Diet-Drug Debacle

One of the realities and frustrations of the practice of clinical pharmacotherapy is the withdrawal of a previously approved medication from the marketplace. Such action engenders anxiety, concern, and disappointment among patients and physicians, as well as the U.S. Food and Drug Administration (FDA) and drug manufacturers. This not-infrequently repeated scenario received great public attention last year when the manufacturers of fenfluramine and its D-isomer, dexfenfluramine, voluntarily removed these agents from the market. Unlike many other pharmaceuticals that were previously recalled, fenfluramine had been on the market for more than two decades (dexfenfluramine was approved in 1996). Both of these medications are serotoninergic agents that are thought to exert their anorectic action through enhanced neurotransmission in the feeding centers of the brain. Fenfluramine was approved in 1973 for short-term monotherapy for obesity; dexfenfluramine was approved as monotherapy for longer-term use with the caveat that its safety beyond 1 year had not been documented. Phentermine, a noradrenergic agent with a different mechanism of action, was approved in 1959-again, for short-term single-drug treatment of obesity. It has frequently been used in combination with dexfenfluramine and, particularly, fenfluramine (a combination known as “fen-phen”).

In some ways, it is enigmatic that the association of valvular heart disease with fenfluramine did not occur or was unrecognized for more than two decades. In retrospect, similar problems were clearly identified with the serotonin antagonist methysergide, which was introduced as breakthrough preventive therapy for migraine in the early 1960s. In that era, it became widely recognized that inflammatory fibroplastic lesions in the heart and lungs occurred as a consequence of prolonged treatment with methysergide [1-3]. Among these complications was cardiac valvular regurgitation, originally reported by Graham in 1967 [1]. At this time, M-mode …