Alprazolam and Ketoconazole Topical: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Alprazolam
Ketoconazole Topical
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased ALPRAZolam exposure and an increased risk of ALPRAZolam-related adverse reactions
Interaction Deep Dive
Concomitant use of ALPRAZolam (CYP3A4 substrate) with a strong CYP3A4 inhibitor (with the exception of ritonavir) is contraindicated due to a profound effect on the clearance of ALPRAZolam, resulting in increased concentrations of ALPRAZolam and increased risk of adverse reactions. Coadministration of ALPRAZolam separately with strong CYP3A4 inhibitors ketoconazole, itraconazole, and nefazodone increased ALPRAZolam AUC by 3.98-fold, 2.66-fold, and 1.98-fold, respectively34.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of ALPRAZolam
Literature reports
10 reports — tap to read
a) In in-vivo drug interactions studies, concomitant use of ALPRAZolam with strong CYP3A4 inhibitors increased ALPRAZolam AUC as follows: ketoconazole by 3.98-fold, itraconazole by 2.66-fold, and nefazodone by 1.98-fold 34.
b) In a pharmacokinetic study in healthy subjects or chronic hepatitis C patients (n=17), concomitant administration of a single-dose of ALPRAZolam 0.5 mg and telaprevir 750 mg every 8 hours for 10 days resulted in increased in ALPRAZolam AUC (ratio estimate with telaprevir to without telaprevir), 1.35 (90% confidence interval, 1.23 to 1.49) 1.
c) Interactions involving HIV protease inhibitors (eg, ritonavir) and ALPRAZolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of ALPRAZolam by about 2.5-fold, and did not significantly affect Cmax of ALPRAZolam. The elimination t(1/2) was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A4 induction offset this inhibition. ALPRAZolam AUC and Cmax were reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination t(1/2) of ALPRAZolam was not significantly changed 34.
d) Healthy male volunteers (n=7) participated in a single-dose, 5-way crossover study to determine the magnitude and clinical consequence of the interaction of ketoconazole with ALPRAZolam. The 5 treatment phases consisted of placebo and ALPRAZolam 1 mg, ketoconazole 200 mg and ALPRAZolam 1 mg, and ketoconazole 200 mg and placebo. The elimination t(1/2) of ALPRAZolam increased from 15.2 hours to 59 hours during ketoconazole coadministration, while the total AUC of ALPRAZolam increased from 237 nanogram/mL x hr to 944 nanogram/mL x hr. The oral clearance of ALPRAZolam decreased from 86 mL/min to 27 mL/min. However, the Cmax was not significantly altered by the presence of ketoconazole. Pharmacodynamically, ketoconazole enhanced the benzodiazepine effects of ALPRAZolam but statistical significance was not always achieved due to the degree of variability and the small sample size 2.
e) Itraconazole significantly increased plasma concentrations of ALPRAZolam via its inhibitory effects on ALPRAZolam metabolism and depressed psychomotor function during a randomized crossover study involving healthy volunteers (N=10). Each study participant received itraconazole 200 mg daily or matching placebo for 6 days while ingesting a single oral dose of ALPRAZolam 0.8 mg on day 4. Itraconazole increased the ALPRAZolam AUC from 252 nanogram/mL x hr to 671 nanogram/mL x hr and decreased the oral clearance from 0.89 mL/min/kg to 0.35 mL/min/kg. ALPRAZolam t(1/2) was also extended from 15.7 hours to 40.3 hours. No significant differences were noted in the ALPRAZolam Cmax or Tmax when itraconazole was present. Measurements of psychomotor function were evaluated by the digit symbol substitution test (DSST), the visual analog scale (VAS), and the Udvalg for kliniske undersogelser (UKU) scales. Itraconazole decreased the AUC (0 to 48 hours) of the DSST and increased the "spacy" item of the VAS and the "sleepiness" item of the UKU 5.
f) Coadministration of ALPRAZolam with nefazodone (strong CYP3A4 inhibitor) was studied in a randomized pharmacokinetic study (N=48). Subjects received either placebo twice daily, ALPRAZolam 1 mg twice daily, nefazodone 200 mg twice daily, or a combination of ALPRAZolam 1 mg and nefazodone 200 mg twice daily for 7 days. Nefazodone significantly increased ALPRAZolam Cmax approximately 2-fold while the Cmax of the alpha-hydroxy ALPRAZolam metabolite decreased by 40% 6.
g) A double-blind, placebo-controlled study of healthy volunteers has found that clearance of intravenously administered midazolam is reduced by about 50% following 5 days of erythromycin therapy versus placebo 7.
h) In a study involving normal volunteers, erythromycin (333 mg TID for 3 days) increased the peak levels of triazolam by 50%, increased the half-life from 4 to 6 hours, and decreased the volume of distribution 8.
i) An 8-year-old boy undergoing adenoidectomy was premedicated with oral midazolam 0.5 mg/kg and oral atropine 0.03 mg/kg, followed in 1 hour by erythromycin 400 mg IV. The patient lost consciousness 40 minutes later after 200 mg had been infused; other vital signs remained normal, and he regained consciousness after 45 minutes. At 170 minutes post-medication, his midazolam plasma concentration was 134 nanograms/mL (411 nanomol/L). Six other children who were similarly premedicated (midazolam 0.5 mg/kg and atropine 0.03 mg/kg) but did not receive erythromycin had a mean midazolam level of 73 nanograms/mL (224 nanomol/L) 9.
j) Macrolide antibiotics may inhibit hepatic enzymes responsible for benzodiazepine metabolism leading to increased plasma concentrations of benzodiazepines through reduced clearance, prolonged half-life, and increased volume of distribution 10879.
Common questions
Can I take Alprazolam and Ketoconazole Topical together?
Increased ALPRAZolam exposure and an increased risk of ALPRAZolam-related adverse reactions Always confirm with your pharmacist or prescriber before making any change.
How serious is the Alprazolam and Ketoconazole Topical interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Alprazolam or Ketoconazole Topical need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (10)
- Product Information: INCIVEK(TM) film coated oral tablets, telaprevir film coated oral tablets. Vertex Pharmaceuticals Incorporated, Cambridge, MA, 2011.
- Greenblatt DJ, Wright CE, von Moltke LL, et al: Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther 1998; 64:237-247. DOI
- Product Information: XANAX(R) oral tablets, alprazolam oral tablets. Pharmacia & Upjohn Co (per FDA), New York, NY, 2023. DailyMed
- Product Information: Xanax(R) XR oral extended-release tablets, alprazolam oral extended-release tablets. Pharmacia & Upjohn Co (per FDA), New York, NY, 2023. DailyMed
- Yasui N, Kondo T, Otani K, et al: Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology 1998; 139:269-273. PubMed
- Greene DS, Salazar DE, Dockens RC, et al: Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15:399-408. DOI
- Olkkola KT, Aranko K, Luurila H, et al: A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993; 53:298-305. PubMed
- Phillips JP, Antal EJ, & Smith RB: A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986; 6:297-299. DOI
- Hiller A, Olkkola KT, Isohanni P, et al: Unconsciousness associated with midazolam and erythromycin. Br J Anaesth 1990; 65:826-828. DOI
- Warot D, Bergougnan L, Lamiable D, et al: Troleandomycin-triazolam interaction in healthy volunteers: pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol 1987; 32:389-393. PubMed
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