WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION
Commentary on application for addition of miconazole nitrate 10 mg mucoadhesive buccal tablet for the treatment of oro-pharyngeal and oesophageal
candidiasis
From WHO Collaborating Center
Discipline of Clinical Pharmacology
Faculty of Medicine and Health Sciences
University of Newcastle
NSW Australia
1. Proposal and claim
Miconazole nitrate 10 mg muco-adhesive buccal tablet, for the treatment of oropharyngeal and oesophageal candidiasis, is proposed for inclusion on the WHO
Model List of Essential Medicines (EML) as a “special mention” as an example of an
anti-fungal drug (Section 6.3 of the list).
The claims made are that:
- the product has advantages in terms of efficacy (presumably compared to
other imidazoles, triazoles and antifungal medicines)
- the product is cost-effective compared to topical nystatin and also
systemic treatment with ketoconazole.
The product is registered in 28 countries and pharmacopoeal standards are provided.
2. Source of application and supporting agencies.
The application has been submitted through Dr. T. Türmen (Executive Director,
WHO, Family and Community Health Cluster). The application indicates that WHO,
MSF, the IDA and PLHIV/AIDS support the proposal.
3. Information supporting the public health relevance
Oesophageal candidiasis is one of the most frequent opportunistic infections in
HIV/AIDs. The application presents some evidence about the estimated prevalence in
African countries, but did not include the references cited. No information is
presented regarding current use of miconazole nitrate, although project proposals from
African countries for its use within treatment programs were included in the dossier.
4. Treatment details
The proposed dosage regimen is one tablet daily for 7 days.
5. Summary of comparative effectiveness
The evidence in the application to support claims of comparative effectiveness is:
- a study comparing treatment with topical miconazole tablets (as proposed) with
systemic treatment with ketoconazole, in 357 subjects with presumed HIV
(attachment 6);
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- a study comparing miconazole gel with oral ketoconazole with and without acid,
or nystatin tablets, in HIV positive patients ( attachment 4)
- a Periodic Safety Update for miconazole provided by the manufacturer.
The application did not include any information about searches of the published
literature. During the evaluation of the application, a literature search was conducted
to obtain clinical evidence addressing the use of miconazole nitrate muco-adhesive
buccal tablets in the treatment of oro-pharyngeal or oesophageal candidiasis. The
databases searched included Medline and Embase. No trials comparing miconazole
nitrate and ketoconazole were found. One cross-over trial comparing miconazole and
nystatin in the treatment of esophageal candidiasis (Ravera et al., 1999) was found.
No systematic reviews were identified.
Summary of available data
5.1
Appraisal of quality
A minimal appraisal of trial quality was provided in the application (‘trial followed
ICH guidelines’). A complete assessment of the quality of the key trial is provided in
the table below, using a modified version of the Schulz criteria.
The trial is a phase IIIb open, randomised comparison of miconazole nitrate 10 mg
muco-adhesive buccal tablets and systemic ketoconazole 400 mg/day in the treatment
of oropharyngeal candidiasis. A total of 357 patients were randomised to treatment.
Trial duration was 14 days.
Table 1:
Criteria
Quality assessment of trial CR-TTT/GUM-C103
Done
score
Randomisation
Blinding
Concealment of treatment
allocation schedule
Inclusion of all randomised
participants in analysis (ITT)


