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{{Short description|Antiviral medication used against influenza A and influenza B}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
| Watchedfields = changed
| Watchedfields = changed
| verifiedrevid = 400838073
| verifiedrevid = 459589411
| drug_name =
| IUPAC_name = ethyl (3''R'',4''R'',5''S'')-5-amino-4-acetamido-3-
| INN =
| type = <!-- empty -->
| image = Oseltamivir.svg
| image = Oseltamivir.svg
| width =
| image2 = Oseltamivir-3D-balls.png
| alt =
| image2 = Oseltamivir-based-on-dihydrogenphosphate-xtal-3D-bs-17.png
| width2 =
| alt2 =
| caption =


<!--Clinical data-->
<!-- Clinical data -->
| pronounce = {{IPAc-en|ɒ|s|əl|ˈ|t|æ|m|ᵻ|v|ɪər}}
| tradename = Tamiflu
| tradename = Tamiflu, Ebilfumin
| Drugs.com = {{drugs.com|monograph|tamiflu}}
| Drugs.com = {{drugs.com|monograph|oseltamivir-phosphate}}
| MedlinePlus = a699040
| MedlinePlus = a699040
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = yes
| DailyMedID = Oseltamivir
| licence_US = Oseltamivir
| pregnancy_AU = B1
| pregnancy_AU = B1
| pregnancy_AU_comment = <ref name=Preg2017 /><ref name="Tamiflu PI" />
| pregnancy_US = C
| pregnancy_category=
| legal_AU = Schedule 4
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Neuraminidase inhibitor]]
| ATCvet =
| ATC_prefix = J05
| ATC_suffix = AH02
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref name="Tamiflu PI">{{Cite web |url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=roptamif10512 |title=Tamiflu ® (oseltamivir phosphate) | work = Australian Product Information | author = Roche Products Pty Limited |access-date=2023-01-09 |archive-date=2023-04-24 |archive-url=https://web.archive.org/web/20230424145821/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=roptamif10512 |url-status=live }}</ref><ref>{{cite web | title=ALEMBIC OSELTAMIVIR, ALEMVIR , ALEMZY , OSELEMBIC, OSELTAMIVIR AGH, OSELTAMIVIR AGHL, OSELTAMIVIR APPL , TAMIRAC (Alembic Pharmaceuticals Australia Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=5 December 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/alembic-oseltamivir-alemvir-alemzy-oselembic-oseltamivir-agh-oseltamivir-aghl-oseltamivir-appl-tamirac-alembic-pharmaceuticals-australia-pty-ltd | access-date=29 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318044942/https://www.tga.gov.au/resources/prescription-medicines-registrations/alembic-oseltamivir-alemvir-alemzy-oselembic-oseltamivir-agh-oseltamivir-aghl-oseltamivir-appl-tamirac-alembic-pharmaceuticals-australia-pty-ltd | url-status=live }}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US = Rx-only
| legal_US_comment =
| routes_of_administration = oral
| legal_EU = Rx-only
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = <!--For countries not listed above-->


<!--Pharmacokinetic data-->
<!-- Pharmacokinetic data -->
| bioavailability = >80%<ref name=PK>{{cite journal | vauthors = Davies BE | title = Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations | journal = The Journal of Antimicrobial Chemotherapy | volume = 65 | issue = Suppl 2 | pages = ii5–ii10 | date = April 2010 | pmid = 20215135 | pmc = 2835511 | doi = 10.1093/jac/dkq015 }}</ref>
| bioavailability = 75%
| protein_bound = 42% (parent drug), 3% (active metabolite)<ref name = PK />
| metabolism = [[Liver|Hepatic]], to GS4071
| metabolism = [[Liver]], to oseltamivir carboxylate<ref name = PK />
| elimination_half-life = 6–10 hours
| metabolites =
| excretion = [[Kidney|Renal]] (GS4071)
| onset =
| elimination_half-life = 1–3 hours, 6–10 hours (active metabolite)<ref name = PK />
| duration_of_action =
| excretion = Urine (>90% as oseltamivir carboxylate), faeces<ref name = PK />


<!--Identifiers-->
<!-- Identifiers -->
| index2_label = as salt
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 196618-13-0 -->
| CAS_number = 196618-13-0
| ATC_prefix = J05
| CAS_supplemental = 204255-11-8
| ATC_suffix = AH02
| PubChem = 65028
| PubChem = 65028
| PubChemSubstance =
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00198
| DrugBank = DB00198
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 58540
| ChemSpiderID = 58540
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 20O93L6F9H
| UNII = 20O93L6F9H
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08306
| KEGG = D08306
| ChEBI_Ref = {{ebicite|changed|EBI}}
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00900
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7798
| ChEBI = 7798
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1229
| ChEMBL = 1229
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = GS-4104


<!--Chemical data-->
<!-- Chemical and physical data -->
| IUPAC_name = ethyl (3''R'',4''R'',5''S'')-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
| C=16 | H=28 | N=2 | O=4
| C=16 | H=28 | N=2 | O=4
| molecular_weight = 312.4 g/mol
| smiles = O=C(OCC)/C1=C/[C@@H](OC(CC)CC)[C@H](NC(=O)C)[C@@H](N)C1
| SMILES = CCC(CC)OC1C=C(CC(C1NC(=O)C)N)C(=O)OCC
| InChI = 1/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
| InChIKey = VSZGPKBBMSAYNT-RRFJBIMHBB
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChI = 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
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VSZGPKBBMSAYNT-RRFJBIMHSA-N
| StdInChIKey = VSZGPKBBMSAYNT-RRFJBIMHSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
}}
{{flu}}
'''Oseltamivir''' [[International Nonproprietary Name|INN]] ({{IPAc-en|icon|ɒ|s|əl|ˈ|t|æ|m|ɨ|v|ɪər}}), an [[antiviral drug]], slows the spread of [[influenza]] (flu) virus between cells in the body by stopping the virus from [[Viral neuraminidase|chemically cutting ties]] with its host cell; median time to symptom alleviation is reduced by 0.5–1 day.<ref name="pmid19665930">{{cite journal |author=Burch J, Corbett M, Stock C, ''et al.'' |title=Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis |journal=Lancet Infect Dis |volume=9 |issue=9 |pages=537–45 |year=2009 |month=September |pmid=19665930 |doi=10.1016/S1473-3099(09)70199-9 |url=http://linkinghub.elsevier.com/retrieve/pii/S1473-3099(09)70199-9}}</ref> The drug is sold under the [[trade name]] '''Tamiflu''', and is taken orally in capsules or as a suspension. It has been used to treat and [[prophylaxis|prevent]] [[influenza A virus]] and [[influenza B virus]] infection in over 50 million people since 1999.{{Citation needed|date=November 2009}}


