Oseltamivir, capsules 30 mg, 45 mg and 75 mg, powder for oral suspension, 12 mg per mL, Tamiflu®, November 2008
Public summary document for Oseltamivir, capsules 30 mg, 45 mg and 75 mg, powder for oral suspension, 12 mg per mL, Tamiflu® November 2008
Page last updated: 19 March 2009
Public Summary Documents
Product: Oseltamivir, capsules 30 mg, 45 mg and 75
mg, powder for oral suspension, 12 mg per mL,
Tamiflu®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
To seek a Restricted Benefit listing for the treatment of
infections due to influenza A and B viruses in adults and children
aged one year and older. The submission also requested PBS listing
in the Emergency Drug (Doctor’s Bag) Supplies.
2. Background
This was the first time oseltamivir had been considered by the
PBAC.
3. Registration Status
Oseltamivir 75 mg capsules were registered by the TGA on 13
September 2000. Oseltamivir powder for oral suspension was
registered by the TGA on 5 June 2003. Oseltamivir 30 mg and 45 mg
capsules were registered by the TGA on 8 August 2008.
All strengths and dosage forms are indicated for:
- the treatment of infections due to influenza A and B viruses in adults and children aged 1 year and older. Treatment should commence as soon as possible, but no later than forty-eight hours after the onset of the initial symptoms of infection.
- the prevention of influenza in adults and children aged 1 year and older. Vaccination is the preferred method of routine prophylaxis against infection with influenza virus.
4. Listing Requested and PBAC’s View
Restricted Benefit
Treatment of infections due to influenza A and B viruses in adults
and children aged one year and older. Treatment should commence as
soon as possible, but no later than 48 hours after the onset of the
initial symptoms of infection.
The submission also requested PBS listing in the Emergency Drug
(Doctor’s Bag) Supplies. The PBAC considered listing in the
Doctor’s Bag was not appropriate.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical Place for the Proposed Therapy
Oseltamivir provides a treatment option for patients with
influenza.
6. Comparator
The submission nominated placebo as the comparator. PBAC accepted
this as appropriate.
7. Clinical Trials
The submission presented 11 randomised trials comparing oral
oseltamivir phosphate 75 mg twice daily for 5 days (or weight
adjusted dose in children) with placebo in patients with
influenza-like illness. The submission presented individual trial
results and a meta-analysis.
The key pivotal trials published at the time of the submission are
presented in the table below.
| Trial/First author | Protocol title/Publication title | Publication citation |
| WV15670 Nicholson KG, et al. | Efficacy and safety of oseltamivir in treatment of acute influenza: A randomised controlled trial. | Lancet, 2000; 355(9218): 1845-1850 |
| WV15671 Treanor JJ, et al. | Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomised controlled trial. | Journal of the American Medical Association 2000; 283(8): 1016-1024 |
| Li, et al. (2003) | A double-blind, randomised, placebo controlled multicentre study of oseltamivir phosphate for treatment of influenza infection in China. | Chinese Medical Journal 2003; 116(1): 44-48 |
| Kashiwagi et al (2000) | Clinical efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir in treating acute influenza – placebo-controlled double-blind multicentre phase III trial. | Kansenshogaku Zasshi 2000; 74(12): 1044-1061 |
| Lin et al. (2006) | A multicentre, randomised, controlled trial of oseltamivir in the treatment of influenza in a high-risk Chinese population. | Current Medical Research Opinion 2006; 22(1): 75-82 |
| WV15758 Whitley RJ, et al. | Oral oseltamivir treatment of influenza in children. | Paediatric Infectious Diseases Journal 2001; 20(2): 127-133 |
| WV15759/15871 Johnston SL, et al. | Oral oseltamivir improves pulmonary function and reduces exacerbation frequency for influenza-infected children with asthma. | Paediatric Infectious Diseases Journal 2005; 24(3): 225-232. |
8. Results of Trials
The submission conducted a meta-analysis of the primary efficacy
outcome (time to alleviation of symptoms (TTAS)) for both the ITT-I
(intention-to-treat infected population) and the ITT
(intention-to-treat) population, and presented time-to-event data
as differences in medians.
The PBAC considered that the appropriate population for analysis
was the ITT population, not the ITT-I population. The PBAC noted
the results in the ITT population showed that oseltamivir treatment
reduced symptoms on average by around 16.8 hours, and by slightly
more in otherwise healthy adults, however with only otherwise
healthy adults achieving statistical significance.
The results for the ITT-I population are summarised in the table
below.
