|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Pregnancy cat.||B1 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Protein binding||42% (parent drug), 3% (active metabolite)|
|Metabolism||Hepatic, to oseltamivir carboxylate|
|Half-life||1-3 hours, 6-10 hours (active metabolite)|
|Excretion||Urine (>90% as oseltamivir carboxylate), faeces|
|Mol. mass||312.4 g/mol|
|(what is this?)|
Oseltamivir INN //, marketed under the trade name Tamiflu, is an antiviral licensed to prevent or slow the spread of influenza A and influenza B (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell. The drug is taken orally in capsules or as a suspension. 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. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences, and is marketed by Genentech.Gilead licensed the exclusive rights to Roche in 1996. The starting material of the Tamiflu production process is shikimic acid. It is extracted from the pods of the Chinese star anise, grown in mountain provinces in the south west of China.
Oseltamivir's benefits in those who are otherwise healthy do not appear to outweigh its risks. No benefit of treatment, on hospitalization or risk of death has been found in randomized trials in those people at high risk for complications or the elderly. The United States Centers for Disease Control continues to recommend the use of oseltamavir treatment for people at high risk for complications and the elderly and those at lower risk who present within 48 hours of first symptoms of infection. Prior to 2013, oseltamivir's effectiveness was debated as its manufacturer, Roche, originally refused to release the data from all of its trials for independent analysis. Together, these published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day. It is unclear whether this medication affects transmission of influenza in adults. Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.
As of December 15, 2010[update], the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir. However, the predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.
- 1 Medical use
- 2 Adverse effects
- 3 Resistance
- 4 Mechanism of action
- 5 Pharmacokinetics
- 6 History
- 7 Commercial issues
- 8 Personal stockpiling
- 9 Veterinary use
- 10 Chemical synthesis
- 11 Manufacturing
- 12 See also
- 13 References
- 14 Further reading
- 15 External links
When used for treatment or prevention in those that are otherwise healthy, it does not appear to have benefits that outweigh the risks.
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. Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.
There is low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1% to 12% in those exposed. It is unclear whether it affects the risk of needing to be hospitalized or the risk of death. Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses. The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.
A 2012 Cochrane review maintains that significant parts of the clinical trials still remains unavailable for public scrutiny, and that the available evidence is not sufficient to conclude that oseltamivir decreases hospitalizations, complications or transmission from influenza-like illnesses. On April 10, 2014 Cochrane published a systematic review using all of the previously unreleased data, concluding that it doesn't 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.
Roche commissioned an independent reanalysis of its data in 2011. One of the authors had received income from an organization sponsored by Roche previously but they were not funded by Roche for this analysis. They concluded that early oseltamivir use for influenza-like illness reduced the number of "lower respiratory tract infection treated with antibiotics" in healthy adults and children. But "lower respiratory tract infection treated with antibiotics" was not the primary or secondary endpoint in the original trials, but was a reconstructed endpoint from the database. No benefit occurred in those without an infection with influenza.
The CDC continues to recommend oseltamivir for a number of uses. These recommendations are based in part on the results of observational studies that suggest that neurinamidase inhibitors reduced mortality in high risk patients. The CDC argues that the clinical trials included in meta analyses conducted by the Cochrane Collaboration and others include too few high risk patients to meaningfully examine the utility of neurinamidase inhibitors in preventing serious complications, and that multiple observational studies suggest reduced mortality in hospitalized and other high risk groups. In particular, the CDC analysis relies on a large meta analysis of cohort studies of adult patients hospitalized during the 2009 H1N1 pandemic, which found a 19% reduction in mortality overall and a 50% reduction in mortality among adults treated within 48 hours of symptom onset. This study failed to find a statistically significant beneficial effect of treatment on survival in children and the study was funded by the manufacturer. This and other observational studies are subject to residual confounding and bias
Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. In adults, oseltamivir increased the risk of nausea for which number needed to harm were 28 and for vomiting 22. So for ever 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir induced vomiting also. Number needed to harm were 19. So for ever 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, and renal and psychiatric events. Its effect on the heart is unclear: it may reduce cardiac symptoms, but also induce serious heart rhythm problems.
Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.
