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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza


Bernd Sebastian Kamps and Christian Hoffmann

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Oseltamivir is a potent and selective inhibitor of the neuraminidase enzyme of the influenza viruses A and B. The neuraminidase enzyme is responsible for cleaving sialic acid residues on newly formed virions and plays an essential role in the release and spread of progeny virions. When exposed to oseltamivir, the influenza virions aggregate on the surface of the host cell, thereby limiting the extent of infection within the mucosal secretions (McNicholl 2001) and reducing viral infectivity.

Oseltamivir is indicated in the prophylaxis of influenza and for the treatment of uncomplicated acute illness due to influenza in patients 1 year and older who have been symptomatic for no more than 2 days. H5N1 strains are generally sensitive against oseltamivir, but there are no data on its clinical efficacy.

Clinical studies have shown that neuraminidase inhibitors can decrease the duration of influenza-related symptoms if initiated within 48 hours of onset. Clinical efficacy is about 60-70 % and, for treatment started within 48 hours, symptoms such as myalgias, fever, and headache were reduced by approximately 0.7-1.5 days (McNicholl 2001). Treatment is more effective if initiated within 30 hours of symptom onset in febrile individuals. Treatment with oseltamivir does not seem to adversely affect the primary in vivo cellular immune responses to influenza virus infection (Burger 2000).

Oseltamivir is generally well-tolerated with the only clinically important side effect being mild gastrointestinal upset (Doucette 2001). Recently, the drug has been linked to a number of cases of psychological disorders and two teenage suicides in Japan. However, there is currently no evidence of a causal relationship between oseltamivir intake and suicide.


Oseltamivir is an ethyl ester prodrug which requires ester hydrolysis to be converted to the active form, oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. The discovery of oseltamivir was possible through rational drug design utilising available x-ray crystal structures of sialic acid analogues bound to the active site of the influenza virus neuraminidase (Lew 2000). Oseltamivir was developed through modifications to the sialic acid analogue framework (including the addition of a lipophilic side chain) that allow the drug to be used orally (Kim 1998). The structural formula is as follows:

During its early development, oseltamivir and its active metabolite were known as GS4104 and Ro 64-0796, and GS4071 and Ro 64-0802, respectively.


Following oral administration, oseltamivir is readily absorbed from the gastrointestinal tract. After conversion to the active metabolite oseltamivir carboxylate in the liver, it distributes throughout the body, including the upper and lower respiratory tract (Doucette 2001). The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80 %. The active metabolite is detectable in plasma within 30 minutes and reaches maximum concentrations after 3 to 4 hours. Once peak plasma concentrations have been attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours (He 1999).

The terminal plasma elimination half-life is 1.8 h in healthy adults. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance, and averages 23 h after oral administration in individuals with a creatinine clearance < 30 ml/min (Doucette 2001). A dosage reduction to 75 mg once daily is recommended for patients with a creatinine clearance < 30 ml/min (1.8 l/h) (He 1999).

Plasma protein binding is 3 %. The drug and the active metabolite are excreted by glomerular filtration and active tubular secretion without further metabolism (Hill 2001). Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases (He 1999). Thus, the potential is low for drug-drug interactions, which appear to be limited to those arising from competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter. Probenecid blocks the renal secretion of oseltamivir, more than doubling systemic exposure oseltamivir carboxylate (Hill 2002). This competition is unlikely to be clinically relevant, but there has been speculation about using probenecid to "stretch" oseltamivir stocks in situations of pandemic shortage (Butler 2005).

The metabolism of oseltamivir is not compromised in hepatically impaired patients and no dose adjustment is required (Snell 2005).

In elderly individuals, exposure to the active metabolite at steady state is approximately 25 % higher compared with young individuals; however, no dosage adjustment is necessary (He 1999).

Young children 1 to 12 years of age clear the active metabolite oseltamivir carboxylate at a faster rate than older children and adults, resulting in lower exposure. Increasing the dose to 2 mg/kg twice daily resulted in drug exposures comparable to the standard 1 mg/kg twice daily dose used in adults (Oo 2001). Infants as young as 1 year old can metabolise and excrete oseltamivir efficiently (Oo, 2003). In younger children, use of oseltamivir is contraindicated (see Toxicity).