0
2

2
Generation of allocation
sequences
Description of withdrawals

Objective outcomes

5.2
0
Comments
N/A
open trial, thus no blinding
adequately concealed
Primary population for efficacy
analysis was per-protocol; results
for ITT population also presented
not reported
reasons for withdrawal provided
in table
clinical response, defined as
being symptom-free, with signs
(scale 0-4) and symptoms
(absent/present) assessed by
investigator
Outcome measures
The primary outcome variable as described in the trial report was clinical response
rate at day 7, defined as the percentage of patients clinically cured at day 7.
5.3
Summary of results
A brief summary of results stated that there was non-inferiority of topical miconazole
nitrate compared to systemic ketoconazole. No other details of the trial results were
presented in the application.
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From the trial report, the results for the analysis of the primary outcome were:
Table 2: Results of main trial
Outcome
Clinical response at day 7
Miconazole
ITT:135/167 (81%)
Per protocol 135/156 (87%)
Ketoconazole
137/165 (83%)
137/153 (90%)
The 90% confidence interval for the difference between treatments, using the perprotocol population was -9%, +3%. Using the ITT results, the difference between the
two response rates was 2%, with a 90% CI for the difference of -9%, 5%.
Results pertaining to the secondary outcome variables (clinical response at different
times, sensitivity analyses of the clinical response rate, clinical global impression,
signs and symptoms, relapse rate, onset of action, and KOH microscopy) were similar
for both treatments.
The second trial (Attachment 4) is used as the basis of an indirect comparison
between miconazole buccal tablets and nystatin. This study, carried out in 373
subjects, compared 4 treatments:
nystatin tablets 100000IU 4 times per day
miconazole 2.5ml 2% oral gel 4 times daily
ketoconazole 400mg daily
ketoconazole + acid 400mg daily
The outcome report was clinical cure at 7 days (and 14 days). The report provided in
the application is the statistical report only, and does not contain full details of the
study methods and results. However, from the data presented, the comparative effects
are summarised in the table below (from Table, page 12, Attachment 4).
Table 3: Results of supporting trial
Treatment
Cumulative per cent cured at day 7*
nystatin (n=93)
72% (63%, 81%)
miconazole (n=93)
80% (72, 89)
ketoconazole (n=94)
81% (73, 89)
ketaconazole +acid (n=93)
91% (85, 97)
*calculated from Kaplan –Meier estimates for time to cure (95% CI).
As the raw data for these estimates was not provided, it was not possible to calculate
the difference between treatments and confidence intervals for the difference. The
conclusions in the study report were that there was ‘very little difference between the
2 ketoconazole groups and miconazole’.
The application uses this study to compare the effects of miconazole buccal tablet
with nystatin. According to the application, the trial populations are the same, and the
sites were the same in the two trials (although it is not possible to verify this from the
study reports). The argument is that ketoconazole is superior to nystatin (on the basis
of the results above) and therefore the buccal miconazole preparation must be superior
to nystatin as well. Table 1 in the application presents the per protocol results from
the trial of miconazole buccal tablet from the first trial (as number of patients at day
3
7) and the results for the Kaplan Meier estimates from the second trial for nystatin.
This is not correct. Firstly, the confidence intervals for the Kaplan –Meier estimates
for the two groups in the second trial (nystatin and ketoconazole) overlap at 7 days, so
the difference in point estimates is unlikely to be statistically significant. From the
study report (page 13) there are no statistically significant differences between
treatment groups in terms of the Cox hazard ratios for time to cure. It is therefore not
correct to interpret this trial to show superiority of ketoconazole over nystatin.
Secondly, without data on the details of the baseline risk of the disease in the two
studies, it is not possible to determine whether the two studies were in fact carried out
in similar populations, or whether there were systematic differences between them
due to the different dates of the trials. This is a common problem with ‘common
reference’ comparisons; at best these types of comparisons can be used as a basis to
demonstrate equivalence. As well, the results from the two trials are based on
different methods of calculation (simple proportions versus K-M estimates); without
the raw data for the second set, the results cannot be verified.
On the basis of the evidence presented, it would be appropriate to conclude that
miconazole buccal tablet is no worse than ketoconazole and nystatin.
6. Summary of comparative evidence on safety
Total patient exposure was based on the periodic safety report for Tibozole
(miconazole nitrate 10 mg muco-adhesive buccal tablet) for the period June 2000 to
September 2002. The report estimates patient exposure to be 552,381 persons
worldwide. The application reports that adverse events are rare given the large
number of units sold.
In addition, the application points out that on the basis of the study in Uganda, adverse
events associated with miconazole buccal tablet were less frequent than those
associated with ketoconazole.
7. Summary of available data on comparative cost and cost-effectiveness
7.1
Range of costs of the proposed medicine
No proposed costs are presented in the application. It is stated that mark-ups of 10%
to 30% by governments, non-governmental agencies and not-for-profit distributors are
anticipated.
7.2
Comparative cost-effectiveness (presented as range of cost per routine
outcome)
Based on the result of the clinical trials, the appropriate economic evaluation would
be a cost-minimisation analysis. The application provides a cost comparison for three
treatments: miconazole buccal tablet, ketoconazole tablet and nystatin.
Source of costs are provided, and assumptions justified. The primary analysis was in
Euros, with a secondary analysis in local drug cost units (UgSh). Upper and lower
estimates were calculated based on the 95% confidence intervals from the trials.
The total cost for 100 patients was similar for miconazole nitrate and ketoconazole,
with a higher cost for nystatin. In the secondary analysis the cumulative costs at week
4
3 were approximately one-third less in the miconazole nitrate-treated patients
compared to the ketoconazole and nystatin-treated patients. Table 4 presents a
summary of the cumulative costs at week 3.
Table 4:
Summary of cumulative costs at week 3, per 100 patients treated
Treatment
Group
miconazole
nitrate
ketoconazole
nystatin
Primary Analysis (Euro)
Estimate (lower bound; upper
bound)
Secondary Analysis (UgSh)
Estimate (lower bound; upper
bound)
1070 (910; 1212)
2073297 (1616682; 2462425)
1030 (894; 1149)
1267 (1009; 1500)
3200600 (2765955; 3579245)
3191120 (2420835; 3882000)
Recommendation
On the basis of the data provided, miconazole buccal adhesive tablets may be
equivalent to ketoconazole and nystatin for the treatment oro-pharyngeal candidiasis.
No specific information is provided about possible advantages in compliance by using
this preparation and formulation, although these might exist.
Currently the EML includes ‘fluconazole’ as the ‘boxed’ example of ‘azole’
antifungals. Strictly, fluconazole is a triazole and miconazole is an imidazole,
although for most purposes the groups are interchangeable.
There are two possible approaches:
1) expand the note for fluconazole to include mention of this particular
formulation as an alternative
2) add ‘miconazole’ to the list as an example of imidazoles, with mention of
this specific formulation. This does not appear to offer significant advantages.
The first course of action is recommended.
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