Manufacturing practices, formulations and reimbursement of topical forms of apamycin in Tuberous Sclerosis of Bourneville: update on French practices

A. Moussali, R. Mazet, M Durand, J. Leenhardt, M-D. Desruet, P. Bedouch
Centre Hospitalier Universitaire Grenoble Alpes, France

Introduction
Almost all patients with Tuberous Sclerosis of Bourneville (TSB) suffer from refractory epilepsy and stigmatizing skin lesions. The skin lesions appear from the first years of life , evolving into facial angiofibromas accompanied by cephalic fibrous plaques and “confetti” wounds. These damages significantly impact patients on their quality of life as well as schooling of children (1-2). Topical administration of rapamycin has been shown to be effective in angiofibroma. As no specialty is currently available in France, community pharmacies and hospital pharmacies realize preparations to meet patient’s needs. Unfortunately, this preparation is expensive and leads to an unequal reimbursement across the country. The objective of this study is to provide an overview of the practices, formulas used and reimbursement methods in France, both in the community pharmacies and hospital pharmacies.

Material and methods
A questionnaire was sent to 32 hospital pharmacies and 26 subcontracting pharmacies. It included questions concerning the realization or not of this preparation, the formula and the concentrations carry out, along with the annual volumes produced and their reimbursement.

Results
We received feedback from 32 hospital pharmacies and 26 subcontracting pharmacies. The French preparation of rapamycin is largely carried out in hospital pharmacies, with 66% (21/32) of them and 42% of subcontracting ones (11/26). The volumes produced also reflect this distribution: of the 2230 units produced per year, 1770 units are realized in hospital pharmacies and 460 in community pharmacies. There are 4 different formulations, of which 2 are most largely used (1-3). Among these formulations, several concentrations are made from 0,1% (60% of French production) to 1% of rapamycin. Reimbursement of these formations seems to be heterogeneous across the country, between regions and between hospital and community pharmacies. The 0.1% concentration formulation seems to be more frequently reimbursed.

Discussion and conclusion
Due to a mutagenic risk, rapamycin requires a specific installation and personal protective equipment to ensure the safety of staff, which limits its preparation and increases its costs. This work shows that despite the publication of the national plan for diagnosis and management of TSB in September 2021 (5), the realization of this preparation is not homogeneous over the national territory. It also appears that there is heterogeneity in formulations and concentrations used. However, published data on their efficacy and safety are weak (1;3-4), and it would be necessary to evaluate them in the context of a clinical trial, which would eventually make it possible to define a harmonized therapeutic strategy throughout the country.

Bibliographioc references
1. Bouguéon G et al. Int J Pharm. 2016;509(1 2):279 84.
2. Ophanet STB, website : https ://www.orpha.net/consor/cgi-bin/OC_Exp.php ?Lng=FR&Expert=805 consulté le 20/10/2021.
3. Malissen N et al. JAMA Dermatol. 2017;77(3):464-472.e3.
4. Le Guyader G et al. Eur J Hosp Pharm. 2020;27(e1):e48 52. 5. PNDS Sclérose tubéreuse de Bourneville, website : https://www.has-sante.fr/upload/docs/application/pdf/2021-10/pnds__stb_versionfinale_30_09_2021.pdf

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