The most frequent side effects are nausea and vomiting which are generally of a mild to moderate degree and usually occur within the first 2 days of treatment.

The following adverse reactions have been identified during post-marketing use of oseltamivir. In many cases, it is not possible to reliably estimate their frequency or establish a cause relationship to oseltamivir exposure:

  • Rash, swelling of the face or tongue, toxic epidermal necrolysis
  • Hepatitis, abnormal liver function tests
  • Arrhythmias
  • Seizures, confusion
  • Aggravation of diabetes

Oseltamivir use does not appear to be associated with an increased risk of skin reactions (Nordstrom 2004); however, anecdotal reports describe isolated skin reactions, i.e. the case of generalised rash after prophylactic use of oseltamivir and zanamivir in two patients with hepatoma associated with liver cirrhosis (Kaji 2005). After a comprehensive review of the available data, the FDA has recently required serious skin/hypersensitivity reactions be added to the oseltamivir product label. Patients should be cautioned to stop taking oseltamivir and contact their health care providers if they develop a severe rash or allergic symptoms (FDA 2005).

The use of oseltamivir in infants younger than 1 year is not recommended as studies on juvenile rats revealed potential toxicity of oseltamivir for this age group. Moreover, high drug levels were found in the brains of 7-day-old rats which were exposed to a single dose of 1,000 mg/kg oseltamivir phosphate (about 250 times the recommended dose in children). Further studies showed the levels of oseltamivir phosphate in the brain to be approximately 1,500 times those seen in adult animals. The clinical significance of these preclinical data for human infants is uncertain. However, given the uncertainty in predicting the exposure in infants with immature blood-brain barriers, it is recommended that oseltamivir not be administered to children younger than 1 year, the age at which the human blood-brain barrier is generally recognised to be fully developed (Dear Doctor-Letter, http://InfluenzaReport.com/link.php?id=2).

Oseltamivir is a pregnancy category C drug, as there are insufficient human data upon which to base a risk evaluation of oseltamivir to the pregnant woman or developing foetus.

In lactating rats, oseltamivir is excreted in the milk, but oseltamivir has not been studied in nursing mothers and it is not known, if oseltamivir is excreted in human milk.

After reports of psychological disorders in patients treated with oseltamivir, Japanese authorities have amended the patient information to list psychiatric effects, such as delusions, in the list of side effects.



Oseltamivir, 75 mg bid for 5 days, administered to otherwise healthy adults with naturally acquired febrile influenza when started within 36 hours of the onset of symptoms, reduced the duration of the disease by up to 1.5 days and the severity of illness by up to 38 % (Treanor 2000). Earlier initiation of therapy was associated with a faster resolution: initiation of therapy within the first 12 h after fever onset reduced the total median illness duration 3 days more than intervention at 48 h. In addition, the earlier administration of oseltamivir reduced the duration of fever, severity of symptoms and the times to return to baseline activity (Aoki 2003).

Body temperature exceeding 39C was an indicator of a longer duration of fever (Kawai 2005). The effect of oseltamivir may be apparent within 24 h of the start of treatment (Nichson 2000). A meta-analysis of 10 placebo-controlled, double-blind trials suggests that oseltamivir treatment of influenza illness reduces lower respiratory tract complications, use of antibacterials, and hospitalisation in both healthy and "at-risk" adults (Kaiser 2003).

The efficacy and safety of oseltamivir in patients with chronic respiratory diseases (chronic bronchitis, obstructive emphysema, bronchial asthma or bronchiectasis) or chronic cardiac disease has not been well defined. In one small randomised trial oseltamivir significantly reduced the incidence of complications (11 % vs. 45 %) and antibiotic use (37 % vs. 69 %) in the treatment group compared with the control group (Lin 2006). The cost of treating influenza and its complications was comparable between the two groups.

