![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
Abstract
Background
Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants.
Methods
Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented.
Results
Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of-specification by several-fold magnitudes. Proprietary fingolimod has a well-defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures.
Conclusion
Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients.
Acknowledgments
Novartis Pharmaceuticals Corporation funded the study and the editorial support for the preparation of this manuscript, which was provided by Robert M Gillies, PhD, from Oxford PharmaGenesis™ Ltd. The authors would like to thank Guido Jordine and Alfons Roth for their valuable contributions.
Disclosure
Dr Jorge Correale is a board member of Merck Serono Argentina, Merck Serono LATAM, and Novartis Argentina. He has received reimbursement for developing educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, Teva Tuteur Argentina, and Novartis LATAM, as well as professional travel/accommodation grants.
Dr Erwin Chiquete has received research grants from Sanofi and Ferrer Grupo, has served as research adviser for Sanofi, Novartis, and Genzyme, and has received speaker honoraria from Novartis Mexico, Genzyme, and Ferrer Grupo.
Dr Snezana Milojevic, Dr Nadina Frider, and Dr Imre Bajusz are employees and stockholders of Novartis Pharmaceuticals Corporation.
The authors report no other conflicts of interest in this work.