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Side effects include psychiatric symptoms and increased rates of vomiting.<ref name=Cochrane2012>{{cite journal |author=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=Cochrane Database Syst Rev |volume=4 |issue= |pages=CD002744 |year=2012 |pmid=22513907 |doi=10.1002/14651858.CD002744.pub4 |editor1-last=Harnden |editor1-first=Anthony|last2=Shun-Shin |last3=Gill |last4=Perera |last5=Harnden }}</ref><ref>{{cite journal|last1=Jefferson|first1=T|last2=Jones|first2=M|last3=Doshi|first3=P|last4=Spencer|first4=EA|last5=Onakpoya|first5=I|last6=Heneghan|first6=CJ|title=Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.|journal=BMJ (Clinical research ed.)|date=Apr 9, 2014|volume=348|pages=g2545|pmid=24811411|pmc=3981975|doi=10.1136/bmj.g2545}}</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=AHFS2014>{{cite web|title=Cephalexin|url=http://www.drugs.com/monograph/cephalexin.html|publisher=The American Society of Health-System Pharmacists|accessdate=Apr 21, 2014}}</ref><ref>{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|work=Australian Government|accessdate=22 April 2014|date=3 March 2014}}</ref>
Side effects include psychiatric symptoms and increased rates of vomiting.<ref name=Cochrane2012>{{cite journal |author=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=Cochrane Database Syst Rev |volume=4 |issue= |pages=CD002744 |year=2012 |pmid=22513907 |doi=10.1002/14651858.CD002744.pub4 |editor1-last=Harnden |editor1-first=Anthony|last2=Shun-Shin |last3=Gill |last4=Perera |last5=Harnden }}</ref><ref>{{cite journal|last1=Jefferson|first1=T|last2=Jones|first2=M|last3=Doshi|first3=P|last4=Spencer|first4=EA|last5=Onakpoya|first5=I|last6=Heneghan|first6=CJ|title=Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.|journal=BMJ (Clinical research ed.)|date=Apr 9, 2014|volume=348|pages=g2545|pmid=24811411|pmc=3981975|doi=10.1136/bmj.g2545}}</ref>


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The U.S. and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.<ref name="Cohen 2014" /><ref name=FDApedsafe>[http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf "Pediatric safety update for Tamiflu"]. [[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="Medscape">{{cite news|url= http://www.medscape.com/viewarticle/547783 |title= Tamiflu May Be Linked to Risk for Self-Injury and Delirium|accessdate= 17 May 2008|last= Waknine|first= Yael |year= 2006 |work= Medscape}}</ref><ref>[http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf "Pediatric safety update for Tamiflu"]. [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA)</ref><ref name=FDApedsafe/> 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.
The U.S. and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.<ref name="Cohen 2014" /><ref name=FDApedsafe>[http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf "Pediatric safety update for Tamiflu"]. [[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="Medscape">{{cite news|url= http://www.medscape.com/viewarticle/547783 |title= Tamiflu May Be Linked to Risk for Self-Injury and Delirium|accessdate= 17 May 2008|last= Waknine|first= Yael |year= 2006 |work= Medscape}}</ref><ref>[http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf "Pediatric safety update for Tamiflu"]. [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA)</ref><ref name=FDApedsafe/> 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|last=Cohen|first=D.|title=Oseltamivir: another case of regulatory failure?|journal=BMJ|date=9 April 2014|volume=348|issue=apr09 8|pages=g2591–g2591|doi=10.1136/bmj.g2591}}</ref>
<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|last=Cohen|first=D.|title=Oseltamivir: another case of regulatory failure?|journal=BMJ|date=9 April 2014|volume=348|issue=apr09 8|pages=g2591–g2591|doi=10.1136/bmj.g2591}}</ref>

It is [[pregnancy category]] C in the United States and category B in Australia.<ref name=2014Label/><ref>[http://www.roche-australia.com/content/dam/internet/corporate/roche/en_AU/files/anti_virals/tamiflu-pi.pdf Tamiflu Australian Label]</ref>


==Resistance==
==Resistance==

Revision as of 02:25, 8 December 2014

Oseltamivir
Clinical data
Trade namesTamiflu
AHFS/Drugs.comMonograph
MedlinePlusa699040
License data
Pregnancy
category
  • AU: B1
Routes of
administration		oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability>80%[1]
Protein binding42% (parent drug), 3% (active metabolite)[1]
MetabolismHepatic, to oseltamivir carboxylate[1]
Elimination half-life1-3 hours, 6-10 hours (active metabolite)[1]
ExcretionUrine (>90% as oseltamivir carboxylate), faeces[1]
Identifiers
  • ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H28N2O8P
Molar mass312.4 g/mol g·mol−1
3D model (JSmol)
  • O=C(OCC)/C1=C/[C@@H](OC(CC)CC)[C@H](NC(=O)C)[C@@H](N)C1
  • InChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1 checkY
  • Key:VSZGPKBBMSAYNT-RRFJBIMHSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Oseltamivir INN /ɒsəlˈtæm[invalid input: 'ɨ']vɪər/, marketed under the trade name Tamiflu, is an antiviral medication used to prevent and treat influenza A and influenza B (flu).[2] The drug is taken orally.