<!-- Definition and recommendations -->
Oseltamivir is a [[prodrug]], a (relatively) inactive chemical which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active [[neuraminidase inhibitor]] commercially developed.{{Citation needed|date=February 2010}} It was developed by [[C.U. Kim]], [[W. Lew]], and [[X. Chen]] of US-based [[Gilead Sciences]], and is currently marketed by [[Hoffmann–La Roche]] (Roche). In Japan, it is marketed by [[Chugai Pharmaceutical Co.]], which is more than 50% owned by Roche.<ref>
'''Oseltamivir''', sold under the brand name '''Tamiflu''', is an [[antiviral medication]] used to treat and prevent [[influenza A virus|influenza A]] and [[Influenza B virus|influenza B]], viruses that cause [[Influenza|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>{{cite web|title=CDC Recommendations for Influenza Antiviral Medications Remain Unchanged |url=https://www.cdc.gov/media/haveyouheard/stories/Influenza_antiviral2.html|website=U.S. [[Centers for Disease Control and Prevention]] (CDC)|access-date=16 January 2017|date=10 April 2014|url-status=live|archive-url=https://web.archive.org/web/20170118062432/https://www.cdc.gov/media/haveyouheard/stories/Influenza_antiviral2.html|archive-date=18 January 2017}}</ref><ref name=ECDC2014>{{cite web|author=European Centre for Disease Prevention and Control|url=https://www.ecdc.europa.eu/en/news-events/new-and-updated-evaluations-neuraminidase-inhibitors-preventing-and-treating-influenza?ID=764&List=a3216f4c-f040-4f51-9f77-a96046dbfd72 |title=New and updated evaluations of neuraminidase inhibitors for preventing and treating influenza published|date=2 June 2014|url-status=live|archive-url=https://web.archive.org/web/20141102192744/http://www.ecdc.europa.eu/en/activities/sciadvice/_layouts/forms/Review_DispForm.aspx?List=a3216f4c-f040-4f51-9f77-a96046dbfd72&ID=764|archive-date=2014-11-02}}</ref><ref name=NICE2009>{{cite web|title=Amantadine, oseltamivir and zanamivir for the treatment of influenza|url=https://www.nice.org.uk/guidance/TA168|website=[[National Institute for Health and Care Excellence]] (NICE)|access-date=16 January 2017|date=25 February 2009|url-status=live|archive-url=https://web.archive.org/web/20170118050618/https://www.nice.org.uk/guidance/TA168|archive-date=18 January 2017}}</ref> It is taken by mouth, either as a pill or liquid.<ref name=AHFS2017>{{cite web| title=Oseltamivir Phosphate Monograph for Professionals | url=https://www.drugs.com/monograph/oseltamivir-phosphate.html| publisher=The American Society of Health-System Pharmacists| access-date=8 January 2017| url-status=live| archive-url=https://web.archive.org/web/20160513062957/http://www.drugs.com/monograph/oseltamivir-phosphate.html| archive-date=13 May 2016}}</ref>
{{cite web
| work = Drugs@FDA
| title = Tamiflu Approval, Review, and Labeling Information
| publisher = [[Food and Drug Administration (United States)|US FDA]]
| url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=TAMIFLU&CFID=17854686&CFTOKEN=c50001319503aac1-21A693AF-1372-5AE1-6A3A380593AD1874
| accessdate = 2009-05-08}}</ref><ref>
{{cite journal
| author = Lew W, Chen X, Kim CU
| title = Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor
| journal = Curr. Med. Chem.
| volume = 7
| issue = 6
| pages = 663–72
| year = 2000
| month = June
| pmid = 10702632
}}</ref>


<!-- Evidence -->
{{As of|2010|12|df=US}}, the [[World Health Organization]] (WHO) reported 314 samples of the prevalent [[2009 flu pandemic|2009 pandemic H1N1 flu]] tested worldwide have shown resistance to oseltamivir.<ref name="Update on oseltamivir resistance to influenza H1N1 (2009) viruses">
Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations.<ref name=CDC2014up /><ref name=IDSA2014>{{cite web|url=http://www.idsociety.org/Influenza_Statement.aspx|title=IDSA Continues to Recommend Antivirals for Influenza|access-date=24 April 2014 |archive-url= https://web.archive.org/web/20140424193055/http://www.idsociety.org/Influenza_Statement.aspx|archive-date=24 April 2014}}</ref><ref name=Brownlee2013>{{cite web | url=https://www.theatlantic.com/health/archive/2013/02/tamiflu-myth-and-misconception/273167/ | title=Tamiflu: Myth and Misconception | website=[[The Atlantic]] | date=19 February 2013 | access-date=7 December 2014 | vauthors = Brownlee S | url-status=live | archive-url=https://web.archive.org/web/20141229111545/http://www.theatlantic.com/health/archive/2013/02/tamiflu-myth-and-misconception/273167/ | archive-date=29 December 2014 }}</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>{{cite journal | vauthors = Butler D | title = Tamiflu report comes under fire | journal = Nature | volume = 508 | issue = 7497 | pages = 439–40 | date = April 2014 | pmid = 24759392 | doi = 10.1038/508439a | bibcode = 2014Natur.508..439B | doi-access = free }}</ref> Two [[meta-analysis|meta-analyses]] have concluded that benefits in those who are otherwise healthy do not outweigh its risks.<ref name=Mich2013>{{cite journal | vauthors = Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S | title = The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e60348 | year = 2013 | pmid = 23565231 | pmc = 3614893 | doi = 10.1371/journal.pone.0060348 | bibcode = 2013PLoSO...860348M | veditors = Jefferson T | doi-access = free }}</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>{{cite journal | vauthors = Ebell MH, Call M, Shinholser J | title = Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials | journal = Family Practice | volume = 30 | issue = 2 | pages = 125–33 | date = April 2013 | pmid = 22997224 | doi = 10.1093/fampra/cms059 | doi-access = free }}</ref> However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels.<ref>{{cite journal | vauthors = Okoli GN, Otete HE, Beck CR, Nguyen-Van-Tam JS | title = Use of neuraminidase inhibitors for rapid containment of influenza: a systematic review and meta-analysis of individual and household transmission studies | journal = PLOS ONE | volume = 9 | issue = 12 | pages = e113633 | date = 9 December 2014 | pmid = 25490762 | pmc = 4260958 | doi = 10.1371/journal.pone.0113633 | bibcode = 2014PLoSO...9k3633O | doi-access = free }}</ref>
{{cite web
|url=http://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= December 15, 2010
| accessdate=December 30, 2010
}}</ref>


