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diazepam injection

Selected Benzodiazepines/Selected Azole Antifungals

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.

Medical warning:

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:

Your antifungal medicine may slow down your body's ability to process the benzodiazepine.

What might happen:

The levels of the benzodiazepine may build up in your body. The effects of the benzodiazepine may increase.

What you should do about this interaction:

Let your healthcare professionals (e.g. doctor or pharmacist) know that you are taking these medicines together. If you notice an increase in the effects of your benzodiazepine, such as drowsiness, contact your doctor. The dose of your benzodiazepine may need to be changed.Your healthcare professionals may already be aware of this interaction and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

References:

1.Saari TI, Laine K, Bertilsson L, Neuvonen PJ, Olkkola KT. Voriconazole and fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol 2007 Oct;63(10):941-9.
2.Ahonen J, Olkkola KT, Takala A, Neuvonen PJ. Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol Scand 1999 May;43(5):509-14.
3.Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. Eur J Clin Pharmacol 1997;51(5):415-9.
4.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.
5.Vanakoski J, Mattila MJ, Vainio P, Idanpaan-Heikkila 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 1995 Sep;33(9):518-23.
6.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.
7.Noxafil (posaconazole) UK summary of product characteristics. Schering-Plough Ltd. February 2, 2006.
8.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc March, 2014.
9.Krishna G, Moton A, Ma L, Savant I, Martinho M, Seiberling M, McLeod J. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther 2009 Feb;31(2):286-98.
10.Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 2006 Apr; 79(4):362-70.
11.Varhe A, Olkkola KT, Neuvonen PJ. Effect of fluconazole dose on the extent of fluconazole-triazolam interaction. Br J Clin Pharmacol 1996 Oct;42(4):465-70.
12.Varhe A, Olkkola KT, Neuvonen PJ. Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. Br J Clin Pharmacol 1996 Apr;41(4):319-23.
13.Allqvist A, Miura J, Bertilsson L, Mirghani RA. Inhibition of CYP3A4 and CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as racemate and four different enantiomers. Eur J Clin Pharmacol 2007 Feb; 63(2):173-9.
14.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 (Berl) 1998 Oct;139(3):269-73.
15.Greenblatt DJ, Wright CE, von Moltke 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 1998 Sep;64(3):237-47.
16.von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI. Inhibitors of alprazolam metabolism in vitro: effect of serotonin- reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994 Jul;38(1):23-31.
17.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.
18.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.
19.Miura M, Otani K, Ohkubo T. Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam. Xenobiotica 2005 May;35(5):455-65.
20.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.
21.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.
22.Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method. J Clin Pharmacol 2002 Feb;42(2):183-91.
23.Valium (diazepam) US prescribing information. Roche Products Inc October, 2013.
24.US Food and Drug Administration (FDA). Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm093664.htm. Updated 08/05/2011.

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