Oseltamivir treatment may be less effective for influenza B than for influenza A (for efficacy against H5N1 strains, see below).

A cost-utility decision model, including epidemiological data and data from clinical trials of antiviral drugs, concluded that for unvaccinated or high-risk vaccinated patients, empirical oseltamivir treatment seems to be cost-effective during the influenza season, while for other patients, treatment initiation should await the results of rapid diagnostic testing (Rothberg 2003).


When used in experimentally infected individuals, prophylactic use of oseltamivir resulted in a reduced number of infections (8/21 in the placebo group and 8/12 in the oseltamivir group) and infection-related respiratory illness (4/12 vs. 0/21; p=.16; efficacy, 61 %) (Hayden 1999a). These findings were confirmed by a clinical trial in 1,559 healthy, non-immunised adults aged 18 to 65 years, who received either oral oseltamivir (75 mg or 150 mg daily) or placebo for six weeks during a peak period of local influenza activity (Hayden 1999b). The risk of influenza among subjects assigned to oseltamivir (1.2 %) was lower than that among subjects assigned to placebo (4.8 %), yielding a protective efficacy of oseltamivir of 74 percent (Hayden 1999a). A meta-analysis of seven prevention trials showed that prophylaxis with oseltamivir reduced the risk of developing influenza by 70-90 % (Cooper 2003).

When administered prophylactically to household contacts of an influenza index case (IC), once daily for 7 days within 48 hours of the onset of symptoms in the IC, oseltamivir had an overall protective efficacy against clinical influenza of 89 % (Welliver 2001). In a randomised trial, 12.6 % (26/206) laboratory-confirmed clinical influenza episodes occurred in the placebo group vs. 1.4 % (3/209) in the oseltamivir group. In another randomised study, efficacy of post-exposure prophylaxis (PEP) and treatment of ill index cases was determined: household contacts of index cases presenting with an influenza-like illness (defined by temperature ≥37.8C plus cough and/or coryza) were randomised to receive PEP with oseltamivir for 10 days or treatment at the time of developing illness during the postexposure period. All index cases received oseltamivir treatment for 5 days (Hayden 2004). PEP was found to have a protective efficacy of 68 % against proven influenza, compared with treatment of index cases alone: 13 % (33/258) episodes of influenza illness in the placebo group vs. 4 % (10/244) in the oseltamivir group (p=0.017).

A cost-effectiveness analysis based on a decision analytic model from a government-payer perspective calculated that the use of oseltamivir post-exposure prophylaxis is more cost-effective than amantadine prophylaxis or no prophylaxis (Risebrough 2005). Another recent meta-analysis, however, found a relatively low efficacy of oseltamivir (Jefferson 2006), leading the authors to conclude that oseltamivir should not be used in seasonal influenza control and should only be used in a serious epidemic and pandemic alongside other public health measures.

Selected Patient Populations

A double-blind, placebo-controlled study investigated the efficacy of once-daily oral oseltamivir for 6 weeks as a prophylaxis against laboratory-confirmed clinical influenza in 548 frail older people (mean age 81 years, > 80 % vaccinated) living in homes for seniors (Peters 2001). Compared with placebo, oseltamivir resulted in a 92 % reduction in the incidence of laboratory-confirmed clinical influenza (1/276 = 0.4 % versus 12/272 = 4.4 %). Oseltamivir also significantly reduced the incidence of secondary complications (Peters 2001).

Children: oral oseltamivir treatment in paediatric patients reduced the median duration of illness by 36 h and also cough, coryza and duration of fever. In addition, new diagnoses of otitis media were reduced by 44 % and the incidence of physician-prescribed antibiotics was lower (Whitley 2001). In a recent study, oseltamivir was well-tolerated among asthmatic children and might help to reduce symptom duration and improve lung function. Patients treated with oseltamivir also experienced fewer asthma exacerbations (51 % versus 68 %) (Johnston 2005).

The efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation. In patients who have undergone bone-marrow transplantation, oseltamivir might be an option during the first 6 months after transplantation when preventive vaccination strategies are precluded due to poor immunogenicity of the vaccine during this period (Machado 2004).