<!-- Side effects -->
==Clinical usage==
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>{{cite journal | vauthors = Wang K, Shun-Shin M, Gill P, Perera R, Harnden A | title = Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD002744 | date = April 2012 | pmid = 22513907 | pmc = 6599832 | doi = 10.1002/14651858.CD002744.pub4 | veditors = Harnden A }}</ref><ref name=Jeff2014>{{cite journal | vauthors = Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ | title = Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments | journal = BMJ | volume = 348 | pages = g2545 | date = April 2014 | pmid = 24811411 | pmc = 3981975 | doi = 10.1136/bmj.g2545 }}</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>{{cite web|title=Oseltamivir (Tamiflu) Use During Pregnancy|url=https://www.drugs.com/pregnancy/oseltamivir.html|website=Drugs.com|access-date=16 January 2017|url-status=live|archive-url=https://web.archive.org/web/20170909094948/https://www.drugs.com/pregnancy/oseltamivir.html|archive-date=9 September 2017}}</ref> Dose adjustment may be needed in those with kidney problems.<ref name=AHFS2017/>
===Mechanism of action===
The prodrug oseltamivir is itself not virally effective; however, once in the [[liver]], it is converted by natural chemical processes, [[hydrolysis|hydrolysed]] hepatically to its active metabolite, the free [[carboxylic acid|carboxylate]] of oseltamivir (GS4071).<ref name="rocheinfo" />


<!-- History, society and culture -->
Oseltamivir is a [[neuraminidase inhibitor]], serving as a [[competitive inhibitor]] towards [[sialic acid]], found on the surface proteins of normal host cells. By blocking the activity of the viral neuraminidase (NA) enzyme, oseltamivir prevents new viral particles from being released by infected cells.<ref name="rocheinfo" />
Oseltamivir was approved for medical use in the US in 1999.<ref name=AHFS2017/> It was the first [[neuraminidase inhibitor]] available by mouth.<ref>{{cite journal | vauthors = Agrawal R, Rewatkar PV, Kokil GR, Verma A, Kalra A | title = Oseltamivir: a first line defense against swine flu | journal = Medicinal Chemistry | volume = 6 | issue = 4 | pages = 247–251 | date = July 2010 | pmid = 20843284 | doi = 10.2174/1573406411006040247 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]] but was downgraded to "complementary" status in 2017.<ref name="WHO TRS 1006" /><ref>{{cite journal | vauthors = Ebell MH | title = WHO downgrades status of oseltamivir | journal = BMJ | volume = 358 | pages = j3266 | date = July 2017 | pmid = 28701339 | doi = 10.1136/bmj.j3266 | s2cid = 206916214 | url = http://www.bmj.com/cgi/content/short/359/nov14_4/j5281 | access-date = 2020-08-31 | archive-date = 2023-04-29 | archive-url = https://web.archive.org/web/20230429051508/https://www.bmj.com/content/359/bmj.j5281 | url-status = live }}</ref><ref name="WHO21st"/> A [[generic medication|generic version]] was approved in the US in 2016.<ref>{{cite web|title=The FDA approves first generic version of widely used influenza drug, Tamiflu|url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-approves-first-generic-version-widely-used-influenza-drug-tamiflu |website=U.S. [[Food and Drug Administration]] (FDA)|access-date=6 August 2016|date=4 August 2016|url-status=live|archive-url=https://web.archive.org/web/20160808151428/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm514854.htm|archive-date=8 August 2016}}</ref><ref>{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=202595 | access-date=9 January 2020 | archive-date=30 November 2017 | archive-url=https://web.archive.org/web/20171130231459/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=202595 | url-status=live }}</ref> In 2020, it was the 178th most commonly prescribed medication in the United States, with more than 3{{nbsp}}million prescriptions.<ref>{{cite web |title=The Top 300 of 2020 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=ClinCalc |access-date=7 October 2022 |archive-date=18 March 2020 |archive-url=https://web.archive.org/web/20200318234059/https://clincalc.com/DrugStats/Top300Drugs.aspx |url-status=live }}</ref><ref>{{cite web | title=Oseltamivir - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Oseltamivir | access-date=7 October 2022 | archive-date=8 October 2022 | archive-url=https://web.archive.org/web/20221008042432/https://clincalc.com/DrugStats/Drugs/Oseltamivir | url-status=live }}</ref>


== Medical use ==
===Indications and dosage===
[[File:A Tamiflu (oseltamivir) capsule.jpg|thumb|An oseltamivir capsule]]
Oseltamivir is marketed by Roche under the trade name Tamiflu, as capsules (containing oseltamivir phosphate 98.5&nbsp;mg equivalent to oseltamivir 75&nbsp;mg) and as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir 12&nbsp;mg/ml).
[[File:Tamiflu dry syrup.png|thumb|Oseltamivir dry syrup type]]


Oseltamivir is used for the prevention and treatment of [[influenza]] caused by influenza A and B viruses.<ref name=AHFS2017 /><ref name="Tamiflu Label">{{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 }}</ref> It is on the [[WHO Model List of Essential Medicines|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">{{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 }}</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>{{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 }}</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">{{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 }}</ref>
Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses.


===High-risk people===
Oseltamivir is approved for use in persons age one and over. There is also currently an FDA Emergency Use authorization temporarily allowing the use of Tamiflu in children less than one year old.<ref>http://www.cdc.gov/h1n1flu/eua/pdf/tamiflu-hcp.pdf</ref> The usual adult dosage for treatment of influenza is 75&nbsp;mg twice daily for five days, beginning within two days of the appearance of symptoms, with decreased doses for children and patients with renal impairment. It may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic dosage is 75&nbsp;mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. The importance of early treatment is that the NA protein inhibition is more effective within the first 48 hours. If the virus has replicated and infected many cells, the effectiveness of this medication will be severely diminished, especially over time.<ref name="rocheinfo">Roche Laboratories, Inc. Tamiflu product information. Last updated August 2008. (Accessed on 15 May 2009 at http://www.rocheusa.com/products/tamiflu/pi.pdf) – prescribing information document from Roche.</ref><ref name="rossi 2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006.</ref>
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>{{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}}</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 review]]s 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 [[Centers for Disease Control and Prevention]] (CDC) recommends physicians prioritize which patients to whom they prescribe oseltamivir: specifically, people hospitalized with more severe illness, children younger than two years old, adults over 65, pregnant women, people with certain chronic medical or immunosuppressive conditions and adults under 19 on long-term [[aspirin]] therapy. However, they also advise children and adults presenting with suspected flu who have symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age.<ref>http://www.cdc.gov/H1N1flu/antiviral.htm</ref>


