Can a patient take itraconazole and alprazolam (Xanax) together?

Contraindication: Itraconazole and Alprazolam Cannot Be Taken Together

No, a patient cannot take itraconazole and alprazolam together—this combination is absolutely contraindicated according to the FDA drug label for alprazolam. 1

Mechanism of the Contraindication

• Itraconazole is a potent CYP3A4 inhibitor that dramatically blocks alprazolam's primary metabolic pathway, leading to severely elevated alprazolam plasma concentrations 2
• This interaction occurs because alprazolam is metabolized almost exclusively through the CYP3A4 enzyme system, which itraconazole powerfully inhibits 1, 3
• The result is dangerous accumulation of alprazolam in the bloodstream, potentially reaching toxic levels 2

Clinical Consequences of This Interaction

• The Infectious Diseases Society of America guidelines classify azole antifungals as having significant drug-drug interactions with benzodiazepines that may adversely affect patient outcomes, including enhanced benzodiazepine toxicity 2
• Excessive benzodiazepine levels can cause profound sedation, respiratory depression, cognitive impairment, and loss of consciousness 2
• The FDA explicitly lists itraconazole as a contraindication for alprazolam use because these medications "significantly impair the oxidative metabolism mediated by cytochrome P450 3A" 1

Management Algorithm

If the patient is currently on alprazolam and needs antifungal therapy:

1. Consider alternative antifungal agents without CYP3A4 interactions: Echinocandins (caspofungin, micafungin, anidulafungin) lack significant CYP450 interactions and may be appropriate alternatives depending on the fungal infection being treated 2

2. If an azole is absolutely necessary: Consider fluconazole as a potential alternative, though it still has some CYP3A4 inhibitory effects—this requires careful monitoring and possible dose adjustment of alprazolam 4

3. Switch the benzodiazepine: Diazepam has less interaction potential with itraconazole compared to alprazolam, midazolam, and triazolam because it lacks significant first-pass metabolism and uses different metabolic pathways 5

If the patient is on itraconazole and needs anxiolytic therapy:

1. Avoid all contraindicated benzodiazepines: The Infectious Diseases Society of America specifically lists midazolam and triazolam as contraindicated with itraconazole 6

• While alprazolam is not explicitly mentioned in these guidelines, the FDA contraindication takes precedence 1

1. Use alternative anxiolytic medications: Consider non-benzodiazepine options such as SSRIs, SNRIs, buspirone, or hydroxyzine that do not rely on CYP3A4 metabolism

2. If a benzodiazepine is essential: Lorazepam, oxazepam, or temazepam undergo glucuronidation rather than CYP3A4 metabolism and are safer alternatives during itraconazole therapy

Critical Pitfalls to Avoid

• Never assume that because other benzodiazepines may have less severe interactions, alprazolam can be used cautiously—the FDA contraindication is absolute 1
• Do not attempt dose reduction of alprazolam as a workaround—even small doses can accumulate to dangerous levels when CYP3A4 is blocked 2
• Remember that the interaction persists for several days after discontinuing itraconazole due to its long half-life and continued enzyme inhibition 7
• Review all concurrent medications before initiating itraconazole, as multiple CYP3A4 substrates can create cumulative toxicity risks 7, 4

Documentation Requirements

• The Infectious Diseases Society of America guidelines state that when itraconazole is prescribed, "reasons for deviation from this practice should be documented in the medical record" if contraindicated medications are given 6
• In this case, there is no acceptable reason to deviate from the contraindication between itraconazole and alprazolam 1