Abstract
Miglustat (Zavesca®) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub-optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat.
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Notes
It is important to keep in mind that, while miglustat has been tested in a number of non-neuronopathic and neuronopathic LSDs, it is currently only indicated for the treatment of GD1 and NP-C. Findings from patients with other LSDs are reviewed solely for the purpose of assessing gastrointestinal tolerability and related clinical management issues.
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Acknowledgments
Matthew Reilly, PhD, associated with InTouch Medical Ltd. provided medical writing assistance in the preparation of this manuscript, funded by Actelion Pharmaceuticals Ltd.
Competing interest
GP has received consultancy fees from Actelion Pharmaceuticals Ltd for participation in clinical trial programmes and other projects, and speaker fees for participation in scientific congresses and sponsored events. NB, has received speaker and consultancy fees, and clinical trial and research funding from Actelion Pharmaceuticals Ltd, all of which was donated to the APRIMI (Association for the Promotion in Research in Infectiology and Internal Medicine). EM and CH have previously received consultancy and speaker fees from Actelion Pharmaceuticals Ltd. AB, PG, DK have all previously received consultancy fees and/or research funding from Actelion Pharmaceuticals Ltd.
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Communicated by: Frits Wijburg
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Belmatoug, N., Burlina, A., Giraldo, P. et al. Gastrointestinal disturbances and their management in miglustat-treated patients. J Inherit Metab Dis 34, 991–1001 (2011). https://doi.org/10.1007/s10545-011-9368-7
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DOI: https://doi.org/10.1007/s10545-011-9368-7