The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and [[Hoffmann-La Roche|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">{{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 }}</ref><ref name=PHE>{{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=2014-12-08}}</ref> The EMA did not change its labeling of the drug in response to the Cochrane study.<ref name=ReutersEMA>{{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=2015-09-24}}</ref>
The standard recommended dose incompletely suppresses viral replication in at least some patients with [[H5N1]] [[avian influenza]], increasing the risk of viral resistance and rendering therapy less effective.<ref name="de jong 2005">{{cite pmid|16371632}}</ref> Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.<ref name="de jong 2005"/><ref name="ward et al. 2005" >{{cite pmid|15709056}}</ref>


A 2014 review in the ''[[New England Journal of Medicine]]'' 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>{{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 }}</ref>
Clinical trials for an increased dosage began in May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam were inducted into the trial. The trial also included 100 cases of severe seasonal influenza from each of those countries and the United States. Half received the current standard dose, and half received a double dose, but for the standard length of time.<ref>{{cite news
|title = Double doses of Tamiflu for worst hit nations
|url = http://www.int.iol.co.za/index.php?art_id=nw20070329094318857C994284
|work = IOL
|date = 2007-03-29
|accessdate = 2009-07-29
}}</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>{{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 }}</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>{{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 }}</ref> The decrease in duration of sickness was about 18 hours.<ref>{{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 }}</ref>
====Coadministration with probenecid====
Coadministration of oseltamivir with [[probenecid]] has been suggested as a method to extend a limited supply of oseltamivir. Probenecid reduces [[renal]] excretion of the active metabolite of oseltamivir. One study showed that 500&nbsp;mg of probenecid given every six hours doubled both the peak plasma concentration (C<sub>max</sub>) and the [[Elimination half-life|half life]] of oseltamivir, increasing overall systemic exposure ([[Area under the curve|AUC]]) by 150 percent.<ref>{{cite pmid|11744606}}</ref> Although the evidence for this interaction comes from a study by Roche, it was publicized only in October 2005 by a doctor who had reviewed the data.<ref>{{cite doi|10.1038/438006a}}</ref> Probenecid was used in similar fashion during [[World War II]] to extend limited supplies of [[penicillin]]. It is still used to increase penicillin concentrations in serious infections.


===Otherwise healthy people===
===Efficacy===
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>{{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 }}</ref>


Two 2013 [[meta-analysis|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>{{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 }}</ref> while three other reviews found a decreased risk.<ref name=Ebe2013 /><ref>{{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 }}</ref><ref>{{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 }}</ref> Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day.<ref name=Burch2009>{{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 }}</ref> Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.<ref name=Jeff2014 />
On December 8, 2009, the [[Cochrane Collaboration]], which reviews medical evidence, in a review published in the [[British Medical Journal]], announced it had reversed its previous findings that the antiviral drug Tamiflu can ward off pneumonia and other serious conditions linked to influenza. They reported an analysis of 20 studies showed Tamiflu offered mild benefits in terms of duration of symptoms for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.<ref>Bloomberg.com http://www.bloomberg.com/apps/news?pid=20601100&sid=a9acc7qIJFdU</ref><ref>{{cite journal|url=http://www.bmj.com/content/339/bmj.b5106.full|title=Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis|journal=BMJ|year=2009|volume=339|page=b5106|doi=10.1136/bmj.b5106|pmid=19995812|pmc=2790574|author=Tom Jefferson, Mark Jones, Peter Doshi, Chris Del Mar}}</ref> These findings relate only to its use in healthy adults with influenza, not in patients judged to be at high risk of complications. Tamiflu may still be a useful drug for reducing the duration of symptoms, although for this use it still has yet to be compared with [[non-steroidal anti-inflammatory drug|NSAID]]s or [[paracetamol]].<ref>{{cite journal|url=http://www.bmj.com/content/339/bmj.b5405.full|title=We want raw data, now|author=Fiona Godlee|journal=BMJ|year=BMJ 2009|volume=339|page=b5405|doi=10.1136/bmj.b5405}}</ref>


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>{{cite web |url=http://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=2014-04-16 | date=30 March 2001 }}</ref>
===Possible side effects===
[[Image:Tamiflu.JPG|right|250px]]
Common [[adverse drug reaction]]s (ADRs) associated with oseltamivir therapy (occurring in over 1% of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: [[hepatitis]] and elevated [[liver]] [[enzyme]]s, rash, allergic reactions including [[anaphylaxis]], and [[Stevens-Johnson syndrome]].<ref name="rocheinfo"/><ref name="rossi 2006"/>


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 />
Various other ADRs have been reported in postmarketing surveillance, including: [[toxic epidermal necrolysis]], [[cardiac arrhythmia]], seizure, confusion, aggravation of diabetes, and [[hemorrhage|haemorrhagic]] [[colitis]].<ref name="rocheinfo"/>


=== Prevention ===
There are concerns that oseltamivir may cause dangerous psychological, [[neuropsychiatric]] side effects including [[self harm]] in some users. These dangerous side effects occur more commonly in children than in adults.<ref>{{cite web|url= http://www.medscape.com/viewarticle/547783?src=mp|title= Tamiflu May Be Linked to Risk for Self-Injury and Delirium|accessdate= 17 May 2008|last= Waknine|first= Yael |year= 2006|author=FDA|work= Medscape }}</ref> This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60% of the world's production.<ref name="Parry - Times">{{cite news|url=http://www.timesonline.co.uk/tol/news/world/asia/article1549260.ece|title=Japan issues Tamiflu warning after child deaths|last=Parry|first=Richard Lloyd |date=March 21, 2007 |work=The Times|accessdate=2009-05-05|location=London}}</ref> Concern has focused on teenagers, but problems have also been reported in children and adults.
{{As of| 2017}}, 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 />


{{As of|2011}}, reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease.<ref name=Cochrane2014 /><ref>{{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 }}</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 people|high risk persons.]]<ref name=Mich2013/>
In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include [[neurological]] and [[psychological]] disorders as possible adverse effects, including impaired consciousness, abnormal behavior, and [[hallucination]]s.<ref name="Parry - Times"/>


== Side effects ==
According to Japan's Health Ministry, between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or falls from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck.<ref name="Stock">{{cite news
[[File:Tamiflu.JPG|thumb|A package of capsules]]
|title=Japan to keep stockpiling Tamiflu
|url=http://www.smh.com.au/news/World/Japan-to-keep-stockpiling-Tamiflu/2007/03/28/1174761539222.html
|agency=Reuters
|newspaper=Sydney Morning Herald
|date=2007-03-28
|accessdate=2009-07-29
}}</ref> A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.<ref>{{cite news
|title=Japan finds 128 abnormal cases in Tamiflu probe
|work=Forbes
|agency=AFX News Limited
|url=http://www.forbes.com/feeds/afx/2007/04/05/afx3585482.html
|date=2007-05-04
|accessdate=2009-07-29
}}</ref><!--nobreak
--><ref>{{cite news
|title=Japan links Tamiflu to 2 teen suicides
|newspaper=San Francisco Chronicle
|url=http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2005/11/15/MNG29FO9K71.DTL
|last=Russell
|first=Sabin
|date=2005-11-15
|accessdate=2009-07-29
}}</ref><!--nobreak
--><ref name="Stock"/><!--nobreak
-->