The Infectious Disease Society of America and the United States' Centers for Disease Control and Prevention recommend the use of oseltamavir for people at high risk for complications and those at lower risk who present within 48 hours of first symptoms of infection.[3][4][5][6] However these recommendations are controversial.[7] Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[8][9] They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.[8][9]

Side effects include psychiatric symptoms and increased rates of vomiting.[10][11]

It was the first orally active neuraminidase inhibitor commercially developed.[12] It was discovered and developed by US-based Gilead Sciences, which licensed the exclusive rights to Roche in 1996.[13] It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical use

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

Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.[14][15]

The Infectious Disease Society of America, the United States' Centers for Disease Control and Prevention, the European Centers for Disease Control, and the American Academy of Pediatrics recommend the use of oseltamavir for people at high risk for complications and those at lower risk who present within 48 hours of first symptoms of infection.[3][4][5][6][16]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[17]

Efficacy

Oseltamivir's risk-benefit ratio is controversial. Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[8] There is low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1% to 12% in those exposed.[8] It is unclear whether it affects the risk of needing to be hospitalized or the risk of death.[8] While it reduces the duration of symptoms by a little less than a day one review found that it does not reduce serious complications among people seeking care for flu-like symptoms, though pneumonia was reduced among those infected with influenza.[9] No evidence was found regarding whether treatment changes the risk of hospitalization in the elderly or other high risk populations, and that it is unclear if it affects rates of death.[8][9] When the analysis was restricted to people with confirmed infection, a Cochrane review found unclear evidence of change in the risk of complications such as pneumonia.[18] A systematic review of systematic reviews found that it prevented influenza, but recommended against its use in healthy, low risk persons due to cost, the risk of resistance development, and side effects. This review concluded it might be useful for prevention in high risk persons who had not been vaccinated. No evidence was found to support the usefulness of oseltamivir for the prevention of serious complications of influenza, as the trials were designed to demonstrate the more trivial outcome of "reduction of duration of symptoms" and were not designed or powered to evaluate impact on more clinically relevant outcomes.[8] A 2011 review found that oseltamivir reduces the risk of lower respiratory tract complications that require antibiotic treatment by 28%,[19] and another 2011 review found that oseltamivir is effective for preventing influenza in healthy adults and in elderly people at a high risk of the disease.[20]

In 2014 Cochrane published an updated systematic review using all of the previously unreleased data, concluding that oseltamivir does not reduce hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. They concluded that guidance should be revised to take account of the evidence of small benefit and increased risk of harms. Moreover the authors stated that their conclusions are similar to those reached by the U.S. FDA at the time of approval; that randomized clinical trial data supported the use of oseltamivir for the prevention and treatment of flu symptoms only, and didn't support claims of prevention of infection, transmission, or complications. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection.[18][21]

The United States and European Centers for Disease Control, Public Health England, Infectious Disease Society of America, and the American Academy of Pediatrics, and Roche (the originator) reject the Cochrane Collaboration conclusions, arguing that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from patients not infected with influenza.[4][5][6][22][23] The EMA did not change its labelling of the drug in response to the Cochrane study.[24]

Side effects

A package of capsules

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the number needed to harm was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious heart rhythm problems.[18]

Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome.[25][26] The incidence of these adverse outcomes is unknown, and a causative role for oseltamivir has not been established.

The U.S. and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.[27][28] The frequency of these appears to be low and a causative role for oseltamivir has not been established.[29][30][28] 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. [18] Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.[27]

It is pregnancy category C in the United States and category B in Australia.[15][31]

Resistance

Influenza (flu)
H1N1 virus
Types
Vaccines
Treatment
Pandemics
Outbreaks
See also

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[32] Meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date.[32] In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.[3]

H1N1 flu or "Swine flu"

As of December 15, 2010, the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.[33]

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.[3]

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.[34]

While there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013 widespread transmission of oseltamivir-resistant pH1N1 has not occurred.[35]

Seasonal flu

Resistance to Oseltamivir was widespread in seasonal flu from 2007-2009. In the 2007-2008 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.[36] In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance.[37] All Oseltamivir-resistant strains maintained sensitivity to zanamivir.

