Terfenadine withdrawn from market

Fleischer Kupec, I. (1998) Seldane and generic terfenadine withdrawn from market, in FDA Talk Paper, FDA, Rockville, MD. 

There is stunning similarity between the penclomedine story and the history of terfenadine (Seldane), a highly successful antihistamine product that was withdrawn from marketing. In early clinical studies of terfenadines, it was not appreciated that the major source of clinical benefit was its metabolite, fexofenadine (Allegra see structures in Chapter 1, Figure 1.2). It became obvious that the metabolite should have been the lead compound only after car-diotoxicity was subsequently discovered for the parent drug but not the metabolite. 

In some patients, torsades de pointes maybe of short duration and may terminate spontaneously. However, torsades de pointes may not terminate on its own, and if left untreated, may degenerate into VF and result in sudden cardiac death.13 Several drugs, including terfenadine, astemizole, and cisapride have been withdrawn from the United States market as a result of causing deaths due to torsades de pointes. 

Terfenadine was introduced into the marketplace as the first nonsedating histamine-1 (Hj) receptor antagonist. It was launched in the United States in 1985 under the brand name Seldane . Its patent protection was near expiration when the drug was voluntarily withdrawn from the antihistamine market in 1997. 

Readers should be aware that terfenadine (Seldane ), the once widely-used, selective Hi histamine receptor antagonist, has been voluntarily withdrawn from the market by the manufacturer. The withdrawal was instituted because of the risk of life-threatening cardiac arrhythmias when terfenadine was taken concomitantly with drugs such as keto-conazole that inhibit the CYP3A4 isozyme of cytochrome P-450. The active metabolite of terfenadine is currently being marketed as fexofenadine [fecks o FEN a deen] (carboxylated terfenadine), which lacks the cardiac toxicity of terfenadine. 

In the USA, terfenadine was withdrawn from the market in 1998, and in other countries terfenadine has been moved from over-the-counter to prescription-only, with only 60 mg tablets available. The active metabolite of terfenadine, fexofenadine, is marketed as an alternative. For astemizole this option was not available, since the main metabolite (desmethylastemizole) is also cardiotoxic and has a half-life of 10 days astemizole was therefore withdrawn from the market worldwide in June 1999. 

Recently a number of pharmaceutical drugs have been withdrawn from the market or not granted approval due to their pro-arrhythmic tendencies linked to inhibition of hERG. Two examples of this are terfenadine (Seldane) [91], a histamine Hl-receptor antagonist, and cisapride (Propulsid) [92], a gastric pro-kinetic. For this reason the safety assessment profile of any novel compound must now consider the IC50 value of the compound for hERG. 

Drug-induced TdP has become an extremely visible hazard plaguing new drugs, sometimes resulting in public health disasters. For instance, cisapride, astemizole, and terfenadine are potent potassium channel blockers that were withdrawn from the market because of TdP. All these agents are metabolized rapidly to active moieties... 

Second-Generation Piperidines (Prototype Terfena-dine). Terfenadine and astemizole were withdrawn from the market. Current drugs in this class include loratadine, deslor-atadine, and fexofenadine. These agents are highly selective for Hi receptors, lack significant anticholinergic actions, and penetrate poorly into the CNS. Taken together, these properties appear to account for the low incidence of side effects of piperidine antihistamines. 

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