblatt International | volume = 111 | issue = 20 | pages = 356–63 | date = May 2014 | pmid = 24882627 | pmc = 4047603 | doi = 10.3238/arztebl.2014.0356 }}

Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. 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,{{cite journal | vauthors = Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ | title = Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD008965 | date = April 2014 | pmid = 24718923 | pmc = 6464969 | doi = 10.1002/14651858.CD008965.pub4 }} while three other reviews found a decreased risk.{{cite journal | vauthors = Hernán MA, Lipsitch M | title = Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials | journal = Clinical Infectious Diseases | volume = 53 | issue = 3 | pages = 277–9 | date = August 2011 | pmid = 21677258 | pmc = 3137795 | doi = 10.1093/cid/cir400 }}{{cite journal | vauthors = Dobson J, Whitley RJ, Pocock S, Monto AS | title = Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials | journal = Lancet | volume = 385 | issue = 9979 | pages = 1729–37 | date = May 2015 | pmid = 25640810 | doi = 10.1016/S0140-6736(14)62449-1 | s2cid = 30589393 }} Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day.{{cite journal | vauthors = Burch J, Corbett M, Stock C, Nicholson K, Elliot AJ, Duffy S, Westwood M, Palmer S, Stewart L | title = Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis | journal = The Lancet. Infectious Diseases | volume = 9 | issue = 9 | pages = 537–45 | date = September 2009 | pmid = 19665930 | doi = 10.1016/S1473-3099(09)70199-9 }} Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.

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.{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu.cfm |title=Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087 |url-status=live |archive-url=https://web.archive.org/web/20140416175805/http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu.cfm |archive-date=16 April 2014 | date=30 March 2001 }}

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.

{{As of| 2017}}, the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development. 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. They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed.

{{As of|2011}}, reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease.{{cite journal | vauthors = Jackson RJ, Cooper KL, Tappenden P, Rees A, Simpson EL, Read RC, Nicholson KG | title = Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review | journal = The Journal of Infection | volume = 62 | issue = 1 | pages = 14–25 | date = January 2011 | pmid = 20950645 | doi = 10.1016/j.jinf.2010.10.003 | doi-access = free }} 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%). 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.

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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).{{cite web |title=FDA Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021087s062lbl.pdf |archive-url=https://web.archive.org/web/20170118192232/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021087s062lbl.pdf |url-status=dead |archive-date=18 January 2017 |publisher=US FDA |access-date=13 February 2025}} 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.{{citation-needed|date=February 2025}} Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious arrhythmias.

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.{{cite web|url=http://www.rocheusa.com/products/tamiflu/pi.pdf|title=Roche – Doing now what patients need next|url-status=dead|archive-url=https://web.archive.org/web/20051103010021/http://www.rocheusa.com/products/tamiflu/pi.pdf|archive-date=3 November 2005}}Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. 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.{{cite journal |vauthors=Antipov EA, Pokryshevskaya EB |title=The effects of adverse drug reactions on patients' satisfaction: evidence from publicly available data on tamiflu (oseltamivir) |journal=International Journal of Medical Informatics |date=2019 |volume=125 |pages=30–36|doi=10.1016/j.ijmedinf.2019.02.005 |pmid=30914178 }}

The US and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf | title = Pediatric safety update for Tamiflu | archive-url = https://web.archive.org/web/20070927235659/https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf | archive-date=27 September 2007 | work = U.S. Food and Drug Administration (FDA) }} The frequency of these appears to be low and a causative role for oseltamivir has not been established.{{cite news | vauthors = Waknine Y | date = 14 November 2006 |url= http://www.medscape.com/viewarticle/547783|title= Tamiflu May Be Linked to Risk for Self-Injury and Delirium|access-date= 17 May 2008 |work= Medscape|url-status= live|archive-url= https://web.archive.org/web/20111125173524/http://www.medscape.com/viewarticle/547783|archive-date= 25 November 2011}} 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.{{cite journal| vauthors = Cohen D |title=Oseltamivir: another case of regulatory failure?|journal=BMJ|date=9 April 2014|volume=348|issue=apr09 8|pages=g2591|doi=10.1136/bmj.g2591|s2cid=72592926}}

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.{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm |website=Australian Government|access-date=22 April 2014|date=3 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm |archive-date=8 April 2014}} Dose adjustment may be needed in those with kidney problems.

