Alprazolam and Itraconazole: Contraindicated Combination
No, a patient cannot take alprazolam with itraconazole—this combination is absolutely contraindicated. The FDA drug label explicitly states that alprazolam is contraindicated with itraconazole because itraconazole significantly impairs the oxidative metabolism of alprazolam mediated by cytochrome P450 3A (CYP3A) 1.
Mechanism of Interaction
Itraconazole is a potent CYP3A4 inhibitor that dramatically increases alprazolam plasma concentrations by blocking its primary metabolic pathway 2.
Clinical pharmacokinetic data demonstrate severe interaction: When itraconazole 200 mg/day was coadministered with alprazolam 0.8 mg, the area under the concentration-time curve increased 2.7-fold (from 252 to 671 ng·h/ml), oral clearance decreased by 61% (from 0.89 to 0.35 ml/min/kg), and elimination half-life prolonged 2.6-fold (from 15.7 to 40.3 hours) 3.
Psychomotor depression was significantly enhanced during concurrent administration, reflecting dangerous accumulation of alprazolam 3.
Clinical Consequences
Enhanced benzodiazepine toxicity including excessive sedation, respiratory depression, cognitive impairment, and prolonged psychomotor dysfunction 4, 3.
Unpredictable duration of effects due to markedly prolonged elimination half-life, creating risk that extends well beyond the expected timeframe 3.
The Infectious Diseases Society of America guidelines classify azole antifungals as having significant drug-drug interactions with psychiatric and neurotropic medications that may adversely affect patient outcomes 2.
Management Algorithm
If both medications are clinically necessary:
Discontinue alprazolam immediately when itraconazole therapy is required 1.
Consider alternative benzodiazepines with different metabolic pathways: Temazepam undergoes glucuronidation rather than CYP3A4 metabolism and shows no clinically significant interaction with itraconazole despite minor pharmacokinetic changes 5. Lorazepam and oxazepam are also metabolized via glucuronidation and would be safer alternatives.
Consider alternative antifungal agents if the patient requires ongoing benzodiazepine therapy: Echinocandins (caspofungin, micafungin, anidulafungin) lack significant CYP450 interactions 6.
Never attempt dose reduction of alprazolam as a strategy to continue both medications—the interaction is too severe and unpredictable for safe coadministration 1, 3.
Common Pitfalls to Avoid
Do not assume other azoles have the same interaction severity: While all azoles inhibit CYP3A4, itraconazole and ketoconazole are the most potent inhibitors and share the same contraindication with alprazolam 1, 4.
Do not confuse this with less severe benzodiazepine interactions: Unlike the modest interaction seen with temazepam and itraconazole, the alprazolam-itraconazole combination produces life-threatening toxicity 3, 5.
Remember that effects persist beyond itraconazole discontinuation: Given itraconazole's long half-life and the prolonged elimination of accumulated alprazolam, allow adequate washout periods (at least 5-7 days after stopping itraconazole) before reinitiating alprazolam 3.