11 December 2002 WHO Essential Drug list Application for inclusion of miconazole nitrate 10 mg muco-adhesive buccal tablet
Summary statement of the proposal for inclusion/change/deletion
Evidence will be provided for:
The requested comparative advantages of miconazole nitrate 10 mg muco-adhesive buccal tablet in terms of efficacy.
Product safety based on updated patient exposure and comparative clinical experience.
In addition, we are providing evidence for the cost-effectiveness of the product versus topical treatment with nystatin and systemic treatment with ketoconazole.
Name of the focal point in the WHO department or program submitting the application
Dr. T. Turmen (Executive Director, WHO Family, Community and Health Program)
Name of the organization consulted and supporting the application
WHO (see copy of the Home based care and community proposals sponsored by the Belgian and the Italian governments in Tanzania, Burundi, Mozambique, and Uganda in Attachment 1)
Information supporting the public health relevance (epidemiological information on disease burden, target population, cost, etc.)
Epidemiological information on disease burden
HIV/AIDS with an estimated 5million new cases for 2001 of which 3.4million for the Africa continent alone, has become the major global health challenge. Oral candidiasis is one of the most frequently occurring opportunistic infections in HIV/AIDS. Repeated infections (2-3 occurrences per year) are estimated in patients with CD4 counts below 200. Oesophageal candidiasis, an AIDS defining disease, is a frequent problem when CD4 counts drop below 50. Among hospitalised African AIDS patients point prevalences of 45% have been reported for oropharyngeal candidiasis. (AIDS epidemic update – December 2001, UNAIDS website; Sonnet J, Taelman H. Clinical and biological profile of African AIDS. In Stacquet M, Hemmer R & Baert A (eds): Clinical aspects of AIDS and AIDS related complex. Oxford University Press, Oxford 1986: 78-89.) The ‘Guidelines for the clinical management of HIV infection in adults’,WHO/GPA, recommend the use of Nystatin 100,000 IU orally 3 times daily for 7 days or gentian violet as first line treatments for oropharyngeal candidiasis. Ketoconazole 200mg twice daily for 2 weeks was recommended for treatment in cases of suspected oesophageal candidiasis. (Global Programme on AIDS. Guidelines for the clinical management of HIV infection in adults. WHO, Geneva, 1991. WHO/GPA/IDS/HCS91.6.) In a cost-effectiveness comparative study sponsored by WHO/GPA, it was concluded that the cure rates between different treatment regimens of miconazole, ketoconazole and ketoconazole+acid, were not significantly different from each other, while ketoconazole+acid was significantly better than the nystatin group (Attachment 4). (Perriens J, Dally G, Katabira E. A comparison of different treatment regimens for oropharyngeal candidiasis: a multi-centre cost-effectiveness study in African HIV seropositive subjects. In preparation.) Although less efficacious, nystatin is still recommended for first line therapy from a purely economic viewpoint.
Recently attention has been drawn to the relationship between HIV and TB. Whereas worldwide approximately one-third of people with HIV have TB, in some countries up to 70% of TB patients are HIV-infected (STOP TB. News, issue 4, Summer 2001 www.stoptb.org.) TB is the leading cause of death in people with HIV and up to half of HIV-infected people will develop TB (Harries A., Hargreaves N., Kemp j., Jindani A., Enarson D., Maher D., Salaniponi F. Deaths from tuberculosis in Sub-Saharan African countries with a high prevalence of HIV-1. Lancet 2001; 357: 1519-1523.). For the avoidance of potential drug interactions, the CDC recommends the use of alternatives to systemic antifungal azoles: ketoconazole, itraconazole and fluconazole, in patients taking TB drugs (Prevention and Treatment of Tuberculosis among patients infected with HIV. Principles of therapy and revised recommendation. MMWR Vol 47/No. RR-20 pg 34 Oct. 30 1998.).
Miconazole nitrate 10 mg muco-adhesive buccal tablet is positioned as first line treatment for oro-pharyngeal and oesophageal candidiasis. The target population is considered to be patients presenting with oro-pharyngeal and oesophageal candidiasis.
Topical treatment, with the miconazole nitrate muco-adhesive buccal tablet is considered an ideal alternative to systemic azoles based on its equivalent efficacy, and its negligible systemic bioavailability.
The miconazole muco-adhesive tablet is available in a generic, bulk package of 50 patient treatments. Currently the price is 1 € per blister of 7 tablets or 1€ per complete treatment of 7 days. This is part of a not-for-profit programme aiming for treatment at the lowest possible cost.
Treatment details (dosage regimen, duration; reference to existing WHO and other relevant clinical guidelines; need for special diagnostic or treatment facilities and skills) (See also Summary of Product Characteristics in Attachment 5).