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.

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The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme. 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.{{cite journal | vauthors = Thorlund K, Awad T, Boivin G, Thabane L | title = Systematic review of influenza resistance to the neuraminidase inhibitors | journal = BMC Infectious Diseases | volume = 11 | issue = 1 | pages = 134 | date = May 2011 | pmid = 21592407 | pmc = 3123567 | doi = 10.1186/1471-2334-11-134 | doi-access = free }} In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.

{{As of|2010|12|15|df=US}}, the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide showed resistance to oseltamivir.{{cite web|url=https://www.who.int/csr/disease/influenza/2010_12_15_weekly_web_update_oseltamivir_resistance.pdf|title=Update on oseltamivir resistance to influenza H1N1 (2009) viruses|publisher=World Health Organization (WHO)|date=15 December 2010|access-date=30 December 2010|url-status=live|archive-url=https://web.archive.org/web/20110127001912/http://www.who.int/csr/disease/influenza/2010_12_15_weekly_web_update_oseltamivir_resistance.pdf|archive-date=27 January 2011}}

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.{{cite web|title=Antiviral Drug Resistance among Influenza Viruses Guidance on the Use of Influenza Antiviral Agents (Current for the 2013–14 Influenza Season)|url=https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|publisher=U.S. Centers for Disease Control and Prevention (CDC)|access-date=21 April 2014|url-status=live|archive-url=https://web.archive.org/web/20140213063541/http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|archive-date=13 February 2014}}

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.{{cite news| vauthors = Hurt AC |title=Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation|url=http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19884|newspaper=Eurosurveillance|date=9 June 2011|url-status=live|archive-url=https://web.archive.org/web/20140423051744/http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19884|archive-date=23 April 2014}}

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|lc=yes}}, widespread transmission of oseltamivir-resistant pH1N1 has not occurred.{{cite web| vauthors = Downing M |title=Antiviral Therapy for Pandemic Influenza A (H1N1) Infection: Dosing, Combination Therapy, and Resistance|url=http://www.nccid.ca/files/Evidence_Reviews/NCCID_Dosing_Combo_rev.pdf|publisher=National collaborating centre for infectious diseases|date=November 2013|url-status=dead|archive-url=https://web.archive.org/web/20140419013328/http://www.nccid.ca/files/Evidence_Reviews/NCCID_Dosing_Combo_rev.pdf|archive-date=19 April 2014|access-date=18 April 2014}}

During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.{{cite web |url= https://www.cdc.gov/flu/weekly/weeklyarchives2007-2008/07-08summary.htm |title=2007–08 U.S. Influenza Season Summary |publisher=U.S. Centers for Disease Control and Prevention (CDC) |url-status=live|archive-url= https://web.archive.org/web/20111020215207/http://www.cdc.gov/flu/weekly/weeklyarchives2007-2008/07-08summary.htm |archive-date=20 October 2011}} In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance.{{cite web|url=https://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/08-09summary.htm|title=Influenza (Flu) – Weekly Report: Influenza Summary Update Week 53, 2008-2009 Season|url-status=live|archive-url=https://web.archive.org/web/20111020200730/http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/08-09summary.htm|archive-date=20 October 2011}}

