Selected Benzodiazepines/Itraconazole; Ketoconazole
This information is generalized and not intended as specific medical advice. Consult your healthcare professional before taking or discontinuing any drug or commencing any course of treatment.
Moderate. These medicines may cause some risk when taken together. Contact your healthcare professional (e.g. doctor or pharmacist) for more information.
How the interaction occurs:
When these two medicines are taken together, your body may not process your anxiety or sleeping medicine properly.
What might happen:
You may experience unwanted drowsiness, dizziness, confusion, or slow reflexes.
What you should do about this interaction:
Let your healthcare professionals (e.g. doctor or pharmacist) know that you are taking these two medicines together. They may already be aware of this interaction and may be monitoring you for it. It may be necessary to adjust the dose of your anxiety or sleeping medicine. Do not start, stop, or change the dosage of any medicine before checking with them first.
1.Nizoral (ketoconazole) US prescribing information. Janssen Pharmaceutica, Inc. February, 2002.
2.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn Company December, 2008.
3.Valium (diazepam) US prescribing information. Roche Products Inc October, 2013.
4.Versed Syrup (midazolam hydrochloride) US Prescribing Information. Roche Pharmaceuticals December, 1998.
5.Versed Injection (midazolam hydrochloride) US prescribing information. Roche Pharmaceuticals June 2000.
6.Osanai T, Ohkubo T, Yasui N, Kondo T, Kaneko S. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam. Br J Clin Pharmacol 2004 Nov;58(5):476-81.
7.Senda C, Kishimoto W, Sakai K, Nagakura A, Igarashi T. Identification of human cytochrome P450 isoforms involved in the metabolism of brotizolam. Xenobiotica 1997 Sep;27(9):913-22.
8.Ahonen J, Olkkola KT, Neuvonen PJ. The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam. Fundam Clin Pharmacol 1996;10(3):314-8.
9.Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, Tateishi T, Otani K. Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism. Eur J Clin Pharmacol 2004 Aug;60(6):427-30.
10.Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, Sellers EM. Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4. Drug Metab Dispos 2001 Apr;29(4 Pt 1):460-5.
11.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 1998 Mar;54(1):53-8.
12.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 1995 Sep;40(3):270-2.
13.Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996 Mar;82(3):511-6.
14.Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994 May;55(5):481-5.
15.Wang JS, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT. Midazolam alpha-hydroxylation by human liver microsomes in vitro: inhibition by calcium channel blockers, itraconazole and ketoconazole. Pharmacol Toxicol 1999 Oct;85(4):157-61.
16.von Moltke 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 1996 Sep;36(9):783-91.
17.Lam YW, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 2003 Nov; 43(11):1274-82.
18.Stoch SA, Friedman E, Maes A, Yee K, Xu Y, Larson P, Fitzgerald M, Chodakewitz J, Wagner JA. Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: shortening the paradigm. J Clin Pharmacol 2009 Apr;49(4):398-406.
19.Tham LS, Lee HS, Wang L, Yong WP, Fan L, Ong AB, Sukri N, Soo R, Lee SC, Goh BC. Ketoconazole renders poor CYP3A phenotype status with midazolam as probe drug. Ther Drug Monit 2006 Apr;28(2):255-61.
20.Patki KC, Von Moltke LL, Greenblatt DJ. In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos 2003 Jul;31(7):938-44.
21.Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T. Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 1998 Oct 9; 358(3):289-94.
22.Wrighton SA, Ring BJ. Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm Res 1994 Jun;11(6):921-4.