Resistance to Oseltamivir has been low in seasonal flu from 2009-2012. In the 2010-2011 flu season, the US CDC reported maintained Oseltamivir sensitivity in 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B.[38] As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all seasonal flu samples tested since October 2011.[39][40] In the US in the season 2013-2014 only 1% of 2009 H1N1 viruses have shown resistance to oseltamivir. No other influenza viruses have shown resistance to oseltamivir.[41]

H3N2

Three studies have found resistance in 0%, 3.3%, and 18% of subjects.[32] In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations.[42]

Influenza B

In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals having not been treated with these drugs. The prevalence was 1.7 percent.[43] According to the CDC, as of October 3, 2009 no influenza B strains tested have shown any resistance to oseltamivir.

H5N1 Avian influenza "Bird flu"

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.[44]

H7N9 Avian influenza

There was emergence of oseltamivir-resistant virus with the Arg292Lys mutation in two patients among 14 adults infected with A(H7N9) during treatment with oseltamivir.[45]

Mechanism of action

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

Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor of the activity of the viral neuraminidase (NA) enzyme upon sialic acid, found on glycoproteins on the surface of normal host cells. By blocking the activity of the enzyme, oseltamivir prevents new viral particles from being released through the cleaving of terminal sialic acid on glycosylated hemagglutinin and thus fail to facilitate virus release.[25]

Pharmacokinetics

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

History

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

Oseltamivir was discovered by scientists at Gilead using shikimic acid as a starting point for synthesis; shikimic acid was originally available only as an extract of Chinese star anise but by 2006 30% of the supply was manufactured recombinantly in E. coli.[46][47] Gilead exclusively rights to their patents to Roche in 1996.[13] The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia, and several other countries.[13] The patents for oseltamivir begin to expire in 2016.[13]

In 1999 the FDA approved oseltamivir for treatment of influenza in adults[48] based on two double-blinded, randomized, placebo-controlled clinical trials.[49] In June 2002 EMA approved oseltamivir for prophylaxis and treatment of influenza. In 2003 a pooled analysis of 10 randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults.[50]

Oseltamivir was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. In response to the epidemic, various governments – including those of the United Kingdom, Canada, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic[51] and there were worldwide shortages of the drug, driven by the high demand for stockpiling.[46] 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.[52]

In 2006 a Cochrane review raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness.[53] The Kaiser 2003 paper drove the result in the meta-analysis.

In December 2008, the Indian drug company, Cipla won ia case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.[54]

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

In 2009 a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009 WHO declared the A/H1N1 influenza a “pandemic”.[55] NICE, the CDC, WHO, and the European Centre for Disease Prevention maintained their recommendation to use oseltamivir, which again caused governments around the world to stockpile the drugs in case of a pandemic.[56][57]

From 2010 to 2012 Cochrane requested the full clinical study reports of their trials from Roche, which did not provide them, but in 2011 a freedom of information request to the European Medicines Agency provided Cochrane with the clinical study reports from 16 Roche oseltamivir trials. In 2012 the Cochrane team published the interim version of the Cochrane review based on EMA’s incomplete clinical study reports, but in 2013 Roche released 77 full clinical study reports of oseltamivir trials, after GSK released the data on zanamivir studies.[citation needed] In 2014 Cochrane published an updated review based solely on full clinical study reports and regulatory documents. In the mean time buying a strategic reserve of Tamiflu the US has spent more than $1.3 billion.[55] In 2013 the UK National Audit Office, said that the government spent £560m (€670; $930m) on antivirals for stockpiling between 2006 and 2013: £424m on oseltamivir and £136m on zanamivir.[58]

Veterinary use

There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection.[59] The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production.[60]