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.{{cite web|url=https://www.cdc.gov/flu/weekly/weeklyarchives2010-2011/10-11summary.htm|title=2010-2011 Influenza Season Summary |publisher=U.S. Centers for Disease Control and Prevention (CDC)|url-status=live|archive-url=https://web.archive.org/web/20120125212234/http://www.cdc.gov/flu/weekly/weeklyarchives2010-2011/10-11summary.htm|archive-date=25 January 2012}} In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible.{{cite web|url=https://www.cdc.gov/flu/weekly/weeklyarchives2011-2012/weekly51.htm|title=2011-2012 Influenza Season Week 51 ending December 24, 2011 |publisher=U.S. Centers for Disease Control and Prevention (CDC)|url-status=live|archive-url=https://web.archive.org/web/20130517165723/http://www.cdc.gov/flu/weekly/weeklyarchives2011-2012/weekly51.htm|archive-date=17 May 2013}}{{cite web | url=https://www.ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/111230_SUR_Weekly_Influenza_Surveillance_Overview.pdf | title=Main surveillance developments in week 51/2011 (19–25 December 2011) | archive-url=https://web.archive.org/web/20120610053628/http://www.ecdc.europa.eu/en/publications/Publications/111230_SUR_Weekly_Influenza_Surveillance_Overview.pdf | archive-date=10 June 2012 | url-status=live | date=January 2012 | publisher=European Centre for Disease Prevention and Control (ECDC) }} In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir.{{cite web|title=CDC Influenza Division Key Points, March 28, 2014 |url=http://www.immunize.nc.gov/PDFs/2014%20PDF/CDC%20Influenza%20Key%20Points/CDC%20Influenza%20Key%20Points%20March%2028%202014.pdf|publisher=U.S. Centers for Disease Control and Prevention (CDC)|date=28 March 2014|access-date=15 April 2014|url-status=dead|archive-url=https://web.archive.org/web/20140402135340/http://www.immunize.nc.gov/PDFs/2014%20PDF/CDC%20Influenza%20Key%20Points/CDC%20Influenza%20Key%20Points%20March%2028%202014.pdf|archive-date=2 April 2014}}

Three studies have found resistance in 0%, 3.3%, and 18% of subjects. 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.{{cite journal | vauthors = Ward P, Small I, Smith J, Suter P, Dutkowski R | title = Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic | journal = The Journal of Antimicrobial Chemotherapy | volume = 55 | issue = Suppl 1 | pages = i5–i21 | date = February 2005 | pmid = 15709056 | doi = 10.1093/jac/dki018 | doi-access = free }}

In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%.{{cite journal | vauthors = Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, Kiso M, Shimizu H, Kawakami C, Koike K, Mitamura K, Kawaoka Y | title = Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors | journal = JAMA | volume = 297 | issue = 13 | pages = 1435–42 | date = April 2007 | pmid = 17405969 | doi = 10.1001/jama.297.13.1435 | doi-access = free }} According to the CDC, {{as of|2019}}, transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare.{{Cite web|url=https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|title=Antiviral Drug Resistance among Influenza Viruses|date=17 April 2019|website=U.S. Centers for Disease Control and Prevention (CDC)|access-date=29 January 2020|archive-date=13 February 2014|archive-url=https://web.archive.org/web/20140213063541/http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|url-status=live}}

{{As of|2013}}, 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.{{cite journal | vauthors = McKimm-Breschkin JL | title = Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance | journal = Influenza and Other Respiratory Viruses | volume = 7 | issue = Suppl 1 | pages = 25–36 | date = January 2013 | pmid = 23279894 | pmc = 4942987 | doi = 10.1111/irv.12047 }}

{{As of|2013}}, two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation.{{cite journal | vauthors = Hay AJ, Hayden FG | title = Oseltamivir resistance during treatment of H7N9 infection | journal = Lancet | volume = 381 | issue = 9885 | pages = 2230–2 | date = June 2013 | pmid = 23809549 | doi = 10.1016/S0140-6736(13)61209-X | s2cid = 39375028 }}

Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver, via esterases. It does not interact with cytochrome P450 enzymes in the liver. It has a volume of distribution of 23–26 litres. Its half-life is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours. More than 90% of the oral dose is eliminated in the urine as the active metabolite.