Common [[adverse drug reaction]]s (ADRs) associated with oseltamivir therapy (occurring in over 1&nbsp;percent of people) 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 arrhythmias.<ref name=Cochrane2014 />
In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama City University, released the results of research involving around 2,800 children which found no difference in the behavior between those who took oseltamivir and those who did not. [[Chugai Pharmaceutical Co.]] (which produces oseltamivir in Japan) gave Yokota's department 10 million yen (about US$105,000) over five years.<ref>{{cite doi|10.1038/446358a}}</ref>


Postmarketing reports include [[hepatitis|liver inflammation]] and elevated liver enzymes, rash, allergic reactions including [[anaphylaxis]], [[toxic epidermal necrolysis]], [[cardiac arrhythmia|abnormal heart rhythms]], seizure, confusion, aggravation of diabetes, and [[hemorrhage|haemorrhagic]] [[colitis]] and [[Stevens–Johnson syndrome]].<ref name="rocheinfo">{{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=2005-11-03}}</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">{{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}}</ref>
To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalized in April 2009. Taking into account all degrees of abnormal behavior, including minor behavioral problems such as incoherent speech, the study found children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behavior that led to injury or death, it found those who had taken oseltamivir were 25% more likely to behave unusually.<ref>{{cite news
|title=Tamiflu linked to abnormal behaviour
|url=http://www.smh.com.au/world/science/tamiflu-linked-to-abnormal-behaviour-20090420-ac3y.html
|newspaper=Sydney Morning Herald
|agency=Associated Press
|date=2009-04-20
|accessdate=2009-07-29
}}</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>{{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=2007-09-27 | work = [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) }}</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">{{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}}</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">{{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}}</ref>
In November 2006, the United States [[Food and Drug Administration]] (FDA) amended the warning label to include the possible side effects of [[delirium]], hallucinations, or other related behavior.<ref>{{cite news|title=Flu Drug Tamiflu May Cause Odd Behavior in Children|date=2006-11-13|url=http://www.forbes.com/forbeslife/health/feeds/hscout/2006/11/13/hscout536084.html|work=Forbes}} {{Dead link|date=December 2010|bot=RjwilmsiBot}}</ref> This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then).<ref>Pediatric Advisory Committee. 2005. [http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf Pediatric safety update for Tamiflu]. Rockville (MD): U.S. Food and Drug Administration.</ref> The change to a more cautionary stance was attributed to 103 new reports the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.<ref>{{cite news
|title=FDA adds 'abnormal behavior' precaution to Tamiflu label
|agency=Associated Press
|newspaper =[[USA Today]]
|date=2006-11-14
|accessdate=2009-07-29
|url=http://www.usatoday.com/news/health/2006-11-13-tamiflu_x.htm
}}</ref>


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.<ref name="Tamiflu Label" /><ref name="Australian Government">{{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}}</ref> Dose adjustment may be needed in those with kidney problems.<ref name=AHFS2017 />
Roche points out that oseltamivir has been used to treat over 50 million people since 1999, and states the influenza may itself cause psychological problems.


== Mechanism of action ==
In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan.


Oseltamivir is a [[neuraminidase inhibitor]], a [[competitive inhibitor]] of influenza's [[neuraminidase]] enzyme. The enzyme cleaves the [[sialic acid]] which is found on [[glycoproteins]] on the surface of human cells that helps new virions to exit the cell, preventing new viral particles from being released.<ref name="Tamiflu Label" />
In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.<ref>{{cite news
|title=SKorea suspends Tamiflu use for young people - official
|url = http://www.forbes.com/feeds/afx/2007/04/05/afx3585631.html
|date=2007-04-05
|accessdate=2009-07-29
|work=Forbes
|agency=AFX News Limited
}}</ref>


== Resistance ==
A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009 <ref>www.bmj.com/ -</ref><ref>Examiner.com</ref> concluded that in otherwise healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about underreporting of side effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61%; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67% in otherwise healthy individuals and lower respiratory tract infections requiring antibiotics by 55%.
{{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>{{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 }}</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" ===
BMJ editor Dr. Fiona Godlee, said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."
{{As of|2010|12|15|df=US}}, the [[World Health Organization]] (WHO) reported 314 samples of the prevalent [[2009 flu pandemic|2009 pandemic H1N1 flu]] tested worldwide showed resistance to oseltamivir.<ref name="Update on oseltamivir resistance to influenza H1N1 (2009) viruses">{{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}}</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>{{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}}</ref>
There is evidence that oseltamivir has a modest effect in reducing some minor flu symptoms and contagiousness in otherwise healthy adults by about one day, but this is probably not the main reason most doctors are prescribing the drug for their patients. This less important benefit may well be offset by the risks of the drug.


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>{{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}}</ref>
====Mutagenesis, cell transformation, impairment of fertility, and carcinogenesis====


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.<ref>{{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=2014-04-19|access-date=2014-04-18}}</ref>
Although found to be nonmutagenic in the [[Ames test]] and the mouse [[micronucleus test]], Tamiflu tested positive in the Syrian hamster embryo (SHE) cell transformation test.<ref>http://www.drugs.com/pro/tamiflu.html</ref><ref>http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM183850.pdf</ref>


During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.<ref>{{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=2011-10-20}}</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>{{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=2011-10-20}}</ref>
==Resistance==
{{expert|date=November 2011}}
Mutations conferring resistance are single [[amino acid]] residue substitutions (His274Tyr) in the [[neuraminidase]] enzyme.<ref name="ward et al. 2005"/>


===2009 pandemic H1N1 flu===
=== Seasonal flu ===
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>{{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=2012-01-25}}</ref> In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible.<ref>{{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=2013-05-17}}</ref><ref>{{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=2012-06-10 | url-status=live | date=January 2012 | publisher=[[European Centre for Disease Prevention and Control]] (ECDC) }}</ref> In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir.<ref>{{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}}</ref>
{{As of|2010|12|df=US}}, the [[World Health Organization]] (WHO) reported 314 samples of the prevalent [[2009 flu pandemic|2009 pandemic H1N1 flu]] tested worldwide have shown resistance to oseltamivir.<ref name="Update on oseltamivir resistance to influenza H1N1 (2009) viruses"/>


