NPC Archive Item: Oseltamivir▼ (Tamiflu®) in children: weigh risks and benefits carefully

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4th September 2009

An updated Cochrane review and an observational study of benefits from the US suggest that for many children with seasonal influenza the benefits of oseltamivir▼ are limited although the benefits in children at higher risk of complications may be greater.  These relate to effects in seasonal influenza: no data on benefits in H1N1 (swine) influenza are available. The most common adverse effect of oseltamivir▼ is vomiting.

Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria

Health professionals should follow Health Protection Agency advice, but it is important to weigh the likely benefits against possible harms, including side effects. The NPC has produced some patient decision aids may be helpful in some consultations.

What is the background to this?
Oseltamivir▼is licensed for treatment (and prophylxais) of influenza for children aged one year or older. (The Chief Medical Officer said in July 2009 prophylaxis should not now usually be offered to contacts of cases unless for example, a household member has serious underlying health problems or there are other special circumstances). As with any medicine, it is important to weigh the likely benefits and risks of treatment. The 2007 Cochrane review (updated 2005) of neuraminidase inhibitors (oseltamivir▼ and zanamivir▼) in children has recently been updated. This found only very limited RCT evidence relating to oseltamivir in children at higher risk of complications of influenza, although a recently published observational study provides more information.  Finally, another observational study gives information about possible side effects of oseltamivir.  This blog summarises the evidence available at present.

Update 27th October 2009
The SPC for Tamiflu 12mg/ml powder for oral suspension has been revised and now states “Depending on the pathogenicity of the circulating influenza virus strain, children between 6 and 12 months of age (as well as older children) can be treated with oseltamivir during an influenza pandemic, although the available data are limited”. According to HPA advice, children up to the age of 6 months (and older children) with symptoms of influenza may also be treated with oseltamivir.

Evidence for benefits
It is important to note that evidence relates to seasonal influenza: no data on benefits in H1N1 (swine) influenza are available. The Cochrane review considered two broad benefits from treatment with oseltamivir▼: reduction in illness duration and reduction in risk of complications (mainly secondary infections).

Only one RCT was found which examined the effect of oseltamivir▼ illness duration in otherwise healthy children, aged 1 to 12 years with influenza like illness <48 hours duration (temperature ≥37.8 °C and at least one of cough or coryza). 351 children received placebo and 344 received oseltamivir▼ 2mg/kg twice daily for 5 days. It did not report sufficient details to be able to determine whether allocation concealment and blinding were adequate. This trial was also discussed in the earlier 2005 iteration of the Cochrane review. In the intention to treat population of children with clinical influenza, oseltamivir▼ reduced the median duration of illness (defined as alleviation of symptoms plus return to normal activities plus being afebrile) from 5.3 to 4.4 days (difference 0.9 days [21 hours], 95% confidence interval [CI] 0.2  to 1.9 days [5 to 46 hours]).  In the 452 children with laboratory-confirmed influenza (217 who received oseltamivir▼ and 235 who received placebo), the median duration of illness was 5.7 days in the in the placebo group and 4.2 days in the oseltamivir▼ group (reduction of 1.5 days, 95%CI 0.3 days to 2.5 days).  These are median values: half of the children in both groups had illness for longer than the median; and half had illness for a shorter time.

The same trial provides the only RCT evidence on overall use of antibiotics in otherwise healthy children.  Data are available only for the 452 children with laboratory-confirmed influenza. The rate of respiratory complications requiring antibiotics (mostly acute otitis media [AOM], also bronchitis, pneumonia and sinusitis) was reduced from 28% to 17% (relative risk reduction [RRR] 40%, P=0.005), giving a number needed to treat (NNT) of 9 (95%CI 5 to 29). Total antibiotic use was reduced from 41% to 31% (RRR 24%, P=0.03), giving an NNT of 10 (95%CI 5 to 100).

With regard to children at greater risk of complications only one RCT is available, in 334 asthmatic children aged 6 to 12 years. In this study, oseltamivir▼ did not significantly reduce the number of asthma exacerbations in the 54% of children who were influenza-positive (data for others not stated), nor did it improve median change in peak flow between study entry and day 6.  This study may have been underpowered to show a difference in this outcome.