File:Illicium verum00.jpg's 1833 "Flore Medicale"]]

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.{{cite journal | vauthors = Farina V, Brown JD | title = Tamiflu: the supply problem | journal = Angewandte Chemie | volume = 45 | issue = 44 | pages = 7330–4 | date = November 2006 | pmid = 17051628 | doi = 10.1002/anie.200602623 }}{{cite journal | vauthors = Rawat G, Tripathi P, Saxena RK | title = Expanding horizons of shikimic acid. Recent progresses in production and its endless frontiers in application and market trends | journal = Applied Microbiology and Biotechnology | volume = 97 | issue = 10 | pages = 4277–87 | date = May 2013 | pmid = 23553030 | doi = 10.1007/s00253-013-4840-y | s2cid = 17660413 | doi-access = free }} Gilead exclusively licensed their relevant patents to Roche in 1996.{{cite web | title = Avian Flu Drugs: Patent Questions | work = WIPO | date = April 2006 | url = http://www.wipo.int/wipo_magazine/en/2006/02/article_0005.html | archive-url = https://web.archive.org/web/20091208132822/http://www.wipo.int/wipo_magazine/en/2006/02/article_0005.html | archive-date=8 December 2009 }} The drug has not been patent-protected in Thailand, the Philippines, Indonesia, and several other countries.

In 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults{{cite web | title=Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087 | website=U.S. Food and Drug Administration (FDA)| date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu.cfm | archive-url=https://web.archive.org/web/20200109193820/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu.cfm | archive-date=9 January 2020 | url-status=live | access-date=9 January 2020 }} based on two double-blind, randomized, placebo-controlled clinical trials.{{cite web | work = U.S. Food and Drug Administration | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_medr_P1.pdf | title = OseltamivirMedical Review | url-status = live | archive-url = https://web.archive.org/web/20140416231911/http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_medr_P1.pdf | archive-date=16 April 2014 }} 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.{{cite journal | vauthors = Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F | title = Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations | journal = Archives of Internal Medicine | volume = 163 | issue = 14 | pages = 1667–72 | date = July 2003 | pmid = 12885681 | doi = 10.1001/archinte.163.14.1667 | doi-access = free }}

Oseltamivir (as Tamiflu) was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005.{{medcn|date=January 2020}} 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{{cite web | url=http://www.cidrap.umn.edu/news-perspective/2005/10/oseltamivir-resistant-h5n1-virus-isolated-vietnamese-girl | title=Oseltamivir-resistant H5N1 virus isolated from Vietnamese girl | website=University of Minnesota | date=14 October 2005 | access-date=7 December 2014 | vauthors = Heiberg M | url-status=live | archive-url=https://web.archive.org/web/20141214172822/http://www.cidrap.umn.edu/news-perspective/2005/10/oseltamivir-resistant-h5n1-virus-isolated-vietnamese-girl | archive-date=14 December 2014 }} and there were worldwide shortages of the drug, driven by the high demand for stockpiling. 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.{{cite web | vauthors = Brownlee S, Lenzer J | date = November 2009 | url = https://www.theatlantic.com/doc/200911/brownlee-h1n1 | title = Does the Vaccine Matter? | archive-url = https://web.archive.org/web/20100104001912/http://www.theatlantic.com/doc/200911/brownlee-h1n1 | archive-date=4 January 2010| work = The Atlantic }}

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.{{cite journal | vauthors = Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D | veditors = Jefferson T | title = Neuraminidase inhibitors for preventing and treating influenza in healthy adults | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD001265 | date = July 2006 | pmid = 16855962 | doi = 10.1002/14651858.CD001265.pub2 | url = https://espace.library.uq.edu.au/view/UQ:82084/UQ82084_OA.pdf | pmc = 2790574 | access-date = 24 September 2019 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828201252/https://espace.library.uq.edu.au/data/UQ_82084/UQ82084_OA.pdf?Expires=1630181659&Key-Pair-Id=APKAJKNBJ4MJBJNC6NLQ&Signature=RFAO3z9hgpGLqVuBtrR9X2yLD-iE8kwx~GyzXdiSgJYAQHN2JlwQYboUM63FslgPhpo4dWoSuDg4l~VvVMCKnH3FoHz3oqHF8cruS2WMG3EX1-dFrKs6i0TJ1PDy5KM4KizkWcqrr6UoSUALpXL6f959HGSGc4K~0BRpc655sGyCoxPRmNLPcit0TanrrKabH4rc-OGHb02XlT1Pyn4kPwFFQb6Vm4uyjPFpYNK0-pLUEM45C9NLPiTPlBP0Ns0Wr9JnOP57SCn4rrpw0QzwkFcc36G~FTsIwWDM--2GhBu7UQurAv~pjaWk0dzHE99Ot6qgQrjBjNX1fRvH2uFmwQ__ | url-status = live }}{{Retracted|intentional=yes||doi=10.1002/14651858.cd001265.pub3}}

