Oseltamivir

Oseltamivir
Clinical data
Pronunciation /ɒsəlˈtæmɪvɪər/
Trade names Tamiflu[1]
AHFS/Drugs.com Monograph
MedlinePlus a699040
License data
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
Routes of
administration		 By mouth (hard capsules)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability >80%[2]
Protein binding 42% (parent drug), 3% (active metabolite)[2]
Metabolism Hepatic, to oseltamivir carboxylate[2]
Biological half-life 1-3 hours, 6-10 hours (active metabolite)[2]
Excretion Urine (>90% as oseltamivir carboxylate), faeces[2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.169.154
Chemical and physical data
Formula C16H28N2O4
Molar mass 312.4 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B (flu).[3] Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection.[4] They recommend it to prevent infection in those at high-risk, but not the general population.[4] The CDC recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection.[4][5][6] It is taken by mouth, either as a pill or liquid.[3]

Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations.[4][7][8][9] A 2014 Cochrane review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza.[9] Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[10][11] They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.[10][11] However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels.[12]

Common side effects include vomiting, diarrhea, headache, and trouble sleeping.[3] Other side effects may include psychiatric symptoms and seizures.[3][13][14] In the United States it is recommended for influenza infection during pregnancy.[15] It has been taken by a small number of pregnant women without signs of problems.[15] Dose adjustment may be needed in those with kidney problems.[3]

Oseltamivir was approved for medical use in the US in 1999.[3] It was the first neuraminidase inhibitor available by mouth.[16] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[17] A generic version was approved in the US in 2016.[18] As of 2014 the wholesale cost in the developing world was about US$4.27 per day.[19] As of December 2016, a treatment course cost US$138.70 in the U.S..[20]

Medical use

Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.[3][21] It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[22] Oseltamivir's risk-benefit ratio is controversial.[8][9] In 2017 it was moved from the core to the complementary list based on its lower cost effectiveness.[23]

High risk people

The United States' Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), Public Health England and the American Academy of Pediatrics (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications.[4][24][25][5][26] This includes those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and Indigenous peoples of the Americas among others.[24] The Infectious Disease Society of America takes the same position as the CDC.[7]

A systematic review of systematic reviews in PLoS One did not find evidence for benefits in people who are at risk, noting that "the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality",[10] as did a 2014 Cochrane review.[27] The Cochrane review nonetheless recommended: "On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza."[27]

The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and Roche (the originator) reject the conclusions of the Cochrane review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza.[4][25][5][7][26] The EMA did not change its labelling of the drug in response to the Cochrane study.[28]

A 2014 review in the New England Journal of Medicine had recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of community-acquired pneumonia receive oseltamivir until the absence of influenza infection is established by PCR testing.[29]

A 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of otitis media. The same review found that oseltamivir did not significantly increase the risk of adverse events.[30] A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of "nausea, vomiting, [and] psychiatric events in adults and vomiting in children."[31]

Otherwise healthy people

In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours.[24] A German clinical practice guideline recommends against its use.[32]

Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[10][11] 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,[27] while three other reviews found a decreased risk.[11][33][34] Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day.[35] Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.[14]

A 2014 Cochrane Collaboration review concluded that oseltamivir did not affect the need for hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms.[27][36]

The US and European Centers for Disease Control (CDC), Public Health England, Infectious Disease Society of America, and the American Academy of Pediatrics, and Roche (the originator) rejected the recommendations of the 2014 Cochrane review to urgently change treatment guidelines and drug labels.[4][25][5][7][26][28]

Prevention

As of 2017, the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development.[24] They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated.[24] They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed.[24]

As of 2011, reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease.[27][37] A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1% to 12% (a relative decrease of 64 to 92%).[10] It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated high risk persons.[10]

Side effects

A package of capsules

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of people) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the number needed to harm was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious heart rhythm problems.[27]

Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, abnormal heart rhythms, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome.[38][39]

The U.S. and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.[40][41] The frequency of these appears to be low and a causative role for oseltamivir has not been established.[41][41][42] 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.[27] Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.[40]

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.[21][43] Dose adjustment may be needed in those with kidney problems.[3]

Resistance

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[44] A 2011 meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher rates among influenza A patients, especially with H1N1 subtype. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia.[44] In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.[4]

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.[45]

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.[46]

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.[47]

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.[48]

Seasonal flu

From 2007–2009, oseltamivir resistance was widespread in seasonal flu: During the 2007–2008 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.[49] In the 2008–2009 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance.[50]

From 2009–2014 oseltamivir resistance was very low in seasonal flu. In the 2010–2011 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US.[51] In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible.[52][53] In the 2013–2014 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir.[54]

H3N2

Three studies have found resistance in 0%, 3.3%, and 18% of subjects.[44] 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.[55]

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.[56] 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"

As of 2013 H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt.[57]

H7N9 Avian influenza

As of 2013 two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation.[58]

Mechanism of action

Oseltamivir is a neuraminidase inhibitor, a competitive inhibitor of influenza´s neuraminidase enzyme. The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells, and helps new virions to exit them. Thus oseltamivir prevents new viral particles from being released.[59]

Pharmacokinetics

Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver.[2] It has a volume of distribution of 23-26 litres.[2] Its half-life is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours.[2] More than 90% of the oral dose is eliminated in the urine as the active metabolite.[2]

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.[60][61] Gilead exclusively licensed their relevant patents to Roche in 1996.[62] The drug´s patent has not been protected in Thailand, the Philippines, Indonesia, and several other countries.[62]

In 1999, the FDA approved oseltamivir phosphate for treatment of influenza in adults[63] based on two double-blinded, randomized, placebo-controlled clinical trials.[64] In June 2002 EMA approved oseltamivir phosphate 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.[65]

Oseltamivir (as Tamiflu) 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[66] and there were worldwide shortages of the drug, driven by the high demand for stockpiling.[60] 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.[67]

In 2006, a Cochrane review raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness.[68]

In December 2008, the Indian drug company, Cipla won a case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.[69]

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.[70] NICE, the CDC, WHO, and the European Centre for Disease Prevention maintained their recommendation to use oseltamivir.[71][6]

From 2010 to 2012, Cochrane requested Roche´s full clinical study reports of their trials, which they did not provide. In 2011, a freedom of information request to the European Medicines Agency provided Cochrane with reports from 16 Roche oseltamivir trials. In 2012, the Cochrane team published an interim review based on those reports. in 2013, Roche released 77 full clinical study reports of oseltamivir trials, after GSK released the data on zanamivir studies. and in 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents.[27] In 2016, Roche´s patents of oseltamivir began to expire.[62]

Veterinary use

There have been reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirus infection.[72] 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.[73]

See also

References

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  2. 1 2 3 4 5 6 7 8 9 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. PMC 2835511 Freely accessible. PMID 20215135. doi:10.1093/jac/dkq015.
  3. 1 2 3 4 5 6 7 8 "Oseltamivir Phosphate". The American Society of Health-System Pharmacists. Retrieved 8 January 2017.
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  55. ↑ Ward, P; Small, I; Smith, J; Suter, P; Dutkowski, R (February 2005). "Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.". The Journal of antimicrobial chemotherapy. 55 Suppl 1: i5–i21. PMID 15709056. doi:10.1093/jac/dki018.
  56. ↑ 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. ISSN 0098-7484. PMID 17405969. doi:10.1001/jama.297.13.1435.
  57. ↑ McKimm-Breschkin JL Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses. 2013 Jan;7(Suppl 1):25-36. doi:10.1111/irv.12047 PMID 23279894
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