Time to alleviation of symptoms (TTAS) (hours) in the ITT-I
population (influenza confirmed)
| Trial | Treatment | N | Median (95% CI) | P-value |
| Otherwise healthy adults | ||||
| WV15670 | Placebo | 161 | 116.5 (101.5, 137.8) | 0.02 |
| Oseltamivir | 157 | 87.4 (73.3, 104.7) | ||
| WV15671 | Placebo | 128 | 103.3 (92.6, 118.7) | <0.001 |
| Oseltamivir | 121 | 71.5 (60.0, 83.2) | ||
| Li et al. (2003) | Placebo | 139 | 95.0 (84.5, 105.3) | 0.0466 |
| Oseltamivir | 134 | 91.6 (80.2, 101.3) | ||
| Kashiwagi et al. (2000) | Placebo | 130 | 93.3 (73.2, 106.2) | 0.0216 |
| Oseltamivir | 121 | 70.0 (53.8, 85.9) | ||
| At-risk adults and the elderly | ||||
| Lin et al. (2006) | Placebo | 29 | 174.4 | NR |
| Oseltamivir | 27 | 110.4 | ||
| Children | ||||
| WV15758 | Placebo | 225 | 137.0 (125, 150) | <0.0001 |
| Oseltamivir | 209 | 101.0 (89, 118) | ||
| WV15759/15871 | Placebo | 95 | 134.3 | 0.542 |
| Oseltamivir | 83 | 123.9 | ||
Abbreviations: CI = confidence interval; ITT-I =
intention-to-treat-infected; NR = not reported.
The results of the meta-analysis of the TTAS data for the ITT-I
population (influenza confirmed cases) showed that across all 11
trials (i.e. otherwise healthy adults, ‘at-risk’ and
elderly adults, and children trials combined), treatment with
oseltamivir was associated with a statistically significant
reduction in TTAS compared with placebo.
However, the PBAC noted the results of the meta-analysis for the
ITT-I population showed that in all children and in at-risk adults
and the elderly, the use of oseltamivir did not statistically
significantly reduce the median TTAS compared to placebo. The
results of the meta-analysis for the ITT-I population showed that
the use of oseltamivir in otherwise healthy adults significantly
reduced the median TTAS compared to placebo.
For the secondary efficacy outcomes, the analyses presented in the
submission were only for the ITT-I population, which the PBAC
considered less applicable to the population to be treated under
the requested restriction. The results were mixed and generally
inconsistent. In the case of ‘antibiotic use for secondary
illness’ the results of the meta-analysis for the ITT-I
population showed that oseltamivir statistically significantly
reduced the risk of requiring antibiotics for secondary illnesses
in ‘all children’ and ‘at-risk adults and the
elderly’ but not in ‘otherwise healthy adults’.
In the case of ‘bronchitis requiring antibiotics’ the
results of the meta-analysis for the ITT-I population showed that
oseltamivir reduced the risk of requiring antibiotics in patients
with bronchitis in ‘otherwise healthy adults’ but not
in ‘all children’ or in ‘at-risk adults and the
elderly’. Similar mixed results were observed across all of
the other secondary efficacy outcomes. The PBAC noted that there
was no firm evidence that oseltamivir treatment reduced the risk of
hospitalisation or the incidence of secondary illness.
The most frequently reported adverse events (AEs) in the key trials
were gastrointestinal disorders including nausea, vomiting and
diarrhoea. In general, nausea and vomiting occurred more frequently
in subjects treated with oseltamivir, whereas diarrhoea occurred
more frequently in subjects treated with placebo. The submission
also presented an extended assessment of comparative harms,
referring to long-term safety data obtained from the oseltamivir
Periodic Safety Update Report (PSUR no. 1025973).
The PBAC was concerned at the adverse events associated with
oseltamivir, particularly as a substantial number of patients with
influenza-like illness are likely to be prescribed this drug.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission claimed that oseltamivir phosphate is superior in
terms of comparative effectiveness and similar in terms of
comparative safety over standard care (no antiviral treatment). The
PBAC considered that based on the evidence presented in the
submission, this claim was not reasonable.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented for three patient
cohorts – healthy adults (aged 13-64 years), at-risk adults
and the elderly, and children (aged 1-12) – and the three
patient cohorts combined (weighted by the proportion of
laboratory-confirmed notifications of influenza in Australia by
age).
The model followed patients who present to their GP with
influenza-like illness (ILI). Patients in the oseltamivir arm who
consult their doctor within 48 hours of the onset of symptoms
receive oseltamivir; those with ILI, but not influenza are assumed
to receive no benefit from oseltamivir treatment. In both arms of
the model, patients who are influenza positive may develop
pneumonia, bronchitis, or otitis media or have no further
complications. Patients with complications have a risk of
hospitalisation. All influenza positive patients have a risk of
influenza-related mortality. All patients have a risk of all-cause
mortality. Oseltamivir-treated patients are assumed to have a lower
risk of bronchitis, pneumonia, antibiotic use, otitis media
(children only), hospitalisations and influenza-related
mortality.