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.{{cite news|title=Cipla's anti-flu drug gets nod|date=14 May 2009|work=The Times of India|access-date=29 July 2009|url=http://timesofindia.indiatimes.com/Business/India-Business/Ciplas-anti-flu-drug-gets-nod/articleshow/4526891.cms|url-status=live|archive-url=https://web.archive.org/web/20121023232717/http://timesofindia.indiatimes.com/Business/India-Business/Ciplas-anti-flu-drug-gets-nod/articleshow/4526891.cms|archive-date=23 October 2012}}

File:tamiflu-display-trailer-miami.jpg

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.{{cite journal | vauthors = Jefferson T, Doshi P | title = Multisystem failure: the story of anti-influenza drugs | journal = BMJ | volume = 348 | issue = apr10 14 | pages = g2263 | date = April 2014 | pmid = 24721793 | doi = 10.1136/bmj.g2263 | s2cid = 13490764 }} The National Institute for Health and Care Excellence (NICE), the CDC, the WHO, and the ECDC maintained their recommendation to use oseltamivir.{{cite web|title=WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses Revised February 2010|url=https://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf|publisher=WHO|url-status=live|archive-url=https://web.archive.org/web/20131027071802/http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf|archive-date=27 October 2013}}

From 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide.{{cite journal | title=Tamiflu campaign | journal=BMJ | url=https://www.bmj.com/tamiflu | access-date=21 January 2020 | archive-date=21 January 2020 | archive-url=https://web.archive.org/web/20200121075906/https://www.bmj.com/tamiflu | url-status=live }} 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.{{cite journal | vauthors = Cohen D | title = Roche offers researchers access to all Tamiflu trials | journal = BMJ | volume = 346 | issue = apr04 3 | pages = f2157 | date = April 2013 | pmid = 23558407 | doi = 10.1136/bmj.f2157 | s2cid = 5469580 }} In 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents. In 2016, Roche's oseltamivir patents began to expire.

There have been{{when|date=January 2020}} reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirus infection.{{cite journal | vauthors = Savigny MR, Macintire DK | title = Use of oseltamivir in the treatment of canine parvoviral enteritis | journal = Journal of Veterinary Emergency and Critical Care | volume = 20 | issue = 1 | pages = 132–42 | date = February 2010 | pmid = 20230441 | doi = 10.1111/j.1476-4431.2009.00404.x }} 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.{{cite web | last = Macintire | first = Douglass K. | title = Treatment of Parvoviral Enteritis | website = Proceedings of the Western Veterinary Conference | year = 2006 | url = http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=wvc2006&PID=pr12457&O=VIN | access-date = 9 June 2007 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828201252/https://id.vin.com/Login/Login?ReturnUrl=%2Fconnect%2Fauthorize%2Fcallback%3Fclient_id%3Dwebsite-vin-members%26redirect_uri%3Dhttps%253A%252F%252Fwww.vin.com%252Fvinmembers%252Fsignin-oidc%26response_type%3Did_token%26scope%3Dopenid%2520profile%26response_mode%3Dform_post%26nonce%3D637657783721030404.OGYyZDI3NTgtNWNlNi00NDcwLTg3NGQtNDVkZGU4NWE1NGFjYThlMWRkNWItMjYxMy00OTI5LTkwNzQtMmIzYmE5NmY5OGMy%26state%3DCfDJ8BJ2EW-jHoVMgGyW5D6H4zCdmSSG3kvr-RacR9beHAW5EO9153j_-45V2B5mi9q5udhg-GwdTxM5jzJHn8_QlMvbm-8oKPunPCGt-tkbtfnXJHPSJ0bDzdgtbsGpBoTs-60HFtL2XDxH1kmRdCC6Xpo7C9W7ZYoEXWvlwOZwraWqqd6HluiR-e32htdSihp65FjK7Nn8fBdxeON1v7CtiuyffMWykztlTr_FqThNgWrsUddxzyiLMvFCwCTSrKwmjtbdeBxf9sXhd5GuCuURHRyH3jy-QwFmFr-L4tyn0lEfqTGhrcFvMi7FiDBogpw73Zie0IrFPjaSkov451JYJuN_x9nK4NHJXg3JiL3DTbcYwgJZz6LiaVc7N5nRCuwNCm7CDuVdGg2l7fK5GFOx2x996wUFL2QC8nfnixQMFF8YRQbnYJJz_TkRdIhvcSmBfzzx2DpshxY534h_uIQrHrbdo1X9-XzDGIthQqZxuJJn%26x-client-SKU%3DID_NETSTANDARD2_0%26x-client-ver%3D5.5.0.0 | url-status = live }}

