A Europe-wide study conducted over three flu seasons finds that the antiviral drug, oseltamivir (Tamiflu), can help people recover from flu-like illness about one-day sooner on average, with older, sicker patients who have been unwell for longer recovering two-to-three days sooner.
Published today in The Lancet, the European Commission-funded “ALIC4E’ study was led by the Universities of Oxford (UK) and Utrecht (The Netherlands).
Despite being stockpiled in the UK since 2006 and being widely prescribed during the swine flu outbreak in 2009, oseltamivir remains one of the most controversial drugs in use.
This is due to a lack of evidence from independent clinical trials to demonstrate its effectiveness in everyday care overall, and whether it benefits key groups of patients.
A member of a class of drugs called neuraminidase inhibitors, oseltamivir is recommended by public health agencies worldwide for treating and preventing severe outbreaks of seasonal and pandemic influenza.
Carried out with 3266 patients recruited from general practices across 15 European countries, and with 26 partner organizations, it is the first large-scale publicly funded, international trial of its kind to assess antiviral treatment for influenza-like illness in primary care.
As well as looking at the overall benefits of oseltamivir, the researchers investigated the effects in key groups of patients, such as the very young or elderly, who consulted their general practitioner (GP) with symptoms of flu-like illness.
Lead Oxford investigator Professor Chris Butler, a GP in the Cwm Taf University Health Board in Wales and Professor of Primary Care at the University of Oxford’s Nuffield Department of Primary Care Health Sciences, said:
“We found that oseltamivir helps people recover from flu-like illness one day sooner, on average, than would be the case without it.
“Older, sicker, patients with comorbidities and a longer duration of previous illness showed greater overall benefit, and could expect to see their symptoms clear up two-to-three days sooner than those who had not received the drug.
However, we also found that people who took oseltamivir experienced more vomiting and nausea.
“By providing evidence through a study of this scale, and using a novel clinical trial approach, we expect the results will be of great interest to governments, policy makers, companies, practitioners and patients.
The vision of the EU in funding this study has to be acknowledged, a study of this kind could only have been done with extensive international clinical and research collaboration supported by far-sighted funders who are committed to improving the evidence to support patient care on a wide scale. Studies of this kind put Europe at the forefront of innovative, large scale clinical trials in clinical settings.”
The study was part of a large multidisciplinary EU project, PREPARE, coordinated by Professor Herman Goossens from the University of Antwerp, Belgium.
Co-lead investigator Professor Theo Verheij, Professor of General Practice at the Julius Center, UMC Utrecht, the Netherlands, explained: “What made the ALIC4E study different to those that came before it was that it took place across three flu seasons, between January 2015 and April 2018 in 15 European countries.
“It was also independently led, designed to better reflect how the drug would be used in real-world practice, and assessed a relevant outcome, combining return to usual activities with fever, headache, and muscle ache being minor or absent.
We used a novel, flexible study design to not only identify average effects but also to see whether there was any specific additional benefit for those with certain risk factors, allowing for more accurate and personalised prescribing decisions to be made.”
The research also found that:
- Contrary to many clinical guidelines, beginning treatment with oseltamivir 48 hours after symptoms first appear results in similar benefits as taking it within 48 hours of symptoms first appearing;
- Slightly fewer antibiotics (a 4% reduction) were used by those who were given oseltamivir;
- There were slightly fewer reports (a 6% reduction) of new influenza-like infections in the households of those that got the drug.
- Participants with confirmed influenza did not benefit more than those who tested negative for the virus.
The study confirmed the known side effects of oseltamivir, with patients taking it showing higher incidences of vomiting or nausea, suggesting that GPs will need to weigh the negative effects of the drug against the potential benefits for different groups of patients.
The full paper, “Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomized controlled trial,” is published in The Lancet.
Oseltamivir is appropriate for the treatment of acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates greater than 2 weeks of age. Neonates less than 2 weeks of age may also receive oseltamivir for treatment of influenza, but safety and efficacy in this population have not been established.
Multiple national advisory bodies have endorsed the use of oseltamivir as soon as possible (ideally less than 48 hours after symptom onset) for patients hospitalized with influenza or with significant comorbidities making them at high risk for complications.
There is some evidence in hospitalized patients that oseltamivir can have efficacy up to 4 to 5 days after symptoms onset and hence, recommendations endorse ordering oseltamivir for hospitalized patients with severe or progressive influenza illness or those patients at high risk of developing complications, regardless of time of symptom onset.
Individuals at high risk for complications include young children (less than two years of age), those in nursing homes, those 65 years of age or older, obese, pregnant, patients with pulmonary, liver, renal, or cardiovascular disease, malignancy, neurodevelopmental disorders, metabolic disorders, epilepsy, muscular dystrophy and immunosuppression.
Empiric treatment with oseltamivir can shorten the duration of illness and is thus recommended for healthy individuals with symptoms suggestive of influenza even before confirmation testing if treatment can commence within 48 hours of symptoms. Oseltamivir is also useful for influenza prophylaxis within 48 hours of contact with an infected individual in adults and children greater than 1 year of age.
Recommendations endorsing oseltamivir as the drug of choice for treatment and prophylaxis of illness caused by avian influenza strains, including the highly pathogenic avian influenza A (H5N1), come from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO).
