Terfenadine toxicity

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Figure 5.3d The metabolism of the drug terfenadine. The double lines indicate the inhibition of metabolism by other drugs such as ketoconazole or the natural product found in grapefruit juice. This leads to a rise in the blood level of the drug and toxicity.

The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

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. 

Q7 Fexofenadine is a metabolite of another antihistamine, terfenadine, but has little or no cardiac toxicity. The development of sedation and antimuscarinic effects are limited since fexofenadine cannot easily cross the blood-brain barrier (only a very small amount can cross this barrier). The recommended adult dosage is 120 mg once daily. It is also recommended for children above 12 years of age. 

GRAPEFRUIT JUICE TERFENADINE Statistically t Q-T interval prolongation, hence the risk of cardiac toxicity, t in AUC, maximum concentration and T max. Two-fold t half-life. Possibly t efficacy and t adverse effects, e.g. torsade de pointes Altered metabolism so the parent drug accumulates. Due to effects of grapefruit juice on CYP isoenzymes and P-gp Avoid concomitant intake. Suitable alternatives that are less harmful are available, e.g. loratidine (which is also metabolized by CYP2D6), cetrizine, desloratidine. This is despite a report that no significant cardiotoxicity is likely in normal subjects... 

Citrus flavinoids in grapefruit (but not orange) juice decrease hepatic metaboUsm and may lead to risk of toxicity from amiodarone, terfenadine (cardiac arrhythmia), benzodiazepines (increased sedation), ciclosporin, felodipine (reduced blood pressure). 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrolides, especially clarithromycin (48-51), typically resulting in prolongation of the QT interval and cardiac dysrhythmias (torsade de pointes) (52). 

This particular regimen apparently resulted in a second interaction, since unexpectedly very high concentrations of terfenadine were found (SEDA-18,283). The phenomenon has been described by others, with a marked rise in terfenadine serum concentrations, and increased toxicity of the drug during concurrent ingestion of itraconazole. The mechanism is not known, but it is likely to be related to inhibition of CYP3A4 (62). 

Ketoconazole can increase the concentrations of astemi-zole and terfenadine by inhibition of CYP3A4. High concentrations of terfenadine can cause cardiac toxicity. Increased plasma concentrations of unmetabohzed terfenadine prolong the QT interval and carry the risk of torsade de pointes and other fatal ventricular arrhythmias (13). 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrohdes, especially clarithromycin (87-89,116), typically resnlting in prolongation of the QT interval and cardiac dysrhjdhmias (torsade de pointes) (111). The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine pins placebo (90). However, azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QTc interval. 

Flockhart, D. A. 1996. Drug interactions, cardiac toxicity and terfenadine from bench to clinic Journal of Clinical Psychopharmacology 16 101-02. 

The carcinogenic potential and reproductive toxicity of fexofenadine hydrochloride were assessed using terfenadine studies with adequate fexofenadine hydrochloride exposure (based on plasma area under the concentration versus time (AUC) values). No evidence of carcinogenicity was observed in an 18 month study in mice and in a 24 month study in rats at oral doses up to 150 mg kg of terfenadine (which led to fexofenadine exposures that were, respectively, 3 and 5 times the exposure from the maximum recommended daily oral dose of fexofenadine hydrochloride in adults and children). 

Accumulation of the parent drug and resultant QT prolongation may occur following a overdose, a drug interaction that limits metabolism of terfenadine (e.g., concomitant administration with erythromycin or other macrolide antibiotic or with the azole derivatives ketoconazole or itraconazole), or significant hepatic dysfunction that limits metabolism of terfenadine. Patients with preexisting cardiac disease or those with electrolyte abnormalities are also at increased risk for cardiac toxicity. 

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