=== H3N2 ===
A study published in the 2009 June issue of [[Nature Biotechnology]] also emphasized the need for augmentation of oseltamivir stockpiles with additional antiviral drugs, including [[zanamivir]] (Relenza), based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 neuraminidase (NA) were to acquire the oseltamivir-resistance mutation, which is currently widespread in seasonal H1N1 strains.<ref>{{cite journal |doi=10.1038/nbt0609-510|title=Extrapolating from sequence — the 2009 H1N1 'swine' influenza virus|author=Venkataramanan Soundararajan, Kannan Tharakaraman, Rahul Raman, S. Raguram, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan |date=9 June 2009 |journal=Nature Biotechnology|volume=27 |issue=6|url=http://www.nature.com/nbt/journal/v27/n6/full/nbt0609-510.html |pages=510–3 |pmid=19513050}}</ref>
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">{{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 }}</ref>


===Seasonal H1N1===
=== Influenza B ===
According to the CDC, oseltamivir is not very effective in the 2008 seasonal [[Influenza A virus subtype H1N1|H1N1 virus]] anymore due to acquired resistance in 99.6% of all 2008 seasonal H1N1 strains, up from 12% in 2007-2008 flu season.<ref>http://abcnews.go.com/Health/wireStory?id=6496257</ref>{{Dead link|date=February 2011}}


In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%.<ref>{{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 }}</ref> According to the CDC, {{as of|2019}}, transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare.<ref>{{Cite web|url=https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|title=Antiviral Drug Resistance among Influenza Viruses|date=2019-04-17|website=U.S. [[Centers for Disease Control and Prevention]] (CDC)|access-date=2020-01-29|archive-date=2014-02-13|archive-url=https://web.archive.org/web/20140213063541/http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm|url-status=live}}</ref>
===H3N2===
[[Mutant]] [[H3N2]] influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir.<ref name="kiso et al. 2004">{{cite pmid|15337401}}</ref> 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.<ref name="kiso et al. 2004"/>


=== H5N1 avian influenza "bird flu" ===
===Influenza B===
{{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.<ref name="pmid23279894">{{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 }}</ref>


=== H7N9 avian influenza ===
In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals who had not been treated with these drugs. The prevalence was 1.7%.<ref>{{cite pmid|17405969}}</ref> According to the CDC, as of October 3, 2009 no influenza B strains tested have shown any resistance to oseltamivir.
{{As of|2013}}, two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation.<ref>{{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 }}</ref>


== Pharmacokinetics ==
===H5N1 avian influenza===
Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver.<ref name = PK /> It has a [[volume of distribution]] of 23–26 litres.<ref name = PK /> Its [[elimination half-life|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 />
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.<ref>{{cite pmid|16228009}}</ref><ref>
{{cite web
|publisher=World Health Organization
|title=WHO intercountry-consultation. Influenza A/H5N1 in humans in Asia. Manila, Philippines, 6–7 May 2005
|date=May 2005
|url=http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/
}}</ref> 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 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.<ref name="moscona 2005">{{cite pmid|16371626}}</ref>


== History ==
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.<ref name="kiso et al. 2004"/> Resistant strains have also appeared in the [[EU]].<ref name=collins>{{cite journal| author=Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. | title=Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants | journal=Nature | year=2008 | pages=1258–61 | volume=453
[[File:Illicium verum00.jpg|thumb|right|Plate from [[François-Pierre Chaumeton]]'s 1833 "Flore Medicale"]]
| doi=10.1038/nature06956| pmid=18480754| issue=7199}}</ref><ref name=garcia-sosa>{{cite journal | author=Garcia-Sosa AT, Sild S, Maran U. | title=Design of Multi-Binding-Site Inhibitors, Ligand Efficiency, and Consensus Screening of Avian Influenza H5N1 Wild-Type Neuraminidase and of the Oseltamivir-Resistant H274Y Variant| journal=J. Chem. Inf. Model. | year=2008 | pages=2074–2080 | volume=48 | issue=10 | pmid=18847186 | doi=10.1021/ci800242z}}</ref>


Oseltamivir was discovered by scientists at [[Gilead Sciences]] using [[shikimic acid]] as a starting point for [[Oseltamivir total synthesis|synthesis]]; shikimic acid was originally available only as an extract of [[Chinese star anise]]; but by 2006, 30% of the supply was manufactured [[recombinant DNA|recombinantly]] in ''E. coli.''<ref name="TamifluSupply">{{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 }}</ref><ref name=Rawat>{{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 }}</ref> Gilead exclusively licensed their relevant patents to [[Hoffmann-La Roche|Roche]] in 1996.<ref name=WIPO>{{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=2009-12-08 }}</ref> The drug has not been patent-protected in Thailand, the Philippines, Indonesia, and several other countries.<ref name=WIPO />
H5N1 has not yet been transmissible from person to person, and is acquired by people working with or near infected poultry.


In 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults<ref>{{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 }}</ref> based on two double-blind, randomized, placebo-controlled clinical trials.<ref>{{cite web | work = U.S. Food and Drug Administration | url = http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_medr_P1.pdf | title = OseltamivirMedical Review | archive-url = https://web.archive.org/web/20140416231911/http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_medr_P1.pdf | archive-date=2014-04-16 }}</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">{{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 }}</ref>
==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.<ref>[http://www.wipo.int/wipo_magazine/en/2006/02/article_0005.html Avian Flu Drugs: Patent Questions], WIPO Magazine, April 2006</ref> Gilead is politically well connected: [[Donald Rumsfeld]] served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State [[George Shultz]] and the wife of former California Governor [[Pete Wilson]] serve on the board.<ref>Schwartz, Nelson (Oct 31, 2005). Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. ''Fortune'' (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes)
</ref>


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]]<ref>{{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 }}</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&nbsp;billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8&nbsp;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>{{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=2010-01-04| work = [[The Atlantic]] }}</ref>
Oseltamivir was widely used during the H5N1 avian influenza [[epidemic]] in [[Southeast Asia]] in 2005. In response to the epidemic, various governments &ndash; including those of the [[United Kingdom]], [[Canada]], [[Israel]], [[United States]] and [[Australia]] &ndash; stockpiled quantities of oseltamivir in preparation for a possible [[pandemic]].