Mechanism of Action
Oseltamivir is an antiviral neuraminidase inhibitor, with potent and selective competitive inhibition of the influenza virus neuraminidase, an enzyme necessary for viral replication. Oseltamivir phosphate is an inactive prodrug that exerts pharmacologic activity when hydrolyzed in vivo to the active form, oseltamivir carboxylate.
This activated form interferes with the release of progeny influenza virus from infected host cells and thus halts the spread of infection to new host cells. Oseltamivir reduces the duration of shedding and the viral titer and can shorten the length of symptoms by 0.5 to 3 days.
Dosing of oseltamivir phosphate is via the oral route, and it is not necessary to time administration with meals. It is available in capsule form of three different dosages (30, 45 and 75 mg) and as an oral powder for reconstitution to suspension for pediatric patients. Therapy should initiate as early as possible, and maximum benefit is derived when initiated within 48 hours of onset of illness. However, in severe illness or patients at risk of complications, treatment must be initiated even beyond the 48-hour window.
Seasonal Influenza A and B treatment (five-day oral course):
- Adults: 75 mg BID
- Infants 0 to 8 months: 3 mg/kg/dose BID
- Infants 9 to 11 months: 3.5 mg/kg/dose BID
- Children 1 to 12 yrs old:
- Less than 15 kg: 30 mg BID
- Greater than 15 kg to less than 23 kg: 45 mg BID
- Greater than 23 kg to less than 40 kg: 60 mg BID
- Over 40 kg: 75 mg PO BID
Patients with severe infections admitted to an intensive care unit or who are immunosuppressed may require oseltamivir treatment for a prolonged indeterminate duration (more than 5 days).
Treatment dosing adjustments for creatinine clearance:
- CrCl 30 to 60: 30 mg BID
- CrCl less than 30: 30 mg daily
- Hemodialysis patients: 30 mg after dialysis x 5 days (assumes 3 HD sessions)
Seasonal Influenza A and B Prophylaxis (seven to 10-day oral course):
- Adults: 75 mg daily
- Infants 0 to 8 months: 3 mg/kg/dose daily (not indicated for under 3 months unless clinically critical)
- Infants 9-11 months: 3 mg/kg/dose daily
- Children 1-12 yrs old:
- Less than 15 kg: 30 mg daily
- Greater than 15 kg to less than 23 kg: 45mg daily
- Greater than 23 kg to less than 40 kg: 60mg daily
- Over 40 kg: 75 mg daily
While recommendations for oseltamivir include the treatment of avian influenza infections, the optimum dosage and duration of treatment are unknown for these infections.
Oseltamivir is generally well tolerated. Most common side effects are nausea (up to 10%), vomiting (2% to 15%), abdominal pain, diarrhea, headache, insomnia, and vertigo. Other side effects occurring less than 1% of the time include conjunctivitis, epistaxis, allergy, arrhythmia, GI bleeding, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, confusion, hepatitis, seizures, and neuropsychiatric events. Vomiting is the most frequently reported side effect in children (16% of children aged 1 to 12 years).
Known allergies or hypersensitivities to oseltamivir or any component of the drug is a contraindication. It is pregnancy class C. Commercially available oral suspension of oseltamivir contains sorbitol and hence, should be used cautiously in patients with hereditary fructose intolerance.
Oseltamivir should not be used in patients with influenza illnesses that are due to strains confirmed as resistant to oseltamivir. It should not be used for diseases that are caused by organisms other than influenza viruses.
Neuropsychiatric events such as self-injury, confusion, and delirium should be monitored, especially in children; this has mainly been reported in children in Japan and has also has correlations with fatalities.[10
Oseltamivir is generally very well tolerated and has few if any, drug interactions. Multiple animal toxicity studies, both pre and post-marketing of oseltamivir, have indicated respiratory suppression, as a result of central nervous system suppression, hypothermia, hypoactivity, and sudden death.
This adverse event correlates with sudden-onset type neuropsychiatric reactions in human patients (especially children from Japan), but no definitive link has been established.
Enhancing Healthcare Team Outcomes
Oseltamivir is used widely across the world for the treatment and prophylaxis of influenza illness, both confirmed and suspected cases. (Level I) However, many practitioners are not aware of the correct indications and uses of oseltamivir as guided by existing scientific evidence. There is a lack of knowledge of the use of oseltamivir in severe or complicated influenza illness, and confusion exists about whether oseltamivir is curative for influenza. (Level I)
When suspicion of influenza illness exists during the viral season in any adult or pediatric patient with chronic conditions or severe illness requiring hospitalization, the treating physician must initiate oseltamivir treatment immediately, regardless of the duration of symptoms. (Level I)
The physician needs to make sure that proper specimens are sent to the laboratory promptly for testing, and the pathologists are responsible for rapid testing and confirmatory results, including susceptibility testing to ensure optimal duration of therapy.
While the efficacy of oseltamivir in immunocompromised patients is not established, the treating physician must consult with specialists regarding the use of oseltamivir in influenza illness in immunocompromised patients. (Level III)
In both pediatric and geriatric patients, as well as neurodevelopmentally challenged patients, the treating physician must partner with the nursing staff and the family members to find the right preparation of oseltamivir that will be tolerated by the patient without side effects. A pharmacist must also be engaged to dispense the proper preparation of oral suspension.
More information: Christopher C Butler et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial, The Lancet (2019). DOI: 10.1016/S0140-6736(19)32982-4