Purpose The therapeutic index (TI) is the range of doses at\nwhich a medication is effective without unacceptable adverse\nevents. Drugs with a narrow TI (NTIDs) have a narrow window\nbetween their effective doses and those at which they\nproduce adverse toxic effects. Generic drugs may be substituted\nfor brand-name drugs provided that they meet the recommended\nbioequivalence (BE) limits. However, an appropriate\nrange of BE for NTIDs is essential to define due to the potential\nfor ineffectiveness or adverse events. Flecainide is an antiarrhythmic\nagent that has the potential to be considered an\nNTID. This review aims to evaluate the literature surrounding\nguidelines on generic substitution for NTIDs and to evaluate\nthe evidence for flecainide to be considered an NTID.\nMethods A review of recommendations from various regulatory\nauthorities regarding BE and NTIDs, and publications\nregarding the NTID characteristics of flecainide, was carried\nout.\nResults Regulatory authorities generally recommend reduced\nBE limits for NTIDs. Some, but not all, regulatory authorities\nspecify flecainide as an NTID. The literature review demonstrated\nthat flecainide displays NTID characteristics including\na steep drug doseââ?¬â??response relationship for safety and efficacy,\na need for therapeutic drug monitoring of pharmacokinetic\n(PK) or pharmacodynamics measures and intra-subject variability\nin its PK properties.\nConclusions There is much evidence for flecainide to be considered\nan NTID based on both preclinical and clinical data. A\nclear understanding of the potential of proarrhythmic effects\nor lack of efficacy, careful patient selection and regular monitoring\nare essential for the safe and rational administration of\nflecainide.
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