Dosage regimen: 1 tablet daily (apply in the morning)
Duration: 7 days
Reference to WHO and other clinical guidelines:
Clinical AIDS Care Guidelines For Resource-poor Settings, Médecins Sans Frontières, Belgium-Luxemburg, First Edition, March 2001, chapter 11 pg 11.6. (Attachment 2)
Need for special diagnostic or treatment facilities and skills: None
Summary of comparative effectiveness in a variety of clinical settings (See Attachment 6 “Clinical research report CR-TTT/GUM-C103”). A Phase IIIb study in Uganda compared topical therapy (miconazole nitrate 10 mg mucoadhesive tablet once daily) to systemic treatment with ketoconazole 400 mg once daily in 357 patients with HIV infection. The study design was based on a previously conducted WHO/GPA study, comparing 4 antifungal treatment regimens.
Specification of the comparator treatment: Ketoconazole was the comparator treatment in the pivotal Phase IIIb study conducted in Uganda. Ketoconazole was the WHO reference drug the time of protocol preparation (late 1999), and was the standard of care at the clinical study site, Makerere Hospital in Uganda. Ketoconazole was since replaced by fluconazole on the WHO essential drug list (12/99), although ketoconazole is an accepted alternative to fluconazole. Ketoconazole was also found to be more effective than nystatin in the WHO/GPA study, and was therefore a more rigorous reference drug.
Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data): The study by WHO/GPA compared 4 treatments for oral candidiasis in HIV infected patients in Uganda, nystatin (3x/d), miconazole oral gel (4x/d), ketoconazole (od) and ketoconazole + acid (od). The design of the study comparing the miconazole nitrate 10 mg muco-adhesive tablet and ketoconazole was based upon the WHO trial design in Attachment 4 (inclusion/exclusion criteria were identical, clinical study sites were the same), to allow for cross-referencing of historical data. Similar methods for analysis of study data were employed. Hence an indirect comparison of miconazole nitrate 10 mg muco-adhsesive buccal tablet and nystatin can be made.
The study was conducted according to GCP/ICH guidelines.
Results indicated non-inferiority of topical therapy versus systemic therapy in the treatment of oro-pharyngeal candidiasis with and without dysphagia, the former being the clinical diagnosis of oesophageal candidiasis in immunocompromised HIV patients.
Summary of estimates of comparative effectiveness: Results indicated statistically significant non-inferiority of miconazole nitrate 10 mg muco-adhesive buccal tablet o.d. (topical therapy) versus ketoconazole 400 mg o.d. (systemic therapy, proven superior to nystatin) after 7 days of treatment.
Given the superiority of ketoconazole over nystatin shown in Attachment 4, and the relative equivalence of miconazole nitrate 10 mg muco-adhesive buccal tablet to ketoconazole in Attachment 6, this allows for an indirect comparison of miconazole to nystatin, illustrated in Table 1.
Table 1 provides the comparative efficacy between miconazole nitrate 10 mg muco-adhesive tablet, and nystatin (based on historical cure rates in identical settings).
Table 1: Cumulative percent cured for miconazole nitrate 10mg muco-adhesive buccal tablet & nystatin
By day 7
End of treatment
% cured (95% confidence limits)
Summary of comparative evidence on safety (estimate of total patient exposure, description of adverse effects/ reactions, identification of variation in safety due to health systems, patient factors, summary of comparative safety against comparator treatment).
General safety experience with miconazole nitrate:
Miconazole nitrate has been used extensively as a treatment for superficial and mucosal infections for more than two decades. Experience has shown that it is effective and well tolerated. A safety update report from Janssen Pharmaceutica on the experience with the miconazole oral gel (20 mg/g; daily dose of about 200 mg) and tablets (250 mg/tablet; daily dose of 1 000 mg) during the period from 02-05-1997 to 14-08-1999) is available upon request. Over a period from 1981 to 14 August 1999, more than 79 million tubes of oral gel, accounting for 60,701 kg active ingredient had been sold. If one assumes a daily dose of 200 mg and a duration of a treatment of 14 days, this accounts for 21.6 million treatments. The report concluded that there were no new relevant safety items identified during the period, and that the benefit-risk balance of miconazole oral gel remained adequate.
Taking into account the large number of units sold, the rarity of reported adverse events (0.0013%) and the fact that no new relevant safety issues could be identified, indicates that this relatively high-dosage formulation and its treatment scheme is well-tolerated and can be considered safe for the indicated use. In addition, the breadth of safety experience with the miconazole gel provides substantial support as to the safety of the miconazole compound.
The miconazole nitrate mucoadhesive buccal tablet formulation allows for a daily dosage reduction from 200 mg with the gel to 10 mg, providing an additional margin of safety compared to the miconazole gel.
Clinical safety experience: Phase IIIB study Uganda:
In the Phase IIIb study conducted in Uganda, the following safety conclusions were made:
Miconazole nitrate mucoadhesive buccal tablet was not associated with any serious or unexpected adverse events. No local irritation was observed.
There were fewer drug related adverse events associated with the use of miconazole nitrate muco-adhesive buccal tablet versus ketoconazole.
There was a higher incidence of vomiting during use of ketoconazole (8%) versus miconazole (1%).
