Postauthorization safety study of betaine anhydrous.

Abstract

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

• Authors: Ulrike Mütze, Florian Gleich, Sven F Garbade, Céline Plisson, Luis Aldámiz-Echevarría, Francisco Arrieta, Diana Ballhausen, Matthias Zielonka, Danijela Petković Ramadža, Matthias R Baumgartner, Aline Cano, María Concepción García Jiménez, Carlo Dionisi-Vici, Pavel Ješina, Henk J Blom, Maria Luz Couce, Silvia Meavilla Olivas, Karine Mention, Fanny Mochel, Andrew A M Morris, Helen Mundy, Isabelle Redonnet-Vernhet, Saikat Santra, Manuel Schiff, Aude Servais, Isidro Vitoria, Martina Huemer, Viktor Kožich, Stefan Kölker
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 45 Issue 4 Pg. 719-733 (07 2022) ISSN: 1573-2665 [Electronic] United States
• PMID: 35358327 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Chemical References

• Homocysteine
• Betaine
• Methylenetetrahydrofolate Reductase (NADPH2)
• Cystathionine beta-Synthase

Topics

• Betaine (adverse effects)
• Cystathionine beta-Synthase
• Homocysteine
• Homocystinuria (drug therapy)
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2) (deficiency, genetics)
• Muscle Spasticity
• Psychotic Disorders