Terfenadine Itraconazole

Ruelle, J. A., Tsinman, 0., Avdeef, A. Acid-base cosolvent method for determining aqueous permeability of amiodarone, itraconazole, tamoxifen, terfenadine and other very insoluble molecules. Chem. Pharm. Bull. 2004, 52, 551-555. 

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, ... 

It seems likely that combining itraconazole with astemi-zole (59) and terfenadine (60,61) will lead to increased effects of these antihistamines (62). 

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). 

Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 1993 33(12) 1201-6. 

In general, itraconazole is more effective and better tolerated than is ketoconazole. Unlike ketoconazolc. it is not hep-atotoxic and does not cause adrenal or testicular suppression in recommended therapeutic doses.Nonetheless, itraconazole can inhibit cytochrome P-4S0 oxidases involved in drug and xenobiotic metabolism and is known to increase plasma levels of the aniihislaminic drugs terfenadine and astemizole. 

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. 

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... 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

CYP3A4 Alfentanil Alprazolam Astern izole Carbamazepine Cisapride Cyclosporine Diltiazem Erythromycin Felodipine Fluconazole Itraconazole Ketoconazole Lidocaine Lova statin Midazolam Nifedipine Quinidine Simvastatin Tacrolimus Terfenadine Verapamil... 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

A4 28 34 clarithromycin, codeine, diazepam, erythromycin, indinavir, midazolam, nifedipine, quinidine, terfenadine, verapamil ketoconazole, itraconazole... 

The azole antifungals raise the levels of astemizole and terfena-dine, which can result in life-threatening arrhythmias. Arrhythmias have been reported for astemizole with ketoconazole, and terfenadine with itraconazole, ketoconazole, and even topical ox-iconazole. Consequently all azoles are contraindicated with astemizole and terfenadine. 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

Terfenadine 120 mg single dose Itraconazole 200 mg daily Single dose 6 healthy subjects Terfenadine 25H, II5H, l56Hlnthe3 subjects who had measurable levels prior to Itraconazole 30% Terfenadine acid metabolite Mean increase of 27 milliseconds when compared to terfenadine alone 15... 

The interactions of astemizole with ketoconazole, and terfenadine with itraconazole or ketoconazole are established and clinically important, although much of the evidence for them is indirect. Astemizole would also be expected to interact similarly with itraconazole. The risk of an interaction with terfenadine or astemizole and other azole antifungals seems smaller. 

Pohjola-Sintonen S, ViitasaloM, ToivonenL,NeuvonenP. Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia. EurJClinPhar-macol ( 993) 45, 191-3. 

Crane JK, Shih H-T. Syncope and cardiac arrhythm ia due to an interaction between itraconazole and terfenadine. HwJMec (1993) 95, 445-6. 

Romkes JH, Froger CL, Wever EFD, Westerhof PW. Wegrakingentijdenssimultaangebruik van terfenadine en itraconazol. NedTijdschr Geneeskd ( 997) 141, 950-3. 

The manufacturers of sertindole contraindicate the concurrent use of cimetidine, diltiazem, erythromycin, itraconazole, ketoco-nazole, terfenadine and verapamil because of an increased risk of cardiac arrhythmias. Carbamazepine and phenytoin reduce plasma sertindole levels whereas fluoxetine and paroxetine increase them. No clinically relevant interactions occur with alprazolam, antacids, food or tobacco smoking. 

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