Efficacy against Avian Influenza H5N1

In vitro studies have demonstrated a potent antiviral activity against all strains of influenza A and B including the avian H5N1 and H9N2 strains implicated in the human cases in Hong Kong (Leneva 2000). A review of H5N1 influenza cases, led by the WHO, suggested that viral shedding and infectivity of index cases could be reduced (Writing Committee of the WHO 2005). However, the clinical benefit of oseltamivir in avian influenza infections in humans remains poorly defined. Recent observations suggest that in some patients with H5N1 virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication, providing opportunities for drug resistance to develop (de Jong 2005). Whether oseltamivir needs to be used in higher doses, or over longer periods of time than currently recommended, is still subject to debate. Another open question is the initiation of treatment late in the course of illness, when there is evidence of ongoing viral replication. There is some very limited evidence that even late treatment initiation reduces viral load to undetectable levels and may have contributed to the survival of some patients (de Jong 2005). These findings would be consistent with studies in mice inoculated with H5N1. While a 5-day regimen at 10 mg/kg/day protected 50 % of mice, 8-day regimens demonstrated an 80 % survival rate (Yen 2005b). In another study, treatment with oseltamivir improved survival in mice from 0 % to 75 %, even when therapy was delayed for up to 5 days after infection with influenza virus (McCullers 2004).

Higher doses of oseltamivir in humans could be safe. Data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens (Ward 2005).

Efficacy against the 1918 Influenza Strain

Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by oseltamivir, suggesting that oseltamivir would be effective against a re-emergent 1918 or 1918-like virus (Tumpey 2002).


In vitro, the NA mutations E119V, R292K, H274Y, and R152K are associated with resistance to oseltamivir (McKimm-Breschkin 2003). Viral strains containing the R292K mutation did not replicate as well as the wild-type virus in culture and were 10,000-fold less infectious than the wild-type virus in a mouse model (Tai 1998). Likewise, the H274Y mutation reduced the replicative ability in cell culture by up to 3 logs (Ives 2002), required a 100-fold-higher dose for infection of donor ferrets, and was transmitted more slowly than was the wild type (Herlocher 2004).

It has been suggested that if mutations compromise viral fitness, they might be without clinical significance. The recently published cases of high-level resistance to oseltamivir in an H5N1 strain shed some doubt on this hypothesis (Le 2005, de Jong 2005). In this case, treatment with the recommended dose of oseltamivir, although started one day after the onset of symptoms, did not suppress viral replication efficiently and eventually led to the development of a drug-resistant strain. The cause for this - overwhelming viral replication or altered pharmacokinetics in severely ill patients - is unclear.

Whereas the incidence of development of resistant strains of seasonal H1N1 and H3N2 influenza has been low among adults and adolescents (0.3 %), paediatric studies have demonstrated higher rates. One study found neuraminidase mutations in viruses from 9/50 patients (18 %), six of whom had mutations at position 292 and two at position 119 (Kiso 2004). As children can be a source of viral transmission, even after 5 days of treatment with oseltamivir, the implications of these findings need to be investigated.

Cross-resistance between oseltamivir-resistant influenza mutants and zanamivir-resistant influenza mutants has been observed in vitro. Two of the three oseltamivir-induced mutations (E119V, H274Y and R292K) in the neuraminidase from clinical isolates occur at the same amino acid residues as two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus (Tamiflu 2005).

Drug Interactions

Information derived from pharmacology and pharmacokinetic studies suggests that clinically significant drug interactions are unlikely (Tamiflu 2005). Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.

Recommendations for Use


Oseltamivir (Tamiflu®) has been approved centrally within the European Union. Treatment indications and dosages correspond to the US marketing authorisation.


In the US, oseltamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients aged 1 year and older who have been symptomatic for no more than 2 days. In addition, oseltamivir is indicated for the prophylaxis of influenza in patients aged 1 year and older.

