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Ketoconazole and Xanax

Determining the interaction of Ketoconazole and Xanax and the possibility of their joint administration.

Check result:

Ketoconazole <> Xanax

Relevance: 02.09.2022 Reviewer: Shkutko P.M., M.D., in

In the database of official manuals used in the service creation an interaction registered by statistical results of studies was found, which can either lead to negative consequences for the patient health or strengthen a mutual positive effect. A doctor should be consulted to address the issue of joint drug administration.

Consumer:

Using ketoconazole and ALPRAZolam is not recommended. Using these drugs together can cause drowsiness and slowed breathing. It is important that you tell your healthcare provider about all other medications that you are using including vitamins and herbs. Do not stop using your medications without talking to your doctor first.

Professional:

CONTRAINDICATED: Coadministration with itraconazole or ketoconazole may significantly increase the plasma concentrations and pharmacologic effects of benzodiazepines that are primarily metabolized by CYP450 3A4. The mechanism is increased bioavailability and/or decreased clearance due to inhibition of intestinal and hepatic CYP450 3A4 by the azole antifungal agents. In pharmacokinetic studies, itraconazole (200 mg/day) and ketoconazole (400 mg/day) individually increased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and elimination half-life (T1/2) of a single 0.25 mg oral dose of triazolam by more than 3-, 22- and 6-fold, respectively, compared to placebo. Similarly, Cmax, AUC and T1/2 of a single 7.5 mg oral dose of midazolam were more than 3,- 10- and 3-fold higher, respectively, during coadministration of itraconazole or ketoconazole relative to placebo. The AUC of a single 2 mg IV dose of midazolam increased 5-fold after pretreatment with ketoconazole. The results for alprazolam have been less dramatic, presumably due to limited first-pass metabolism in the intestine. In separate studies, itraconazole and ketoconazole increased the AUC of alprazolam (0.8 and 1 mg single oral dose) by 2.5- and 4-fold, respectively, compared to placebo, while Cmax was not significantly affected. Pharmacodynamic changes associated with the interaction include increased and prolonged sedation, enhanced benzodiazepine-related EEG effects, and increased impairment of psychomotor performance. The interaction is subject to a high degree of interpatient variability.

MANAGEMENT: The concomitant use of itraconazole or ketoconazole with alprazolam, oral midazolam, and triazolam is considered contraindicated. Fluconazole and miconazole are weaker inhibitors of CYP450 3A4 but may still cause the interaction, while terbinafine 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 itraconazole or ketoconazole.

References

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
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
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
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
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
"Product Information. Halcion (triazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
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
"Product Information. Xanax (alprazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
Brown MW, Maldonado AL, Meredith CG, Speeg KV "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther 37 (1985): 290-7
Greenblatt DJ, Vonmoltke LL, Harmatz JS, Harrel LM, Tobias S, Shader RI, Wright CE "Interaction of triazolam and ketoconazole." Lancet 345 (1995): 191
"Product Information. Sporonox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
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
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
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
"Product Information. Versed (midazolam)." Roche Laboratories, Nutley, NJ.
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
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
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
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

Ketoconazole

Generic Name: ketoconazole

Brand name: Nizoral

Synonyms: Ketoconazole (Systemic)

What is Ketoconazole?

Xanax

Generic Name: alprazolam

Brand name: Niravam, Xanax, Xanax XR, Alprazolam Intensol

Synonyms: n.a.

What is Xanax?

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In the course of checking the drug compatibility and interactions, data from the following reference sources was used: Drugs.com, Rxlist.com, Webmd.com, Medscape.com.

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