Terfenadine Azoles

Jurima-Romet, M., Crawford, K. et al. (1994). Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab. Dispos., 22(6), 849-57. 

WARNING Co administration w/ ritonavir assoc w/ Hep hepatic decomp w/ fatalities. D/C w/ S/Sxs of H Uses HIV 1 Infxn w/ highly Tx-experienced pts or HIV 1 strains resistant to multiple protease inhibitors. Must be used w/ ritonavir 200 mg Action Antiretroviral HIV-1 protease inhibitor Dose 500 mg PO bid w/ food, administer w/ ritonavir 200 mg PO bid Caution [C, -] Sulfa aU gy, Uvct Dz Contra Mod-severe hepatic insuff concomitant use w/ amiodarone, astemizole, bepridil, cisapride, ergots, flecainide, lovastatin, midazolam, pimozide, propafenone, quinidine, rifampin, simvastatin, terfenadine, triazolam, St. John s wort Disp Caps SE HA, GI distress, rash, fati e, fat redistribution, hyperglycemia, Hep, liver Dz, lipid elevations Interactions T Effects OF anticoagulants, antipits, azole antifun-... 

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, ... 

Contraindications Hypersensitivity to fluconazole or to any of its excipients Caution should be used in patients with hypersensitivity to other azoles Should not be used with terfenadine orastemizole ... 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinupristin/ dalfbpristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS - arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine S. ANTIEMETICS-dolasetron 6. ANTIFUNGALS - fluconazole, posacon-azole, voriconazole 7. ANTIHISTAMINES-terfenadine, hydroxyzine, mizolastine... 

Von Moltke LL, Greenblatt DJ, Duan SX, et al. Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants Relations to pharmacokinetic interactions in vivo. / Clin Psychopharmacol. 1996 16 104-112. 

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. 

Jurima-Romet, M. Crawford, K. Cyr, T. Inaba, T. Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab.Dispos., 1994, 22, 849—857 [extracted metabolites microsomal incubations rat column temp 35 LOQ 92 nM] von Moltke, L.L. Greenblatt, D.J. Duan, S.X. Harmatz, J.S. Shader, R.I. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J.Clin.Pharmacol., 1994, 34, 1222—1227 [clomipramine (IS) microsomal incubations]... 

In the presence of CYP3A4 inhibitors such as azole antifungal drugs, erythromycin and grapefruit juice, blood concentrations of the antihistamine terfenadine significantly increase, resulting in cardiotoxicity. Terfenadine has been withdrawn from sale in the US. 

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. 

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. 

The incidence of an interaction is probably low, but because of the potential severity and unpredictability of this interaction, the concurrent use of astemizole and terfenadine is contraindicated with all azole antifungals... 

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