Neuropsychiatric side effects
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. This included events such as nervousness, aggression, hallucinations, psychosis, suicide ideation and paranoia. Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.Neither the US FDA nor the European Medicines Agency found any psychiatric harms when they licensed oseltamivir. Regulatory reports examining harms in the prophylaxis trials, were analysed while participants were receiving treatment only and not after they stopped taking it, although this information was available in the full clinical study reports.
From about 2004 there were concerns that oseltamivir caused dangerous psychological, neuropsychiatric side-effects including self-harm in some users. These dangerous side-effects occured more commonly in children than in adults.
In 2006 the FDA and Roche Laboratories Inc have notified healthcare professionals with warnings of the potential risk for neuropsychiatric events associated with its use, notably possible increased risk of self-injury and confusion shortly after taking.  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.
The European Medecines Agency added a warning label in 2006 stating that neuropsychiatric events such as convulsion and delirium had been reported in patients with influenza taking oseltamivir, but also they occurred in those not taking the drug.
A survey conducted in 2009 by the Health Protection Agency and the European Centre for Disease Prevention and Control found that out of 85 children treated with the drug 18% reported a neuropsychiatric side effect (defined as one or more of the following symptoms: poor concentration or unable to think clearly, problems sleeping, feeling dazed or confused, bad dreams or nightmares, behaving strangely.
The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.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.
2009 pandemic H1N1 flu or "Swine flu"
There is concern that antiviral resistance will develop in people with haematologic malignancies due to their inability to reduce viral loads. Several surveillance studies found oseltamivir resistant pH1N1 after administration of oseltamivir in those people, however widespread transmission of oseltamivir-resistant pH1N1 did not occur.
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. In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance. 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. As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all seasonal flu samples tested since October 2011.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.
Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18 percent of a group of 50 Japanese children treated with oseltamivir in 2002-2003. 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. Inadequate dosage may also have been an issue.
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. According to the CDC, as of October 3, 2009[update] no influenza B strains tested have shown any resistance to oseltamivir.
H5N1 avian influenza
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. 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 that 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.
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. Resistant strains have also appeared in the EU.
Mechanism of action
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 by infected cells.
Oseltamivir might induce a low immune response with low levels of pro-inflammatory cytokines. This may reduce symptoms of influenza, but is not related to inhibition of virus replication. There is also a potential temperature lowering effect that can contribute to symptom reduction. The influenza virus specific mechanism of action proposed by the producers does not fit the clinical evidence. Evidence rather suggests a multi-system and central action.
Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver. It has a volume of distribution of 23-26 litres. Its half-life is about 1-3 hours and its active metabolite has a half-life of 6-10 hours. It is predominantly eliminated in the urine as the active carboxylate metabolite (>90% of oral dose).
Around 40 Hoffman-LaRoche sponsored randomised clinical trials of oseltamivir were completed around the end of the nineties. In October 1999 and November 2000 FDA approved oseltamivir for treatment and profylaxis of influenza. In June 2002 EMA approved oseltamivir for prophylaxis and treatment of influenza. In 2003 the Kaiser 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. From 2004 governments around the world begun stockpiling oseltamivir by fears of avian influenza H5N1. In January 2006 a Cochrane review concluded that oseltamivir reduced complications such as pneumonia. The Kaiser 2003 paper drove the result in the meta-analysis. 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”. The CDC, WHO, and the European Centre for Disease Prevention claimed the effectiveness of Tamiflu against complications, which made governments around the world to stockpile these drugs in case of a pandemic. Also in 2009 Nice advises them to use in people at risk for complications. From 2010 to 2012 Cochrane in vain requested the full clinical study reports of their trials to Roche, but in 2011 a freedom of information request to the European Medicines Agency provided them 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. 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. The British government has spent almost 424 million pounds ($703 million) on a stockpile of some 40 million Tamiflu doses.After the Cochrane analysis EMA stated that it did not alter the Agency's view that the benefits of oseltamivir outweighed its risks. The US Centers for Disease Control continued to recommend the use of oseltamavir treatment for people at high risk for complications and those at lower risk who present within 48 hours of first symptoms.NICE considers to review its guidance on using of oseltamivir in light of the new Cochrane findings.
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.
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.
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. 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.
On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic oseltamivir was produced in February 2006, and was to have been available to the public in July 2006.
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.
In 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.
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.
