Hydroxyzine Drug Interactions: What to Avoid and What to Tell Your Doctor

Hydroxyzine has moderate to major interactions with more than 200 other drugs — and that's not a typo. Because it works on multiple receptor systems (histamine, serotonin, muscarinic, and cardiac potassium channels), it can interact with a wide range of medications in different ways.

This guide focuses on the most clinically important interactions — the ones that can cause serious harm — and explains clearly what to tell your doctor.

The Two Main Interaction Types to Know

Hydroxyzine's drug interactions fall into two main categories:

1. CNS (central nervous system) depression. Hydroxyzine is a sedative. Combining it with other sedating substances increases the risk of dangerous over-sedation, respiratory depression, and in extreme cases, death.
2. QT prolongation. Hydroxyzine can prolong the QT interval (a measurement of the heart's electrical cycle). Combining it with other QT-prolonging drugs increases the risk of a dangerous arrhythmia.

Major Interaction #1: Opioids

Combining hydroxyzine with opioids (fentanyl, morphine, oxycodone, hydrocodone, buprenorphine, tramadol) significantly increases the risk of respiratory depression — the leading cause of opioid overdose death. Both drugs suppress the CNS, and their effects on slowing breathing are additive.

If you must take both: use the lowest possible doses of both, avoid alcohol, and never drive. Signs of dangerous interaction include extreme sleepiness, slow or shallow breathing, and difficulty waking.

Major Interaction #2: Benzodiazepines

Benzodiazepines — including alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and others — are CNS depressants that, combined with hydroxyzine, dramatically increase sedation and respiratory depression risk. Many prescribers choose hydroxyzine specifically as an alternative to benzodiazepines. If you're already on a benzodiazepine, your doctor needs to know before starting hydroxyzine.

Major Interaction #3: QT-Prolonging Drugs

Hydroxyzine can prolong the QT interval, and the following drug classes also prolong QT. Combining them raises the risk of a life-threatening heart arrhythmia called torsades de pointes:

• Certain antidepressants: Citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), venlafaxine
• Antipsychotics: Haloperidol, clozapine, amisulpride, ziprasidone, quetiapine
• Cardiac medications: Amiodarone, sotalol, quinidine
• Antibiotics: Azithromycin (Z-Pack), ciprofloxacin, levofloxacin, clarithromycin
• Antifungals: Fluconazole, ketoconazole

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Interaction #4: Alcohol

Alcohol is a CNS depressant. Drinking while taking hydroxyzine significantly worsens sedation, impairs coordination and judgment, and increases the risk of falls and accidents. Even moderate alcohol use combined with hydroxyzine can cause unexpected levels of impairment. Avoid alcohol while taking hydroxyzine.

Interaction #5: Other Antihistamines

Taking hydroxyzine with other antihistamines — including diphenhydramine (Benadryl), doxylamine (Unisom), or even OTC allergy medications — adds anticholinergic and sedative effects. This is especially risky in older adults, where additive anticholinergic burden increases the risk of confusion, urinary retention, and falls. Check the labels of all OTC medications before taking them with hydroxyzine.

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Interaction #6: Grapefruit

Grapefruit and grapefruit juice can slow the liver's metabolism of hydroxyzine by inhibiting the CYP3A4 enzyme. This leads to higher-than-expected hydroxyzine blood levels, increasing the risk of QT prolongation and sedation. Avoid grapefruit while taking hydroxyzine.

Interaction #7: Anticholinergic Drugs

Hydroxyzine has anticholinergic properties. Combining it with other anticholinergic drugs can increase dry mouth, constipation, blurred vision, and urinary retention. Common anticholinergic medications include: tricyclic antidepressants (amitriptyline, nortriptyline), bladder medications (oxybutynin, solifenacin), antiparkinson drugs, some antipsychotics, and certain antiemetics.

What to Tell Your Doctor and Pharmacist

Before starting hydroxyzine, give your prescriber and pharmacist a complete medication list including:

• All prescription medications
• All OTC medications, including allergy, sleep, and pain medications
• Vitamins, herbs, and supplements
• Any personal or family history of heart rhythm problems (QT prolongation, arrhythmia)
• Alcohol and recreational substance use

For related reading, see our guide on hydroxyzine side effects.

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