Basic Information
ID DDInter743 and DDInter54
Interaction Coadministration with potent inhibitors of CYP450 3A4 including azole antifungal agents may significantly increase the plasma concentrations of benzodiazepines that are primarily metabolized by the isoenzyme.
Management Although clotrimazole, fluconazole, miconazole, and voriconazole are weaker inhibitors of CYP450 3A4 than itraconazole and ketoconazole, product labelings for alprazolam and triazolam recommend against use with any azole antifungal agent. The same precaution probably applies also to oral midazolam and high dosages of intravenous midazolam. Terbinafine may be an appropriate alternative, as it is not an inhibitor of CYP450 3A4 and has been shown to have no effect on the pharmacokinetics of midazolam and triazolam. Alternatively, benzodiazepines that are not metabolized by CYP450 3A4 (e.g., lorazepam, oxazepam, temazepam) may be considered in patients requiring treatment with azole antifungal agents. Limited data suggest that fluconazole given intermittently (e.g., 150 mg once or once a week) may be safely administered in combination with midazolam and possibly other benzodiazepines.
References [1] Vonmoltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI "Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents." J Clin Pharmacol 36 (1996): 783-91 [2] Ahonen J, Olkkola KT, Neuvonen PJ "Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers." Br J Clin Pharmacol 40 (1995): 270-2 [3] "Product Information. Halcion (triazolam)." Pharmacia and Upjohn, Kalamazoo, MI. [4] Vonmoltke LL, Greenblatt DJ, Cotreaubibbo MM, Harmatz JS, Shader RI "Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine." Br J Clin Pharmacol 38 (1994): 23-31 [5] Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ "The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin." Eur J Clin Pharmacol 54 (1998): 53-8 [6] Greenblatt DJ, Vonmoltke LL, Harmatz JS, Harrel LM, Tobias S, Shader RI, Wright CE "Interaction of triazolam and ketoconazole." Lancet 345 (1995): 191 [7] Varhe A, Olkkola KT, Neuvonen PJ "Effect of fluconazole dose on the extent of fluconazole-triazolam interaction." Br J Clin Pharmacol 42 (1996): 465-70 [8] Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4 [9] Varhe A, Olkkola KT, Neuvonen PJ "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 56 (1994): 601-7 [10] Tsunoda SM, Velez RL, vonMoltke LL, Greenblatt DJ "Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole." Clin Pharmacol Ther 66 (1999): 461-71 [11] Ahonen J, Olkkola KT, Neuvonen PJ "Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam." Ther Drug Monit 18 (1996): 124-7 [12] Greenblatt DJ, Wright CE, vonMoltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, Shader RI "Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences." Clin Pharmacol Ther 64 (1998): 237-47 [13] Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57 [14] "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn, Kalamazoo, MI. [15] Vanakoski J, Mattila MJ, Vainio P, Idanpaanheikkila JJ, Tornwall M "150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects." Int J Clin Pharmacol Ther 33 (1995): 518-23 [16] Brown MW, Maldonado AL, Meredith CG, Speeg KV "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther 37 (1985): 290-7 [17] Varhe A, Olkkola KT, Neuvonen PJ "Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism." Br J Clin Pharmacol 41 (1996): 319-23 [18] Neuvonen PJ, Varhe A, Olkkola KT "The effect of ingestion time interval on the interaction between itraconazole and triazolam." Clin Pharmacol Ther 60 (1996): 326-31 [19] Olkkola KT, Backman JT, Neuvonen PJ "Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 55 (1994): 481-5 [20] Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K "Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam." Psychopharmacology 139 (1998): 269-73 [21] Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther 58 (1995): 127-31 [22] Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther 58 (1995): 20-8 [23] Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77 [24] "Product Information. Valium (diazepam)." Roche Laboratories, Nutley, NJ. [25] "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn, Kalamazoo, MI. [26] "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4 [27] "Product Information. Halcion (triazolam)." Pharmacia and Upjohn, Kalamazoo, MI. [28] Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm 66 (2009): 1438-67 [29] "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals, New York, NY.
Alternative for Fluconazole J01R
Cefixime Secnidazole Levofloxacin Tinidazole

J02A
Caspofungin Flucytosine Anidulafungin Micafungin Oteseconazole

D01A
Econazole Thiabendazole
More
Alternative for Alprazolam N05B
Halazepam Clorazepic acid Chlordiazepoxide
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.