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Xanax Interactions: What to Avoid

Documented interactions for Xanax (alprazolam). Each entry cites the prescribing information or FDA safety communication it is based on.

6 major3 moderate

Interaction summary

SeverityInteracts withClassConcern
MajorAlcohol (ethanol)CNS depressantAlprazolam with alcohol: additive CNS and respiratory depression
MajorAlcohol (ethanol)CNS depressantBenzodiazepine with alcohol: additive CNS and respiratory depression
MajorFlumazenil (benzodiazepine antagonist)Benzodiazepine antagonistFlumazenil can precipitate withdrawal or seizures
MajorOther opioids (morphine, fentanyl, methadone, oxycodone, hydromorphone, tramadol)OpioidOpioid with benzodiazepine: risk of profound sedation, respiratory depression, coma, and death
MajorStrong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice)CYP3A4 inhibitorStrong CYP3A4 inhibitors raise alprazolam exposure
MajorStrong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice)CYP3A4 inhibitorStrong CYP3A4 inhibitors raise benzodiazepine exposure
ModerateOther CNS depressants (opioids, benzodiazepines, sleep aids, sedating antihistamines, gabapentinoids, muscle relaxants)CNS depressantAdditive sedation with other CNS depressants
ModerateOther CNS depressants (opioids, benzodiazepines, sleep aids, sedating antihistamines, gabapentinoids, muscle relaxants)CNS depressantBenzodiazepine with other CNS depressants: additive sedation
ModerateSedating H1 antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine, doxylamine, promethazine)Sedating antihistamineBenzodiazepine with sedating antihistamines: additive sedation

Detailed interactions

Major

Alprazolam with alcohol: additive CNS and respiratory depression

With: Alcohol (ethanol) CNS depressant

Why it happens

Alcohol and benzodiazepines both depress the central nervous system; combined use compounds sedation and slows breathing.

What can happen

Labeling warns against alcohol use with alprazolam because of the risk of excessive sedation, respiratory depression, impairment of judgment and motor function, and death.

What to do

Avoid alcohol entirely while taking alprazolam, and for at least a few days after the last dose.

Basis: Alprazolam (Xanax) prescribing information, Warnings and Precautions. source

Major

Benzodiazepine with alcohol: additive CNS and respiratory depression

With: Alcohol (ethanol) CNS depressant

Why it happens

Both agents depress the central nervous system and breathing.

What can happen

Excessive sedation, respiratory depression, and death.

What to do

Avoid alcohol during benzodiazepine therapy.

Basis: Benzodiazepine prescribing information, Warnings. source

Major

Flumazenil can precipitate withdrawal or seizures

With: Flumazenil (benzodiazepine antagonist) Benzodiazepine antagonist

Why it happens

Flumazenil blocks benzodiazepine receptor binding, abruptly removing the drug's effect.

What can happen

Patients dependent on benzodiazepines may develop seizures, which can be life-threatening.

What to do

Flumazenil is used only in monitored clinical settings with seizure precautions.

Basis: Flumazenil prescribing information, Warnings. source

Major

Opioid with benzodiazepine: risk of profound sedation, respiratory depression, coma, and death

With: Other opioids (morphine, fentanyl, methadone, oxycodone, hydromorphone, tramadol) Opioid

Why it happens

Additive depression of the central nervous system and respiratory drive. Benzodiazepines potentiate opioid-induced respiratory depression without reliably improving analgesia or anxiety.

What can happen

FDA added a boxed warning to benzodiazepines and is requiring labeling changes on opioids. Deep sedation, respiratory arrest, coma, and death have been reported. Respiratory depression is most likely in elderly patients, those with COPD, and those with other CNS depressants.

What to do

Avoid the combination where possible. If coadministration is necessary, use the lowest effective dose for the shortest duration, and monitor closely for sedation and breathing. Tell the prescriber about all other CNS depressants, including alcohol and sleep aids.