Oseltamivir has been deemed ineffective at treating COVID-19, consistent with the SARS-CoV-2 virus lacking influenza's neuraminidase enzyme.{{cite journal | vauthors = Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z | title = Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China | journal = JAMA | volume = 323 | issue = 11 | pages = 1061–1069 | date = March 2020 | pmid = 32031570 | doi = 10.1001/jama.2020.1585 | pmc = 7042881 }}

{{Reflist}}

{{refbegin}}

• {{cite news | vauthors = Pollack A | title = Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu | work = The New York Times | date = 5 November 2005 | url = https://www.nytimes.com/2005/11/05/business/05tamiflu.html }}
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• {{Cite journal| vauthors = Rohloff JC, Kent KM, Postich MJ, Becker MW, Chapman HH, Kelly DE, Lew W, Louie MS, McGee LR, Prisbe EJ, Schultze LM | title = Practical Total Synthesis of the Anti-Influenza Drug GS-4104 | journal = The Journal of Organic Chemistry | volume = 63| issue = 13 | pages = 4545–4550 | year = 1998 | doi = 10.1021/jo980330q }}
• {{cite journal | vauthors = Karpf M, Trussardi R | title = New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu) | journal = The Journal of Organic Chemistry | volume = 66 | issue = 6 | pages = 2044–51 | date = March 2001 | pmid = 11300898 | doi = 10.1021/jo005702l }}
• {{Cite journal| vauthors = Abrecht S, Harrington P, Iding H, Karpf M, Trussardi R, Wirz B, Zutter U | title = The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu): A Challenge for Synthesis & Process Research | journal = CHIMIA International Journal for Chemistry | volume = 58| issue = 9 | pages = 621–629 | year = 2004 | doi = 10.2533/000942904777677605 | doi-access = free }}
• {{cite journal | vauthors = Yeung YY, Hong S, Corey EJ | title = A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid | journal = Journal of the American Chemical Society | volume = 128 | issue = 19 | pages = 6310–1 | date = May 2006 | pmid = 16683783 | doi = 10.1021/ja0616433 | bibcode = 2006JAChS.128.6310Y }}
• {{cite journal | vauthors = Tse N, Cederbaum S, Glaspy JA | title = Hyperammonemia following allogeneic bone marrow transplantation | journal = American Journal of Hematology | volume = 38 | issue = 2 | pages = 140–1 | date = October 1991 | pmid = 1951305 | doi = 10.1002/ajh.2830380213 | s2cid = 45068099 }}
• {{cite news | vauthors=Schneider RU | title=The race to develop GS4104 | newspaper=Neue Zürcher Zeitung | date=April 2001 | url=https://folio.nzz.ch/2001/april/race-develop-gs4104 | language=de |url-access=subscription }}
• {{cite web | title=FDA Drug Safety Communication: Important safety changes to the influenza drug Tamiflu (oseltamivir phosphate) for oral suspension | website=U.S. Food and Drug Administration (FDA) | date=31 August 2011 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-changes-influenza-drug-tamiflu-oseltamivir-phosphate }}

{{refend}}

{{Commons and category|Oseltamivir|Oseltamivir}}

• {{cite web | title=Tamiflu (oseltamivir phosphate) Information | website=U.S. Food and Drug Administration (FDA) | date=3 November 2018 | url=http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/tamiflu-oseltamivir-phosphate-information }}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}

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