Terfenadine Nefazodone

Contraindications Co-administration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine hypersensitivity to other phenylpiperazine antidepressants those who were withdrawn from nefazodone due to evidence of hepatic injury use within 14 days of MAOIs... 

Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, and fluconazole), acetazolamide, verapamil, grapefruit juice, ... 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

Nefazodone is a weak inhibitor of CYP2D6 but a potent inhibitor of CYP3A4 and it increases plasma concentrations of drugs that are substrates of CYP3A4, such as alprazolam, astemizole, carbamazepine, ciclosporin, cisapride, terfenadine, and triazolam. 

Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTC interval. This can cause potentially dangerous interactions. In a double-blind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTC interval (27). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTC interval. This effect of nefazodone on... 

Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE. Loratadine and terfenadine interaction with nefazodone both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001 69(3) 96-103. 

Nefazodone is a phenylpiperazine antidepressant that is predominantly metabolized by CYP3A. In a randomized, double-blind, double-dummy, parallel-group, multiple-dose study in healthy men and women who were given terfenadine 60 mg every 12 hours or nefazodone 300 mg every 12 hours, the plasma concentrations of terfenadine were significantly increased by co-administration of nefazodone (10). The mean QTc interval was unchanged by terfenadine alone, but was markedly prolonged with co-administration of nefazodone, and the extent of prolongation correlated with the plasma terfenadine concentration. 

Clinically important, potentially hazardous interactions with alprazolam, astemizole, carbamazepine, cisapride, clarithromycin, dexamethasone, diltiazem, docetaxel, ifosfamide, imatinib, irinotecan, itraconazole, ketoconazole, methylprednisolone, midazolam, nefazodone, oral contraceptives, paroxetine, phenytoin, pimozide, rifampin, ritonavir, terfenadine, tolbutamide, trabectedin, troleandomycin, vinblastine, vincristine, warfarin... 

Clinically important, potentially hazardous interactions with amiodarone, azithromycin, bepredil, bosentan, bretylium, cisapride, clarithromycin, disopyramide, erythromycin, erythromycin fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nefazodone, nilotinib, paroxetine, pimozide, probucol, procainamide, quinidine, quinine, ritonavir, saquinavir, sertraline, sotalol, SSRIs, terfenadine, troleandomycin, voriconazole, zileuton, ziprasidone... 

Nefazodone inhibits the metabolism of terfenadine and thereby prolongs the QT interval. This combination should be avoided. There is also some evidence that the combination of nefazodone and loratadine increases the QT interval, although to a lesser extent than terfenadine. In vitro evidence suggests nefazodone will also inhibit the metabolism of astemizole. 

A randomised, placebo-controlled study in healthy subjects found that when they were given nefazodone 300 mg twice daily with loratadine 20 mg once daily, the loratadine AUC was increased by 39%. Similarly, the QTc interval was increased by 21.6 milliseconds by the combination, which was about half the increase seen with terfenadine 60 mg twice daily given with the same dose of nefazodone. Neither nefazodone, loratadine nor terfenadine alone prolonged the QTc interval. The findings for loratadine in this study were unexpected, since this antihistamine was considered to have no clinically relevant effect on the QT interval (but see also Table 15.2 , (p.583)). The use of the Bazett formula to calculate QTc has... 

In a randomised, placebo-controlled study, healthy subjects were given nefazodone 300 mg twice daily and terfenadine 60 mg twice daily, given alone and in combination. Nefazodone increased the AUC of terfenadine by about fivefold, which was associated with a mean increase in the QTc interval of 42.4 milliseconds. This was considered to result in a clinically significant, increase in the risk of torsade de pointes arrhythmias. Studies using human liver microsomes found that nefazodone is a moderately weak inhibitor of the CYP3A4-mediated A-dealkylation and C-hydroxy-lation of terfenadine. Nefazodone is contraindicated with terfenadine, - and it has been suggested that this explains the lack of clinical reports. ... 

Buspirone does not appear to interact with amitriptyline, cimetidine or terfenadine. An isolated report describes mania when an alcoholic patient taking huspirone was given disulfiram. Nefazodone greatly increases huspirone levels. 

---