Basis: FDA Drug Safety Communication: Benzodiazepines and opioids can dangerously interact (2016); benzodiazepine and opioid boxed warnings. source

Major

Strong CYP3A4 inhibitors raise alprazolam exposure

With: Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice) CYP3A4 inhibitor

Why it happens

Alprazolam is metabolized by CYP3A4. Strong inhibitors slow its clearance and raise plasma levels.

What can happen

Labeling states that potent CYP3A inhibitors can increase alprazolam exposure and recommends considering a reduction in dose.

What to do

Prescribers should expect to reduce the alprazolam dose when a strong CYP3A4 inhibitor is started.

Basis: Alprazolam prescribing information, Drug Interactions and Dosage Modifications. source

Major

Strong CYP3A4 inhibitors raise benzodiazepine exposure

With: Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice) CYP3A4 inhibitor

Why it happens

CYP3A4 inhibition slows clearance of benzodiazepines metabolized by this pathway.

What can happen

Increased sedation; labeling recommends dose reduction for some agents.

What to do

Expect the prescriber to reduce the benzodiazepine dose.

Basis: Benzodiazepine prescribing information, Drug Interactions. source

Moderate

Additive sedation with other CNS depressants

With: Other CNS depressants (opioids, benzodiazepines, sleep aids, sedating antihistamines, gabapentinoids, muscle relaxants) CNS depressant

Why it happens

Benzodiazepines potentiate the sedative effect of other central nervous system depressants.

What can happen

Excessive sedation, confusion, impaired coordination, and respiratory depression are possible.

What to do

Discuss every sedating medication, including over-the-counter sleep aids and sedating antihistamines, with the prescriber or pharmacist.

Basis: Alprazolam prescribing information, Drug Interactions. source

Moderate

Benzodiazepine with other CNS depressants: additive sedation

With: Other CNS depressants (opioids, benzodiazepines, sleep aids, sedating antihistamines, gabapentinoids, muscle relaxants) CNS depressant

Why it happens

Additive central nervous system depression.

What can happen

Excessive sedation, confusion, and impaired coordination.

What to do

Review all sedating medications with the prescriber.

Basis: Benzodiazepine prescribing information, Drug Interactions. source

Moderate

Benzodiazepine with sedating antihistamines: additive sedation

With: Sedating H1 antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine, doxylamine, promethazine) Sedating antihistamine

Why it happens

Additive sedative effects.

What can happen

Marked drowsiness and impaired coordination.

What to do

Avoid combining without prescriber approval.

Basis: Benzodiazepine prescribing information, Drug Interactions. source

Common questions

What should I know about Xanax interactions?

We have documented 9 interaction classes for Xanax in our dataset. Usually avoided, or used only with explicit prescriber oversight and close monitoring. The most serious items on this page are marked contraindicated or major.

Can I take Xanax with alcohol?

Alcohol interacts with most of the medications on this site because it adds to sedation and slows breathing. For the specific documented risk, see the relevant entry above. The general rule from labeling is to avoid alcohol.

Does an empty result mean Xanax is safe with other drugs?

No. An empty result only means our curated dataset has no matching rule. A pharmacist can run a full interaction screen against every medication and supplement you take.

Related

Editorial Review Board

Clinical review by licensed pharmacists (PharmD)

Every page on this site is reviewed against current FDA prescribing information, DailyMed labelling, DEA scheduling regulations and MedlinePlus monographs before publication. Reviewers have no commercial relationship with any manufacturer or pharmacy.

Last substantive review: October 01, 2026

Sources & references

DailyMed — full prescribing information (National Library of Medicine)
FDA prescribing information (accessdata.fda.gov)
MedlinePlus drug information (National Library of Medicine)
PubChem compound record (National Institutes of Health)
21 CFR Part 1308 — Controlled Substances (eCFR)
Drug Enforcement Administration — drug scheduling

Important

This site provides educational information only and does not sell, prescribe or dispense medications. Always consult a licensed healthcare provider. This page is not medical advice.