Oseltamivir

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Oseltamivir
Oseltamivir.svg
Oseltamivir-3D-balls.png
Systematic (IUPAC) name
ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
Clinical data
Trade names Tamiflu
AHFS/Drugs.com monograph
MedlinePlus a699040
Licence data US Daily Med:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability >80%[1]
Protein binding 42% (parent drug), 3% (active metabolite)[1]
Metabolism Hepatic, to oseltamivir carboxylate[1]
Half-life 1-3 hours, 6-10 hours (active metabolite)[1]
Excretion Urine (>90% as oseltamivir carboxylate), faeces[1]
Identifiers
CAS number 196618-13-0 N
ATC code J05AH02
PubChem CID 65028
DrugBank DB00198
ChemSpider 58540 YesY
UNII 20O93L6F9H YesY
KEGG D08306 YesY
ChEBI CHEBI:7798 YesY
ChEMBL CHEMBL1229 YesY
Chemical data
Formula C16H28N2O8P 
Mol. mass 312.4 g/mol
 N (what is this?)  (verify)

Oseltamivir INN /ɒsəlˈtæmɨvɪər/, 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.[2] 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.[3] It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences,[4][5] and is marketed by Genentech.[6] 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.[7]

Oseltamivir's benefits in those who are otherwise healthy do not appear to outweigh its risks.[8] Randomized clinical trials have failed to find a benefit of treatment among people seeking care for flu-like symptoms.[9] Among those at high risk for complications, as well as the elderly, treatment does not appear to be a change in the risk of hospitalization and 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.[10] while another review found a decreased risk.[9] 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.[11] 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.[10] Together, these published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day.[2] It is unclear whether this medication affects transmission of influenza in adults.[10] Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.[12][13]

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.[14] 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.[15] 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.[16]

Medical use[edit]

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

When used for treatment or prevention in those that are otherwise healthy, it does not appear to have benefits that outweigh the risks.[8]

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.[17] Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.[17][18]

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] Oseltamivir was approved for the treatment and prevention of infections due to influenza A and B viruses.[19] The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.[15]

Efficacy[edit]

A 2012 Cochrane review maintained that significant parts of the clinical trials remained unavailable for public scrutiny, and that the available evidence were not sufficient to conclude that oseltamivir decreases hospitalizations, complications or transmission from influenza-like illnesses.[20] On April 10, 2014 Cochrane published an updated 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.[10][21]

Roche requested an independent reanalysis of its data in 2011. One of the authors had received income from an organization performing a study sponsored by Roche previously but they were not funded by Roche for this analysis.[22] 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.[22]

The CDC continues to recommend oseltamivir for a number of uses.[11] 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. One study cited by CDC is 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.[23]

In April 2014, the Infectious Disease Society of America endorsed the CDC statement, and announced that it will continue to recommend neuramidase inhibitors for the treatment of influenza. The IDSA expressed concerns that the Cochrane analysis included both influenza virus-infected and non-infected subjects, and questioned the validity of using trial reports in patients with mild illness to direct treatment decisions for patients with severe illness or at high risk of influenza complications.[24]

Adverse effects[edit]

A package of capsules

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 the number needed to harm was 28 and for vomiting 22. So for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir induced vomiting also. The number needed to harm was 19. So for every 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.[10]

Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens–Johnson syndrome.[25][26]

Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.[25]

Neuropsychiatric side effects[edit]

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.[10] Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.[27] 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.[27]

From about 2004 there were concerns that oseltamivir caused dangerous psychological, neuropsychiatric side-effects including self-harm in some users. These dangerous side-effects occurred more commonly in children than in adults.[28]

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.[28] 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.[29]

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.[27]

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.[27]

Resistance[edit]

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[18] 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.[30] In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after cessation of oseltamivir treatment.[31]

Swedish researches warn for overuse of oseltamivir as low levels of oseltamivir passed virtually unchanged through basic sewage treatment processes. In certain countries, the level discharged through these outlets might be so high that influenza viruses in nature could develop resistance to oseltamivir. The biggest threat is from waterfowl such as ducks that often forage near sewage outlets.[32] Oseltamivir carboxylate is present in sewage treatment outlets only during the flu season. Ozonation as tertiary treatment in sewage treatment processes will substantially reduce the load during an influenza epidemic or pandemic.[33] Studies indicate that consumption by wild ducks of oseltamivir carboxylate in drinking water may promote selection of a resistance mutation in some strains of H5N2 avian influenza viruses that could contribute to viruses infecting human populations.[34]

2009 pandemic H1N1 flu or "Swine flu"[edit]

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.[14]

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.[35]

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.[31]

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.[36]

Seasonal flu[edit]

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.[37] In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance.[38] 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.[39] As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all seasonal flu samples tested since October 2011.[40][41] 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.[42]

H3N2[edit]

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.[43] 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.[43] Inadequate dosage may also have been an issue.[18]

Influenza B[edit]

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.[44] 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"[edit]

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.[45][46] 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.[47]

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.[43] Resistant strains have also appeared in the EU.[48][49]

Established markers of neuraminidase inhibitor resistance were found in 2.4% of human and 0.8% of avian isolates of H5N1 influenza.[50]

H7N9 Avian influenza[edit]

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.[51]

Mechanism of action[edit]

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]

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.[10]

Pharmacokinetics[edit]

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[edit]

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[52] 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”.[53] 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.[54] Also in 2009 Nice advises them to use in people at risk for complications.[55] 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.[53] 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.[56] After the Cochrane analysis EMA stated that it did not alter the Agency's view that the benefits of oseltamivir outweighed its risks.[57] 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.[11] NICE considers to review its guidance on using of oseltamivir in light of the new Cochrane findings.[58]

Commercial issues[edit]

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.[59]

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.[citation needed]

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.[60] 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.[61]

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir.[62] The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand.[63] The first Thai generic oseltamivir was produced in February 2006, and was to have been available to the public in July 2006.[citation needed]

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.[64]

In December 2005, Roche 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.[65][66]

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.[67]

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.[68]

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

Production shortage/shikimic acid[edit]

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.[69][70][71]

Personal stockpiling[edit]

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).[citation needed]

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.[47] 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.[17]

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.[69]

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.[72]

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.[70] 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[edit]

There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection.[73] 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.[74]

Chemical synthesis[edit]

Aqueous solubility of oseltamivir in form of phosphate salt is 588 mg/ml at 25 °C (77 °F).[75]

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.[76]

Synthesis of Tamiflu

Manufacturing[edit]

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).[25][77]

See also[edit]

References[edit]

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