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>{{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 = 2019-09-24 | archive-date = 2021-08-28 | 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}}</ref>
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.<ref>{{cite news
|title=Roche to suspend Tamiflu shipments to US private sector
|url=http://www.forbes.com/feeds/afx/2005/10/27/afx2305441.html
|agency=AFX News Limited
|work=Forbes
|date=2005-10-27
|accessdate=2009-07-29
}}</ref> 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.<ref>{{cite news
|title=Man dies of bird flu in Vietnam
|date=2005-11-09
|url=http://www.gulf-times.com/site/topics/article.asp?cu_no=2&item_no=59824&version=1&template_id=45&parent_id=25
|work=Gulf Times
|accessdate=2009-09-27
}}</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>{{cite news|title=Cipla's anti-flu drug gets nod|date=2009-05-14|work=[[The Times of India]]|access-date=2009-07-29|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=2012-10-23}}</ref>
On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir.<ref>{{cite news
|author=Tran Van Minh
|title=Vietnam to produce generic bird-flu drug
|date=2005-11-09
|agency=Associated Press
|newspaper=The Washington Post
|accessdate=2009-07-29
|url=http://www.washingtonpost.com/wp-dyn/content/article/2005/11/09/AR2005110900384.html
}}</ref> The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand.<ref>{{cite news
|title=Roche lets Vietnam make Tamiflu
|author=Le Thang Long
|date=2005-11-10
|newspaper=The Standard
|accessdate=2009-07-29
|url=http://www.thestandard.com.hk/news_print.asp?art_id=5316&sid=5402626
}}</ref> The first Thai generic oseltamivir was produced in February 2006 and was to have been available to the public in July 2006.


[[File:tamiflu-display-trailer-miami.jpg|thumb|right|300px|Marketing display used at festivals features a person living in a hermetically sealed environment]]
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.<ref>Shannon Brownlee and Jeanne Lenzer (November 2009) [http://www.theatlantic.com/doc/200911/brownlee-h1n1 Does the Vaccine Matter?], ''The Atlantic''</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">{{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 }}</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">{{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=2013-10-27}}</ref>
In December 2005, Roche also 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.<ref name="people 1">{{cite news
|title=China-made Tamiflu approved for production
|work=People's Daily
|date=2006-06-13
|url=http://english.people.com.cn/200606/13/eng20060613_273717.html
|accessdate=2009-07-29
}}</ref><ref>{{cite news
|title=Making Tamiflu
|date=2006-03-20
|work=Chemical & Engineering News
|last=McCoy
|first=Michael
|url=http://pubs.acs.org/cen/news/84/i12/8412notw7.html
|accessdate=2009-07-29
}}</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">{{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 }}</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>{{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 }}</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 />
In late 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.<ref>{{cite news
|title=WHO puts Tamiflu maker on alert after suspected human-to-human transmission
|date=2006-05-27
|work=Medical News Today
|accessdate=2009-07-29
|url=http://www.medicalnewstoday.com/articles/44155.php
}}</ref>


== Veterinary use ==
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.<ref>{{cite news
There have been{{when|date=January 2020}} reports of oseltamivir reducing disease severity and hospitalization time in [[canine parvovirus]] infection.<ref>{{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 }}</ref> The drug may limit the ability of the virus to invade the [[crypt (anatomy)|crypt]] cells of the [[small intestine]] and decrease gastrointestinal [[bacteria]]l colonization and toxin production.<ref>{{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 = 2007-06-09 | archive-date = 2021-08-28 | 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 }}</ref>
|title=Cipla's anti-flu drug gets nod
|date=2009-05-14
|work=Times of India
|accessdate=2009-07-29
|url=http://timesofindia.indiatimes.com/Business/India-Business/Ciplas-anti-flu-drug-gets-nod/articleshow/4526891.cms
}}</ref>
[[Image:tamiflu-display-trailer-miami.jpg|thumb|right|300px|Marketing display used at festivals features a person living in a hermetically sealed environment]]


==Research==
===Production shortage/shikimic acid===
Oseltamivir has been deemed ineffective at treating [[COVID-19]], consistent with the [[SARS-CoV-2|SARS-CoV-2 virus]] lacking influenza's neuraminidase enzyme.<ref>{{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 }}</ref>
In early 2005, Roche announced a production shortage. (See [[#Pandemic Fears|Pandemic Fears]], above). 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.<ref name="roche.com"/><ref name="Boost"/><ref>{{cite press release
|title=Roche update on Tamiflu for pandemic influenza preparedness
|date=2006-03-16
|url=http://www.roche.com/med-cor-2006-03-16
|accessdate=2009-07-29
}}</ref>


== See also ==
While current demand for seasonal influenza treatment and pandemic stockpiling are being met, it is unclear what the situation would be if a pandemic actually started. Doctors are now testing a doubling of the standard dose with the hope it would cut H5N1 influenza virus death rate.<ref>{{cite news
[[Oseltamivir total synthesis]]
|title=Doctors test double Tamiflu dose to cut H5N1 deaths
|agency=Retuers
|date=2007-03-28
|accessdate=2009-07-29
|url=http://www.alertnet.org/thenews/newsdesk/HKG133031.htm
}}</ref> If this became the new standard, it would decrease the effective supply.


== References ==
According to Roche, the major bottleneck in oseltamivir production is the availability of [[shikimic acid]], which cannot be synthesised economically and is only effectively isolated from Chinese [[star anise]], an ancient cooking spice; the herb is also used in [[traditional Chinese medicine]]. Although most [[autotroph]]ic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as of 2005). Star anise is grown in four provinces in China and harvested between March and May. It is also produced in Lang Son province, Vietnam. The shikimic acid is extracted from the seeds in a ten-stage process. Thirteen grams of star anise make 1.3&nbsp;grams of shikimic acid, which can be made into 10 oseltamivir 75&nbsp;mg capsules. Ninety percent of the harvest is already used by Roche in making oseltamivir.
{{Reflist}}


== Further reading ==
Some academic experts{{Who|date=April 2009}} and other drug companies are disputing the difficulty of producing [[shikimic acid]] by means other than [[star anise]] extraction. An alternative method for production of the acid involves fermentation of genetically modified bacteria. Recently, biosynthetic pathways in ''[[Escherichia coli]]'' have been enhanced to allow the organism to accumulate enough shikimic acid to be used commercially.<ref>{{cite doi|10.1038/nrd1917}}</ref><ref>
{{refbegin|30em}}
{{cite doi|10.1016/j.ymben.2003.09.001}}</ref><ref>
* {{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 }}
{{cite doi|10.1002/bit.20546}}</ref> Canadian generic drug company [[Apotex]] is attempting to modify oseletamivir to use a synthetic alternative to shikimic acid. Other potential sources of shikimic acid include the [[sweetgum]] and [[Ginkgo biloba|ginkgo]] trees. [[Quinic acid]], derived from the bark of the [[cinchona]] tree, is a potential alternative base material for the production of oseltamivir. In addition, [[aminoshikimic acid]], biosynthesized via fermentation of genetically modified bacteria (Guo and Frost),<ref>{{cite doi|10.1021/ol049666e}}</ref> is a very promising alternative starting material for the production of oseltamivir.
* {{cite journal | vauthors = Wong SS, Yuen KY | title = Avian influenza virus infections in humans | journal = Chest | volume = 129 | issue = 1 | pages = 156–68 | date = January 2006 | pmid = 16424427 | doi = 10.1378/chest.129.1.156 | pmc = 7094746 }}
* {{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 }}
* {{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=http://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-changes-influenza-drug-tamiflu-oseltamivir-phosphate }}
{{refend}}