Production shortage/shikimic acid
In early 2005, Roche announced a production shortage. 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.
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 (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. Many stockpilers will have only ten pills of 75 mg each (the current[when?] recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.
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 having 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.
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 the appearance of counterfeit Tamiflu outside of the United States: incorrectly labeled tablets found in the Netherlands, which contained only vitamin C and lactose.
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. 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.
There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection. 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.
Aqueous solubility of oseltamivir in form of phosphate salt is 588 mg/ml at 25 °C (77 °F).
The current[when?] production method features a number of reaction steps, two of which involving potentially hazardous azides. A reported azide-free Roche synthesis of the drug is summarized graphically below.
Oseltamivir is marketed by Genentech under the trade name Tamiflu, as capsules (containing oseltamivir phosphate 98.5 mg equivalent to oseltamivir 75 mg) and as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir 6 mg/ml).
- 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.
- 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.
- Lew W, Chen X, Kim CU (June 2000). "Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor". Curr. Med. Chem. 7 (6): 663–72. doi:10.2174/0929867003374886. PMID 10702632.
- "Tamiflu Approval, Review, and Labeling Information". Drugs@FDA. U.S. Food and Drug Administration (FDA). Archived from the original on 2011-05-21. Retrieved 2012-11-08.
- Wang, Guo-Wei; Hu, Wen-Ting; Huang, Bao-Kang; Qin, Lu-Ping (June 2011). "Illicium verum: A review on its botany, traditional use, chemistry and pharmacology". Journal of Ethnopharmacology 136 (1): 10–20. doi:10.1016/j.jep.2011.04.051.
- Coenen, B; Van Puyenbroeck, K; Verhoeven, V; Vermeire, E; Coenen, S (2013). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews". In Jefferson, Tom. PLoS ONE 8 (4): e60348. Bibcode:2013PLoSO...860348M. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.
- 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.
- "CDC Online Newsroom - "Have You Heard?" Archive: 2014 - Influenza A Variant Virus".
- Jefferson T, Jones MA, Doshi P, et al. (2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". Cochrane Database Syst Rev 1: CD008965. PMID 22258996.
- Jefferson, T; Jones, MA; Doshi, P; Del Mar, CB; Heneghan, CJ; Hama, R; Thompson, MJ (Jan 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". In Jefferson, Tom. Cochrane database of systematic reviews (Online) 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996.
- Wang K, Shun-Shin M, Gill P, Perera R, Harnden A (2012). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)". In Harnden, Anthony. Cochrane Database Syst Rev 4: CD002744. doi:10.1002/14651858.CD002744.pub4. PMID 22513907.
- "Update on oseltamivir resistance to influenza H1N1 (2009) viruses". World Health Organization (WHO). December 15, 2010. Retrieved December 30, 2010.
- De Jong, D.; Tran, T.; Truong, K.; Vo, H.; Smith, J.; Nguyen, C.; Bach, C.; Phan, Q.; Do, H.; Guan, Y.; Peiris, J. S. M.; Tran, T. T.; Farrar, J. (Dec 2005). "Oseltamivir resistance during treatment of influenza A (H5N1) infection". The New England Journal of Medicine 353 (25): 2667–2672. doi:10.1056/NEJMoa054512. ISSN 0028-4793. PMID 16371632.
- Ward, P.; Small, I.; Smith, J.; Suter, P.; Dutkowski, R. (Feb 2005). "Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic" (Free full text). The Journal of antimicrobial chemotherapy 55 (Suppl 1): i5–i21. doi:10.1093/jac/dki018. ISSN 0305-7453. PMID 15709056.
- Tamiflu (oseltamivir phosphate) Information U.S. Food and Drug Administration (FDA)
- "Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087".
- Jefferson T, Jones MA, Doshi P, et al. (April 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.
- Hernán MA, Lipsitch M (August 2011). "Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials". Clin. Infect. Dis. 53 (3): 277–9. doi:10.1093/cid/cir400. PMC 3137795. PMID 21677258.