The weighted incremental cost effectiveness ratio (ICER) per
quality adjusted life year (QALY) gained for the combined patient
cohorts estimated in the model was less than $15,000.
11. Estimated PBS Usage and Financial Implications
The financial cost to the PBS was estimated to be less than $10
million per year. The PBAC considered the estimate was likely to be
highly uncertain.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC noted that there were a number of issues with the
requested listing and clinical place of oseltamivir. Although the
wording requested is consistent with the TGA approved indication
for treatment of influenza, oseltamivir is also TGA approved for
prophylaxis. Also the diagnosis of influenza is usually made on
clinical grounds and no diagnostic tests are usually performed to
confirm the diagnosis, a view confirmed in the submission to the
PBAC from the Influenza Specialist Group (ISG). There are likely to
be a large number of presentations for influenza-like-illness that
are not actually influenza. In addition, treatment is only
effective if people commence treatment within 48 hours of onset of
symptoms. The existence of all these factors means that there is a
high potential for the drug to be used outside the restriction and
thus in a manner for which there is no evidence of clinical or
cost-effectiveness.
The PBAC noted that the sponsor proposed mitigating some of this
risk by limiting reimbursement to months of May to October, but the
Committee did not accept that such a restriction was workable or
clinically appropriate. PBAC also considered that an authority
restriction was not suitable and agreed with RWG and DUSC Advices
that listing in the Doctor’s Bag was not appropriate.
PBAC agreed with the ESC that the analysis using the intention to
treat (ITT) population was the most appropriate. The evidence
presented showed oseltamivir was effective in shortening illness
duration by 16.8 hours on average; however, benefits were
principally seen in ‘otherwise healthy’ adults and
children. The benefit of reducing symptoms of influenza was
statistically significant in ‘otherwise healthy’ adults
only, with reductions in symptoms for ‘at risk’ adults
not achieving statistical significance. PBAC did however note that
NICE in the UK had recommended subsidising oseltamivir in ‘at
risk’ populations. A listing for patients at high-risk of
influenza complications was also supported by the ISG.
The secondary outcomes were only presented for the
intention-to-treat-proven influenza population which PBAC
considered less applicable to the population likely to be treated
under the requested restriction. The PBAC noted the
intention-to-treat-proven influenza (ITT-I) analysis results were
mixed and generally inconsistent, with benefits principally seen in
‘otherwise healthy’ adults with confirmed influenza,
while efficacy in ‘at risk’ adults and children was not
convincingly demonstrated. It was accepted that there was some
reduction in use of antibiotics, but perhaps more importantly no
change in hospitalisation rates, or in the incidence of secondary
illnesses.
The PBAC was concerned at the adverse events associated with
oseltamivir, particularly as a substantial number of patients with
influenza-like-illness are likely to be prescribed this drug. It
was noted that the adverse events reports are difficult to
definitely associate with oseltamivir for example neuropsychiatric
events have also been reported in patients with influenza who have
not taken oseltamivir.
The extent to which resistance to oseltamivir is developing is
uncertain. The sponsor’s monitoring of resistance was noted.
The uncertainty about developing resistance in various influenza
virus subtypes (discussed by sponsor and ISG) was also considered.
PBAC agreed with ESC that there is a potential public health issue
associated with increasing environmental exposure and the
implications for effective treatment in the event of a future
pandemic remain uncertain.
The PBAC considered that there were significant uncertainties in
the economic model and that these had been well captured in the ESC
advice. For example, the model included non-significant results
(such as reductions for complications and reduced
hospitalisations). Therefore, the stepped economic evaluation
should not have included certain steps, and a more reasonable base
case might have been derived at an earlier step. However, the ICER
is also highly uncertain because of the assumptions in the model
that only patients with symptoms of less than 48 hours will be
treated. The PBAC noted that previous research by O’Brien has
demonstrated that the cost effectiveness of oseltamivir is highly
sensitive to the percentage of patients who receive oseltamivir
greater than 48 hours after onset of symptoms. The model did not
adequately deal with patients who start taking oseltamivir more
than 48 hours after onset of symptoms, or how prevalence in
practice might differ from that in the trials.
The PBAC agreed with the DUSC that the financial estimates were
highly uncertain and that the true number of presentations to
general practitioners was influenced by health system capacity and
the fluctuations in influenza. In addition, there is a risk of
prescribers providing prescriptions for prophylaxis, or ‘just
in-case’ which adds additional uncertainty to the numbers of
prescriptions dispensed.
Therefore, the PBAC rejected the submission on the grounds of
uncertain cost-effectiveness, uncertainty about the clinical
benefit in all groups, concern about the use in a way that is not
intended in the restriction, potential for toxicity and the
uncertain impact on resistance patterns in influenza viruses.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor has no further comment.