== External links ==
The multistep synthesis above shows that although the major bottleneck for Roche may be the availability of shikimic acid, production of oseltamivir is very involved. Increasing production volume (by Roche or others) would require construction of extensive new facilities (which may not be amenable to scaleup and, even if identical on paper, may not necessarily produce acceptable yields), and even if current facilities could handle a larger feedstock quantity, there would be a delay in production as the material makes it down the pipeline (~6 months or so). Producing large amounts of Tamiflu not only takes months to complete, but is also hazardous. Some of the steps in the synthesis require careful handling and relatively mild reaction conditions, as they involve the use of potentially explosive azide chemistry. Roche has explored ways to speed up production (Chimia 2004, 58, 621). It has developed an azide-free allylamine route from the epoxide to Tamiflu. It has also crafted routes that do not rely on (–)-shikimic acid: a Diels-Alder-based one that uses furan and ethyl acrylate as starting materials, and another that relies on catalytic hydrogenation of an [[isophthalic acid]] derivative followed by enzymatic desymmetrization. In addition, Frost and Guo at [[Michigan State University]] have developed a microbial synthesis of aminoshikimic acid, which could reduce the need for azide chemistry if used as a starting material.<ref>{{cite journal| author= Frost, John. and Guo, Jiantao.
{{Commons and category|Oseltamivir|Oseltamivir}}
| title = Synthesis of oseltamivir carboxylates, US patent 2007/0190621 A1
* {{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 }}
| year = 2007
| url = http://www.google.com/patents?id=ZCeBAAAAEBAJ&dq=%22Synthesis+of+oseltamivir+carboxylates%22
}}</ref>

==Personal stockpiling==
A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states issued advisories strongly discouraging this practice. Production has since caught up with current demand ([[#Production shortage/shikimic acid|see above]]).

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.<ref name="moscona 2005"/> Many stockpilers will only have ten 75&nbsp;mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.<ref name="de jong 2005" />

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 who actually have 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.<ref name="roche.com">{{cite press release
|title=Tamiflu readily available for 2006/2007 season
|publisher=Roche
|date=2006-10-02
|accessdate=2009-07-29
|url=http://www.roche.com/med-cor-2006-10-02
}}</ref>

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 counterfeit Tamiflu appearing outside of the United States: incorrectly labelled tablets found in Holland, which contained only vitamin C and lactose.<ref>{{cite pmid|15070787}}</ref>

An argument in favor of individual stockpiling is that Roche is on the record as saying that without more orders, they may have to actually curtail production.<ref name="Boost">{{cite news
|title=Roche boosts Tamiflu production; CDC cites signs of hoarding
|work=CIDRAP
|url=http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/mar1606roche.html
|date=2006-03-16
|accessdate=2009-07-29
}}</ref> 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 anecdotal reports of oseltamivir reducing disease severity and hospitalization time in [[canine parvovirus]] infection. The drug may limit the ability of the virus to invade the [[crypt (anatomy)|crypt]] cells of the [[small intestine]] and decrease gastrointestinal [[bacteria]]l colonization and toxin production.<ref>{{cite web | last = Macintire | first = Douglass K. | title = Treatment of Parvoviral Enteritis | work = Proceedings of the Western Veterinary Conference | year = 2006 | url = http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=wvc2006&PID=pr12457&O=VIN | accessdate = 2007-06-09 }}</ref>

==Chemical synthesis==
{{Main|Oseltamivir total synthesis}}

Aqueous solubility of oseltamivir in form of phosphate salt is 588&nbsp;mg/ml at 25°C. <ref>http://www.medicinescomplete.com/mc/ahfs/current/a399040.htm</ref>

The current production method features a number of reaction steps, two of which involve potentially hazardous [[azide]]s. A reported azide-free Roche synthesis of the drug is summarized graphically below:

[[Image:Tamiflu2.gif|center|synthesis of Tamiflu]]

==See also==
*[[Amantadine]] and [[rimantadine]] - [[M2 protein|M2]] inhibitors, other drugs used for influenza treatment
*[[Avian influenza]]
*[[H5N1]]
*[[Influenza]]
*[[Relenza]] / [[Zanamivir]] - another [[neuraminidase inhibitor]]

==References==
{{Reflist|2}}

==Further reading==
*Pollack, Andrew. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. ''The New York Times'' (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html)
*{{cite pmid|16424427}}
*{{cite doi|10.1021/jo980330q}}
*{{cite doi|10.1021/jo005702l}}
*{{cite doi|10.2533/000942904777677605}}
*{{cite doi|10.1021/ja0616433}}
*{{cite pmid|1951305}}

==External links==
{{Commons+cat|Oseltamivir|Oseltamivir}}
*[http://www.bmj.com/cgi/content/full/339/dec07_2/b5106 New: Neuraminidase inhibitors have modest effectiveness]
*[http://www.tamiflu.com www.tamiflu.com] – Roche's page on Tamiflu (oseltamivir)
*[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699040.html MedlinePlus Drug Information: oseltamivir (systemic)] –Last Revised - 05/01/2009 Advice for the Patient
*[http://www.pharmasquare.org/flash/Tamiflu.html Pharmasquare – Tamiflu Mode of Action] – [[Macromedia Flash|Flash]] animation showing the mode of action of oseltamivir
*[http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107838.htm FDA information page on oseltamivir]
*[http://www.niaid.nih.gov/factsheets/fludrugs.htm Flu Drugs FAQ] – U.S. National Institute of Allergy and Infectious Diseases
*Reto U. Schneider: [http://www.nzzfolio.ch/www/d80bd71b-b264-4db4-afd0-277884b93470/showarticle/52e8d9fe-7076-4440-998f-b0afe1d1dd31.aspx 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).
*[http://www.journalresponse.com/search.php?query=Oseltamivir Journal Response – Oseltamivir] – abstracts of recent oseltamivir research
* [http://www.bi-mar.com//Pomeranian_Health_Tamiflu.aspx * TREATMENT OF PARVOVIRUS & KENNEL COUGH USING TAMIFLU<nowiki></nowiki>]


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