- http://www.thelancet.com/journals/lanres/article/PIIS2213-2600%2814%2970041-4/abstract, retrieved 2014-04-11 Missing or empty
- http://www.cidrap.umn.edu/news-perspective/2014/03/large-study-shows-tamiflu-cut-h1n1-pandemic-deathsbstract, retrieved 2014-04-11 Missing or empty
- Fry, Alicia M (March 2014). "Effectiveness of neuraminidase inhibitors for severe influenza". The Lancet Respiratory Medicine. doi:10.1016/S2213-2600(14)70068-2.
- 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 (2014 Apr 10). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.". The Cochrane database of systematic reviews 4: CD008965. PMID 24718923. Regulatory information on trials of oseltamivir (Tamiflu) and zanamivir (Relenza) for influenza in adults and children Updated
- Tamiflu Prescribing Information
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
- Cohen, D. (9 April 2014). "Oseltamivir: another case of regulatory failure?". BMJ 348 (apr09 8): g2591–g2591. doi:10.1136/bmj.g2591.
- Waknine, Yael (2006). "Tamiflu May Be Linked to Risk for Self-Injury and Delirium". Medscape. Retrieved 17 May 2008.
- Pediatric Advisory Committee. 2005. "Pediatric safety update for Tamiflu". U.S. Food and Drug Administration (FDA)
- Thorlund, Kristian; Awad, Tahany; Boivin, Guy; Thabane, Lehana (2011). "Systematic review of influenza resistance to the neuraminidase inhibitors". BMC Infectious Diseases 11 (1): 134. doi:10.1186/1471-2334-11-134.
- Downing, Mark. "Antiviral Therapy for Pandemic Influenza A (H1N1) Infection: Dosing, Combination Therapy, and Resistance". National collaborating centre for infectious diseases.
- "CDC Influenza Division Key Points March 28, 2014". CDC. Retrieved 15 April 2014.
- Kiso, M.; Mitamura, K.; Sakai-Tagawa, Y.; Shiraishi, K.; Kawakami, C.; Kimura, K.; Hayden, F.; Sugaya, N.; Kawaoka, Y. (2004). "Resistant influenza a viruses in children treated with oseltamivir: descriptive study". The Lancet 364 (9436): 759–765. doi:10.1016/S0140-6736(04)16934-1.
- Hatakeyama, S.; Sugaya, N.; Ito, M.; Yamazaki, M.; Ichikawa, M.; Kimura, K.; Kiso, M.; Shimizu, H.; Kawakami, C.; Koike, K.; Mitamura, K.; Kawaoka, Y. (Apr 2007). "Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors" (Free full text). Journal of the American Medical Association 297 (13): 1435–1442. doi:10.1001/jama.297.13.1435. ISSN 0098-7484. PMID 17405969.
- Le, M.; Kiso, M.; Someya, K.; Sakai, T.; Nguyen, H.; Nguyen, H.; Pham, D.; Ngyen, H.; Yamada, S.; Muramoto, Y. et al. (Oct 2005). "Avian flu: isolation of drug-resistant H5N1 virus". Nature 437 (7062): 1108. Bibcode:2005Natur.437.1108L. doi:10.1038/4371108a. ISSN 0028-0836. PMID 16228009.
- "WHO intercountry-consultation. Influenza A/H5N1 in humans in Asia. Manila, Philippines, 6–7 May 2005". World Health Organization. May 2005.
- Moscona, A. . (Dec 2005). "Oseltamivir resistance--disabling our influenza defenses". The New England Journal of Medicine 353 (25): 2633–2636. doi:10.1056/NEJMp058291. ISSN 0028-4793. PMID 16371626.
- Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ (June 2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature 453 (7199): 1258–61. Bibcode:2008Natur.453.1258C. doi:10.1038/nature06956. PMID 18480754.
- Garcia-Sosa AT, Sild S, Maran U (October 2008). "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". J. Chem. Inf. Model. 48 (10): 2074–80. doi:10.1021/ci800242z. PMID 18847186.
- Jefferson, T.; Doshi, P. (10 April 2014). "Multisystem failure: the story of anti-influenza drugs". BMJ 348 (apr10 14): g2263–g2263. doi:10.1136/bmj.g2263.
- "WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses Revised February 2010". WHO.
- "Amantadine, oseltamivir and zanamivir for the treatment of influenza (review of existing guidance No. 58)". Nice. 2009.
- "Researchers, regulators and Roche row over stockpiled drug Tamiflu | Reuters".