See also

References

  1. ^ a b c d e f g h i j Davies, BE (April 2010). "Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations" (PDF). The Journal of antimicrobial chemotherapy. 65 Suppl 2: ii5–ii10. doi:10.1093/jac/dkq015. PMC 2835511. PMID 20215135.
  2. ^ Burch J; Corbett M; Stock C; et al. (September 2009). "Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis". Lancet Infect Dis. 9 (9): 537–45. doi:10.1016/S1473-3099(09)70199-9. PMID 19665930. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  3. ^ a b c d "CDC Online Newsroom - "Have You Heard?" Archive: 2014 - Influenza A Variant Virus". Cite error: The named reference "CDC" was defined multiple times with different content (see the help page).
  4. ^ a b c "Recommendations for Prevention and Control of Influenza in Children, 2014-2015". Pediatrics. September 2014. doi:10.1542/peds.2014-2413. PMID 25246619.
  5. ^ a b c European Centre for Disease Prevention and Control (02 Jun 2014). "New and updated evaluations of neuraminidase inhibitors for preventing and treating influenza published". {{cite web}}: Check date values in: |date= (help)
  6. ^ a b c "IDSA : IDSA Continues to Recommend Antivirals for Influenza". Retrieved April 24, 2014.
  7. ^ Brownlee, Shannon (19 February 2013). "Tamiflu: Myth and Misconception". The Atlantic. Retrieved 7 December 2014.
  8. ^ a b c d e f g Coenen, B; Van Puyenbroeck, K; Verhoeven, V; Vermeire, E; Coenen, S; Verhoeven, Veronique; Vermeire, Etienne; Coenen, Samuel (2013). Jefferson, Tom (ed.). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews". PLoS ONE. 8 (4): e60348. Bibcode:2013PLoSO...860348M. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  9. ^ a b c d Ebell, MH; Call, M; Shinholser, J (April 2013). "Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials". Family practice. 30 (2): 125–33. doi:10.1093/fampra/cms059. PMID 22997224.
  10. ^ Wang K, Shun-Shin M, Gill P, Perera R, Harnden A; Shun-Shin; Gill; Perera; Harnden (2012). Harnden, Anthony (ed.). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)". Cochrane Database Syst Rev. 4: CD002744. doi:10.1002/14651858.CD002744.pub4. PMID 22513907.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Jefferson, T; Jones, M; Doshi, P; Spencer, EA; Onakpoya, I; Heneghan, CJ (Apr 9, 2014). "Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments". BMJ (Clinical research ed.). 348: g2545. doi:10.1136/bmj.g2545. PMC 3981975. PMID 24811411.
  12. ^ Agrawal, R; Rewatkar, PV; Kokil, GR; Verma, A; Kalra, A (Jul 2010). "Oseltamivir: a first line defense against swine flu". Medicinal chemistry (Shariqah (United Arab Emirates)). 6 (4): 247–51. PMID 20843284.
  13. ^ a b c d WIPO April 2006 Avian Flu Drugs: Patent Questions
  14. ^ "Tamiflu". The American Society of Health-System Pharmacists. Retrieved Dec 12,2014, 2014. {{cite web}}: Check date values in: |accessdate= (help)
  15. ^ a b Tamiflu label Linked from Drugs@FDA Label history page
  16. ^ CDC Influenza Antiviral Medications: Summary for Clinicians
  17. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  18. ^ a b c d Jefferson T, Jones MA, Doshi P; Doshi; Del Mar; Hama; Thompson; Spencer; Onakpoya; Mahtani; Nunan; Howick; Heneghan; et al. (2014). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". Cochrane Database Syst Rev. 4: CD008965. doi:10.1002/14651858.CD008965.pub4. PMID 24718923. {{cite journal}}: Explicit use of et al. in: |author2= (help); Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)CS1 maint: multiple names: authors list (link)
  19. ^ Hernan, M. A.; Lipsitch, M. (15 June 2011). "Oseltamivir and Risk of Lower Respiratory Tract Complications in Patients With Flu Symptoms: A Meta-analysis of Eleven Randomized Clinical Trials". Clinical Infectious Diseases. 53 (3): 277–279. doi:10.1093/cid/cir400.
  20. ^ Jackson, RJ; Cooper, KL; Tappenden, P; Rees, A; Simpson, EL; Read, RC; Nicholson, KG (January 2011). "Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review". The Journal of infection. 62 (1): 14–25. PMID 20950645.
  21. ^ "Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087".
  22. ^ "www.gov.uk" (PDF).
  23. ^ "Recommendations for Prevention and Control of Influenza in Children, 2014-2015". Pediatrics. September 2014. doi:10.1542/peds.2014-2413. PMID 25246619.
  24. ^ "Researchers, regulators and Roche row over stockpiled drug Tamiflu | Reuters".
  25. ^ a b Tamiflu Prescribing Information
  26. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  27. ^ a b Cohen, D. (9 April 2014). "Oseltamivir: another case of regulatory failure?". BMJ. 348 (apr09 8): g2591–g2591. doi:10.1136/bmj.g2591.
  28. ^ a b "Pediatric safety update for Tamiflu". U.S. Food and Drug Administration (FDA)
  29. ^ Waknine, Yael (2006). "Tamiflu May Be Linked to Risk for Self-Injury and Delirium". Medscape. Retrieved 17 May 2008.
  30. ^ "Pediatric safety update for Tamiflu". U.S. Food and Drug Administration (FDA)
  31. ^ Tamiflu Australian Label
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Further reading

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