Estimate of total patient exposure: Periodic Safety update report Tibozole® dated October 2, 2002 (Attachment 7):
The periodic safety update report for Tibozole® (miconazole nitrate 10 mg muco-adhesive buccal tablet), covering the period from June 2000 through September 2002 estimated that patient exposure to the product has been approximately 552,381 persons worldwide. There have been no individual case histories relating to the use of miconazole nitrate 10 mg muco-adhesive buccal tablet. The safety update report concluded that no new data had become available since the granting of the Belgian Marketing Authorization in April 2002, and that no changes to the product labeling were required.
Overall safety conclusions:
Patient exposure to the miconazole nitrate 10 mg muco-adhesive buccal tablet has been substantial, with an estimated > 500,000 patients having received treatment.
No severe or unexpected adverse reactions have been reported during the use of miconazole nitrate 10 mg muco-adhesive buccal tablet
Comparative safety for the topical use of miconazole nitrate 10 mg muco-adhesive buccal tablet versus systemic treatment has been favorable.
Summary of comparative cost and, where feasible, cost-effectiveness within the same therapeutic group
Tibotec is providing the miconazole nitrate to non-governmental agencies and not-for profit distributors, such as IDA, Mission Pharma International, MSF/Transfer, CHMP, Action Medeor, and Orbipharma for 1 Euro per treatment (blister of 7 tablets). We anticipate that mark-ups by governments, non-governmental agencies, and not-for-profit distributors will range from 10% to 30% by the time the product reaches the end user.
Comparative cost-effectiveness presented as (range of) cost per routine outcome
The total costs of initial treatment and rescue treatment (in case of failure) were calculated per treatment group, assuming the following treatment scenario:
After a visit to the clinic, subjects started 7-days treatment with 10 mg miconazole nitrate o.d. or 400 mg ketoconazole o.d. Subjects who were not cured after 1 week of treatment, had to return to the clinic and received a second week of treatment with the same drug. If not cured after the second week of treatment, subjects returned to the clinic and received a third week of treatment with fluconazole rescue medication. No visit was planned after the third week as no fluconazole treatment failures are assumed.
These costs were calculated based on the daily costs of the treatment (drug costs and visit costs (including transport costs)), the duration of treatment and the cure rates.
The cure rates for miconazole nitrate and ketoconazole were retrieved from the intent-to-treat population. For fluconazole rescue medication, a 100% cure rate after 1 week was assumed.
A nystatin arm was not included in this trial, but an extrapolation for a hypothetical nystatin group was added based on the previous study conducted by WHO using the same study design and comparing the following 4 groups: nystatin, miconazole gel, ketoconazole and ketoconazole+acid). The following probability of not being cured (and 95% CI) were used for nystatin (historical control (6)) after 7 days: 27.7% (18.5%; 37.0%) and after 14 days: 15.7% (8.1%; 23.4%).
Two analyses were done: a primary analysis using the IDA price indicator list (November 2000) without transport costs (expressed in Euro) and a secondary analysis using the local drug units costs (expressed in UgSh). Results of these analyses are presented in Table 2. In Table 2, the cumulative total costs at week 3, i.e., the total costs to cure all patients, is presented for the 3 treatment groups.
The following assumptions are made:
N = number of subjects to be treated during that week = 100 in week 1
IDA International Drug Unit costs are utilized:
1 ketoconazole tablet is 0.0945 Euro or 0.189 Euro / day
1 miconazole 10 mg buccal tablet is 0.1679 Euro / day
1 nystatin 100,000 Unit tablet is 0.020 Euro or 0.06 / day
Visit costs = $5.7 per visit (transport costs included 6.27 Euro)
Exchange rates: 1 Euro = 1500 UgSh and 1 US$ = 1.1 Euro.
The total costs to cure all patients (primary analysis) was similar for miconazole nitrate and ketoconazole and was about one fifth higher in the nystatin arm. Results of the secondary analysis showed that cumulative costs at week 3 were about one third lower in the miconazole nitrate arm compared to the two other treatment arms.
Table 2: Cumulative costs at week 3
Primary analysis (Euro)
Secondary analysis (UgSh)
Estimate (lower bound – upper bound)
1 As miconazole nitrate is not yet on the market in Uganda as a muco-adhesive buccal tablet, local price was simulated.
In conclusion: topical treatment with miconazole nitrate 10 mg muco-adhesive buccal tablet is a cost-effective alternative to systemic treatment with ketoconazole for oro-pharyngeal candidiasis.
Summary of regulatory status of the drug (country of origin, preferably in other countries as well)
NA = not applicable, MAA = Marketing Authorisation Application
*: Provisional approval
**: Irish MAA withdrawn due to Belgian approval.
***: No regulatory body/No official approval process
****: Thai dossier withdrawn due to delays in obtaining requested information.
Availability of pharmacopoeal standards (USP, BP, International Pharmacopoea)
See attached certificate of suitability (Attachment 8).
Proposed (new/adapted) text for the WHO Model Formulary
Section 6: Anti-infective Drugs
˚Fluconazole capsule, injection and oral suspension is listed as an example of a therapeutic group (the “azoles”). Various drugs can serve as alternatives.