Interchangeability Problems of Drugs with Narrow Therapeutic Indices

Abstract

Problems pertaining to evaluation of the interchangeability of drugs with the same international nonproprietary name and a narrow therapeutic index (NTI) are discussed. An analysis of 2073 spontaneous reports in the Russian database for the period 2009 – 2015 revealed information about adverse reactions that occurred upon mutual substitution of NTI drugs. Most communications about adverse side reactions referred to the substitution of calcineurin inhibitors and synthetic hypoglycemic drugs, in particular, cyclosporine (20.4% of the total body of data), tacrolimus (11.3%), and glibenclamide (16.5%). Most disorders with substitution of calcineurin inhibitors were observed in kidneys and the urinary tract; of glibenclamide, in the gastrointestinal tract. Significant percentages of cases referred to ineffective replacement of levothyroxine and warfarin besides glibenclamide. In most cases, the reference drug was tolerated well whereas switching to a generic led to a lack of efficacy and/or the development of adverse reactions. An analysis of the database showed that spontaneous communications can and should be taken into account during post-registration control of drugs that were initially accepted as interchangeable.