key: cord-0006698-ac1vobj1 authors: Smith, James R.; Rayner, Craig R.; Donner, Barbara; Wollenhaupt, Martina; Klumpp, Klaus; Dutkowski, Regina title: Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience date: 2011-11-01 journal: Adv Ther DOI: 10.1007/s12325-011-0072-7 sha: 540d6dac7f1b43770697aec20776513d06cf999e doc_id: 6698 cord_uid: ac1vobj1 Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of oseltamivir with other agents. This is followed by a summary of data on the effectiveness of oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies. Recommended dosages are shown in Table 1 . For seasonal influenza, oseltamivir is indicated for children ≥1 year old and adults of all ages, and dosing recommendations for infants <1 year old infected with pandemic influenza are also provided. 6 Oseltamivir is an inactive prodrug: its clinically active metabolite is oseltamivir carboxylate (OC). In infected individuals, OC selectively binds to and inhibits the conserved active site of the neuraminidase enzymes that are present as major surface antigens on all types of influenza viruses. As neuraminidase is essential for the release of progeny virions from infected cells, 8 WHO advice is to consider using the drug at higher doses and/or longer treatment duration, depending on clinical response; 9 however, UK national guidelines recommend zanamivir. 10 For treatment of influenza caused by viruses known to be resistant to oseltamivir, WHO recommends zanamivir. 9 Earlier WHO guidelines also recommend oseltamivir as the primary antiviral agent for treatment of confirmed and suspected cases of avian H5N1 influenza infection in humans; treatment should begin as soon as possible, but can be beneficial even in patients who present later in the disease course. 11, 12 Again, consideration should be given to higher doses and/or longer treatment duration, depending on the clinical course of disease. Following its first regulatory approval in Switzerland in 1999, oseltamivir is now registered in more than 100 countries worldwide as of February 2011, with more than 83 million patients having been exposed to the product since As already described, oseltamivir prevents the release of progeny virions from cells infected by influenza viruses, through inhibition of viral neuraminidase by its active metabolite, OC. In humans, the standard oseltamivir dosing regimen produces a mean minimum plasma concentration of the carboxylate metabolite of approximately 330 nmol/L. 13 The pharmacokinetics of oseltamivir after oral administration have been studied in young, healthy adults and children, as well as in elderly and very elderly subjects. [19] [20] [21] There are no clinically relevant differences between pharmacokinetics in healthy volunteers and individuals with influenza. 13 The main difference between children >1 year of age and adults in oseltamivir pharmacokinetics is that children aged Oseltamivir has limited potential for clinically relevant interactions with other drugs commonly administered to influenza patients. When oseltamivir was given with amantadine, The inhibition of influenza virus replication by The published evidence on the efficacy of oseltamivir in the treatment and prophylaxis of seasonal influenza has been extensively reviewed at various stages through the first 10 years of oseltamivir use. 59 There was also a consistent association between starting treatment within 48 hours of symptom onset and better outcomes. Studies that have *Subjects who reported nausea alone (without vomiting). †Statistically significant difference between oseltamivir and placebo. Various neuropsychiatric AEs (NPAEs) have been Safety data on children aged 1-12 years with seasonal influenza have demonstrated that oseltamivir is well tolerated with a similar AE profile to placebo ( The decision to recommend the use of oseltamivir pregnancy by comparing 239 mothers exposed to these agents with roughly 82,000 unexposed controls, and found no effect on maternal and neonatal outcomes of antepartum exposure to oseltamivir or M2 ion channel inhibitors, such as amantadine. 151 The pandemic-specific safety evaluation referred to above also reviewed data on pregnant women, and found no evidence of AEs of oseltamivir in 207 maternal exposures. 143 Two groups have reported safety and tolerability data on oseltamivir in immunocompromised patients in the seasonal influenza setting. 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