- Price, Caroline (10 april 2014). "Gold standard review casts further doubt on benefit of antivirals for flu". Pulse. Retrieved 19 April 2014.
- Avian Flu Drugs: Patent Questions, WIPO Magazine, April 2006
- "Roche to suspend Tamiflu shipments to US private sector". Forbes. AFX News Limited. 2005-10-27. Archived from the original on 2009-05-13. Retrieved 2009-07-29.
- "Man dies of bird flu in Vietnam". Gulf Times. 2005-11-09. Retrieved 2009-09-27.
- Tran Van Minh (2005-11-09). "Vietnam to produce generic bird-flu drug". The Washington Post. Associated Press. Retrieved 2009-07-29.
- Le Thang Long (2005-11-10). "Roche lets Vietnam make Tamiflu". The Standard. Retrieved 2009-07-29.
- Shannon Brownlee and Jeanne Lenzer (November 2009) "Does the Vaccine Matter?", The Atlantic
- "China-made Tamiflu approved for production". People's Daily. 2006-06-13. Retrieved 2009-07-29.
- McCoy, Michael (2006-03-20). "Making Tamiflu". Chemical & Engineering News. Retrieved 2009-07-29.
- "WHO puts Tamiflu maker on alert after suspected human-to-human transmission". Medical News Today. 2006-05-27. Retrieved 2009-07-29.
- "Cipla's anti-flu drug gets nod". Times of India. 2009-05-14. Retrieved 2009-07-29.
- "Tamiflu readily available for 2006/2007 influenza season" (Press release). Roche. 2006-10-02. Retrieved 2009-07-29.
- "Roche boosts Tamiflu production; CDC cites signs of hoarding". CIDRAP. 2006-03-16. Retrieved 2009-07-29.
- "Roche update on Tamiflu for pandemic influenza preparedness" (Press release). 2006-03-16. Retrieved 2009-07-29.
- Rudolf, M.; Bernstein, B. (Apr 2004). "Counterfeit drugs". The New England Journal of Medicine 350 (14): 1384–1386. doi:10.1056/NEJMp038231. ISSN 0028-4793. PMID 15070787.
- Savigny, M. R.; MacIntire, D. K. (2010). "Use of oseltamivir in the treatment of canine parvoviral enteritis". Journal of Veterinary Emergency and Critical Care 20 (1): 132–142. doi:10.1111/j.1476-4431.2009.00404.x. PMID 20230441.
- Macintire, Douglass K. (2006). "Treatment of Parvoviral Enteritis". Proceedings of the Western Veterinary Conference. Retrieved 2007-06-09.
- Karpf, Martin, Martin; Trussardi, René (February 24, 2001). "New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu)". Journal of Organic Chemistry 66 (6): 2044–2051. doi:10.1021/jo005702l. PMID 11300898.
- Tamiflu Prescribing InformationU.S. Food and Drug Administration (FDA)
- Pollack, Andrew (November 5, 2005). "Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu". The New York Times.
- Wong, Y. K. (January 2006). "Avian influenza virus infections in humans". Chest 129 (1): 156–168. doi:10.1378/chest.129.1.156. PMID 16424427.
- Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. (1998). "Practical Total Synthesis of the Anti-Influenza Drug GS-4104". The Journal of Organic Chemistry 63 (13): 4545–4550. doi:10.1021/jo980330q.
- Karpf, T. R.; Trussardi, R. (March 2001). "New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)". J. Org. Chem. 66 (6): 2044–2051. doi:10.1021/jo005702l. PMID 11300898.
- Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. (2004). "The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu®): A Challenge for Synthesis & Process Research". CHIMIA International Journal for Chemistry 58 (9): 621. doi:10.2533/000942904777677605.
- Yeung, H. S.; Hong, S.; Corey, E. J. (May 2006). "A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid". J. Am. Chem. Soc. 128 (19): 6310–6311. doi:10.1021/ja0616433. PMID 16683783.
- Tse, N.; Cederbaum, S.; Glaspy, J. A. (Oct 1991). "Hyperammonemia following allogeneic bone marrow transplantation" (Free full text). American journal of hematology 38 (2): 140–141. doi:10.1002/ajh.2830380213. ISSN 0361-8609. PMID 1951305.
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- Reto U. Schneider: 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).
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