The standard dosage for treatment of patients 13 years of age and older is 75 mg bid for 5 days. Paediatric patients or adults who cannot swallow capsules, receive oseltamivir 30, 45 and 60 mg oral suspension twice daily. Recommended dose:

Body Weight

Recommended Dose for 5 Days

≤ 15 kg (≤ 33 lb)

30 mg twice daily

> 15 kg to 23 kg (> 33 lb to 51 lb)

45 mg twice daily

> 23 kg to 40 kg (> 51 lb to 88 lb)

60 mg twice daily

> 40 kg (> 88 lb)

75 mg twice daily

A 75 mg capsule may be a viable formulation in children (e.g. over 8 years of age) who are able to swallow solid dosage forms.

For prophylaxis, the recommended dose is 75 mg once daily for at least 7 days. The recommended oral dose of oseltamivir suspension for paediatric patients aged 1 year and older following contact with an infected individual:

Body Weight

Recommended Dose for 7 Days

≤ 15 kg (≤ 33 lb)

30 mg once daily

> 15 kg to 23 kg (> 33 lb to 51 lb)

45 mg once daily

> 23 kg to 40 kg (> 51 lb to 88 lb)

60 mg once daily

> 40 kg (> 88 lb)

75 mg once daily



Oseltamivir is a selective neuraminidase inhibitor. Treatment must start within 48 hours after the onset of symptoms, but is most effective if initiated as soon as possible (< 24 hours). The drug is generally well-tolerated.

Oseltamivir is not a substitute for early vaccination on an annual basis, as recommended by the national authorities.

Efficacy, optimal dosage and duration of treatment in H5N1 infection has still to be defined.

Trade name: Tamiflu™

75 mg capsules (blister packages of 10).

Powder for oral suspension, to be constituted with water (12 mg/ml; available in glass bottles containing 25 ml of suspension).

Drug class: neuraminidase inhibitor.

Manufacturer: Hoffmann-La Roche.

Indications: uncomplicated acute illness due to influenza infection in patients aged 1 year and older who have been symptomatic for no more than 2 days.

Prophylaxis of influenza in patients older than 1 year.

Standard Dosage for Treatment: 75 mg bid for 5 days.

Paediatric patients or adults who cannot swallow, receive the oral suspension. Recommended dose: see above.

Standard Dosage for Prophylaxis: 75 mg once daily for at least 7 days following contact with an infected individual.

Paediatric patients or adults who cannot swallow, receive the oral suspension. Recommended dose: see above.

Special Dosage: patients with a serum creatinine clearance between 10 and 30 ml/min are treated with 75 mg once daily for 5 days; the prophylactic dose is 75 mg every other day or 30 mg oral suspension every day. No recommended dosing regimens are available for patients undergoing routine haemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.

Pharmacokinetics: oseltamivir is readily absorbed from the gastrointestinal tract following oral administration and is extensively converted to oseltamivir carboxylate. Oseltamivir carboxylate is eliminated in the urine with a half-life of 6 to 10 hours.

Contraindications: oseltamivir is not indicated for the treatment of influenza in paediatric patients younger than 1 year.

Oseltamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus (Pregnancy Category C).

Interactions: significant drug interactions are unlikely.

Side effects: the most frequent side effects are nausea and vomiting which are generally mild to moderate in degree and usually occur on the first 2 days of treatment.

Comments/Warnings: patients should be instructed to begin treatment with oseltamivir as soon as possible after the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible following exposure.

Transient gastrointestinal disturbance may be reduced by taking oseltamivir after a light snack.

No dose adjustment is required for geriatric patients.

Co-administration with food has no significant effect on the peak plasma concentration and the AUC.

Store capsules at 25C (77 F); excursions permitted to 15 to 30 C (59 to 86 F).

It is recommended that the oral suspension be constituted by the pharmacist prior to dispensing to the patient (see the product information on the Internet).

Store constituted suspension under refrigeration at 2 to 8 C (36 to 46 F). Do not freeze.

Oseltamivir is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination according to the national guidelines on immunisation practices.

Internet sources:

EU: http://influenzareport.com/link.php?id=14

USA: http://influenzareport.com/link.php?id=1



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