Seldane - Terfenadine

Figure 1.10 Thalomid (thalidomide), Revlimid (lenaiidomide), Vioxx (rofecoxib), Lamprene (clofazimine), and Seldane (terfenadine).

Figure 6.31 Top Claritin (loralidine) and its active metabolite Clarinex (desloralidine). Bottom Seldane (terfenadine) and its active metabolite AUegra (fexofenadine).

Terfenadine (Seldane) Allergy Cardiovascular (potentially fatal heart condition) 1998 [58]... 

Fleischer Kupec, I. (1998) Seldane and generic terfenadine withdrawn from market, in FDA Talk Paper, FDA, Rockville, MD. 

Terfenadine Seldane, Seldane-D Hoechst Marion Roussel Antihistamine 5/8/1985 2/27/1998 2.75 years Heart rhythm abnormalities Not available... 

Synthetic drugs, brompheniramine (Dimetapp) and terfenadine (Seldane), act as antihistamines. They interfere with the natural action... 

One can find many more examples where a subtle modification in a side chain leads to a new drug that produces a drastically different therapeutic or toxicological outcome. This is clearly illustrated by the nonsedating antihistamine terfenadine (Seldane), which produces cardiotoxicity when given with certain drugs that inhibits its metabolism. This product is no longer marketed. It has been replaced by its safer but no less effective carboxylic oxidative metabolite fexofenadine (Allegra). 

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 Its patent protection was near expiration when the drug was voluntarily withdrawn from the antihistamine market in 1997.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that terfenadine (Seldane ), the once widely-used, selective Hi histamine receptor antagonist, has been voluntarily withdrawn from the market by the manufacturer.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. 

Terfenadine Seldane , Triludan acetonide Kenalog , Kenalone ,... 

Sometimes an active pharmaceutical produces another active agent after biotransformation. An example of a commercially popular drug with an active metabolite is terfenadine (Seldane )/ as shown in Scheme 11.3. As discussed in Chapter 1/ the terfenadine oxidative metabolite/ fexofenadine (Allegra )/ is now marketed as a safer alternative that avoids potentially fatal cardiac terfenadine side effects. 

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. 

Wyim RL. Erythromycin and ketoconazole (Nizoral) associated with terfenadine (Seldane)-induced ventricular arrhythmias. Gen Dent 1993 41(l) 27-9. 

Terfenadine/Seldane (antihistamine, February 1998), Cisapride/Propulsid (GI prokinetic, July 2000), Grepafloxacin/Raxar (antibiotic, November 1999), Sertindole (antipsychotic, December 1998), and As-temizole (antihistamine, June 1999). See Table 1 for a list of nonantiarrhythmic drugs associated with QT interval prolongation. 

Antihistamines terfenadine (Seldane) astemizole (Hismanol) loratadine (Claritin) diphenhydramine (Benadryl)... 

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. 

Terfenadine (Seldane/Seldane-D) Antihistamine Torsades de Pointes Drugdrug interactions... 

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