A much larger US cohort (observational) study has been published about the same time as the updated Cochrane review. This looked at 5,355 at-risk children and adolescents aged 1-17 years. This study used data from medical and pharmacy benefits databases of health care insurance plans, and included people who had a pre-existing diagnosis of certain chronic medical conditions and a clinical diagnosis of influenza. Data were collected for six influenza seasons (2000/01 to 2005/06) and compared complication rates in the 1634 people who had a claim for oseltamivir within one day of diagnosis and the 3721 who had no antiviral claims that flu season. About 81% had chronic lung conditions (78% of the cohort had asthma), 10% had central nervous system diseases or disorders, 5% had diabetes, 4% had heart disease, 2% were  immunocompromised (e.g. HIV/AIDs). The authors calculated hazard ratios (HRs) for the risk of developing complications for those taking oseltamivir▼ compared to those who did not, adjusting for factors including age, gender, previous vaccination and co-morbidities

The number of pneumonia events was small, and there was no statistically significant reduction in risk of pneumonia or hospitalisations related to pneumonia. In the 14 days after influenza diagnosis, the risk of respiratory illnesses other than pneumonia was reduced in the group taking oseltamivir▼ (19.8% vs 23.8%, adjusted HR 0.74, 95%CI 0.63 to 0.87) and a reduction was also seen during the 30 days after diagnosis (30.5% vs 32.3%, adjusted HR 0.87, 95%CI 0.77 to 0.97). Applying the adjusted HR to the rate in the group not taking antivirals, this suggests NNTs of 16 and 24, respectively. All cause-hospitalisations (but not hospitalisations related to respiratory illness other than pneumonia) were also reduced at 14 days (0.6% vs 1.3%, adjusted HR 0.33, 95%CI 0.13 to 0.83) and 30 days (0.9% vs 1.6%, adjusted HR 0.49, 95%CI0.27 to 0.89). The NNTs (calculated as above) are 115 and 123, but the very small numbers and wide 95%CI for the adjusted HRs limit the confidence  which can be placed in these NNTs.

Evidence of harms
The updated Cochrane review combined the two oseltamivir▼ RCTs discussed above to look at adverse effects. An extra 5% (95%CI 2% to 9%) of children taking oseltamivir▼ developed vomiting: a number needed to harm (NNH) of 20 (95%CI 11 to 50). Across four studies (these two plus two of zanamivir▼) of 852 children with clinical influenza untreated with neuraminidase inhibitors, 6.7% developed vomiting. There was no significant increase in risk of nausea or diarrhoea associated with neuraminidase inhibitors.

Two UK observational studies provide data on self-reported side effects in children taking oseltamivir▼ for prophylaxis (ie at half the treatment dose). The first related to 248 children aged 11–12 years prescribed oseltamivir▼ 75mg daily for 10 days. 77% took the full course and 91% took at least seven days treatment: none developed H1N1 influenza.  All the children completed a questionnaire and half of them reported symptoms.  These included gastrointestinal symptoms such as nausea (31%), stomach ache (21%),vomiting (11%) and diarrhoea (7%). Neuropsychiatric symptoms were also reported: 24% said that they had headaches, 17% reported tiredness and 8% found difficulty concentrating.  The second study looked at responses to an electronic questionnaire in 256 children aged 4 to 14 years from one primary and two secondary schools. The response rate was low (40%) but a broadly similar range of symptoms was seen.  Without a control group it is difficult to know the extent to which these symptoms were caused by oseltamivir▼, and it is also difficult to know how they would relate to children with influenza like illness, where similar gastrointestinal and mild neuropsychiatric symptoms are not uncommon.

So what?
As with any medicine, it is important to weigh the likely benefits and risks of treatment. This is made more difficult by the limited data available: no published data relates to the effectiveness of oseltamivir▼ in H1N1 (pandemic) influenza and the evidence for effectiveness in seasonal influenza relates to small RCTs and one observational study. For most children, H1N1 (pandemic) influenza seems to be relatively mild, although unpleasant.  Children with co-morbidities such as asthma may well be at greater risk of complications.

The NPC has produced some patient decision aids may be helpful in some consultations.

Study details

Updated Cochrane review

Shun Shin M, Thomson M, Heneghan C, Perera R, Harnden R, Mant D. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. BMJ 2009;339:b3172 doi:10.1136/bmj.b3172

US Observational study of benefits

Piedra PA, Schulman KL, Blumentals WA Effects of oseltamivir on influenza-related complications in children with chronic medical conditions Pediatrics2009;124;170-178

UK observational studies of possible side effects

Wallensten A, Oliver I, Lewis D, Harrison S. Compliance and side effects of prophylactic oseltamivir treatment in a school in South West England Euro Surveill. 2009;14(30):pii=19285

Kitching A, Roche A, Balasegaram S, Heathcock R, Maguire H. Oseltamivir adherence and side effects among children in three London schools affected by influenza A(H1N1)v, May 2009 – an internet-based cross-sectional survey . Euro Surveill. 2009;14(30):pii=19287

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