Is Hydroxyzine Safe with Prolonged QTc?

Hydroxyzine is often chosen because it is not a benzodiazepine and not a controlled substance. The reflex is to treat it as a mild, safe add-on for anxiety or sleep. That reflex misses what is in its own label: QT prolongation and torsade de pointes have been reported, and a prolonged QT interval is a contraindication. It ends up alongside antipsychotics, citalopram, methadone and opioids, and in older adults, where the risks stack up. Not controlled does not mean low risk.

Why is hydroxyzine a QT risk at all?

Because QT prolongation and torsade de pointes have been reported with it after marketing, mostly in patients who already had another risk factor. The US label contraindicates it with a prolonged QT interval.

The risk is in the label, not in the folklore. Most reported cases occurred in patients with pre-existing heart disease, an electrolyte imbalance or another drug that can cause arrhythmia. That is exactly the patient psychiatry tends to see: someone already on an antipsychotic or an antidepressant, sometimes with a diuretic and a low potassium.

The US and Europe disagree. Which rules should I follow?

With other QT-prolonging drugs, the US label advises caution, while the European Medicines Agency contraindicates the combination. The European dose limits do not bind US prescribing. Our view: 100 mg a day is the more conservative ceiling for a US patient in whom hydroxyzine remains appropriate after risk assessment.

After a 2014–2015 review that confirmed the known risk, the European Medicines Agency contraindicated hydroxyzine both with other QT-prolonging drugs and in patients with any known QT risk factor, and set a lower daily limit to reduce the risk of QT prolongation. It found that most cases involved other risk factors, electrolyte abnormalities or other treatments that may have contributed.

Our view, from the chapter: for a US patient in whom hydroxyzine remains appropriate after risk assessment, 100 mg a day is the more conservative ceiling. A lower dose does not make it appropriate with a prolonged QT interval, or with the QT risk factors and QT-prolonging drugs that the European Medicines Agency contraindicates. And because neither source sets a routine ECG schedule, our approach is simple: before prescribing it to a patient with a risk factor or another QT-prolonging drug, check an ECG and electrolytes, or choose another option.

What should I check before prescribing it?

Five things, in about a minute: every QT-prolonging drug, the heart history, the patient's age and anticholinergic load, every other sedating drug, and any rash.

1. List every QT-prolonging drug. Including antipsychotics, citalopram, fluoxetine, methadone and ondansetron. Many are added by other prescribers, so ask about medicines for nausea, infections and pain.
2. Ask about the heart. Fainting, palpitations, an abnormal heart rhythm, a family history of long QT or sudden death when young, and anything that could lower potassium or magnesium.
3. In a patient 65 or older, count every anticholinergic drug. Hydroxyzine adds to the load.
4. List every CNS depressant, including opioids and alcohol. Hydroxyzine potentiates their effects. The US label advises against using other CNS depressants at the same time, says their doses should be reduced when they are given together, and warns that the effects of alcohol may be increased.
5. Ask about any rash since starting it. Hydroxyzine can rarely cause acute generalized exanthematous pustulosis (AGEP). Stop it at the first sign of a rash, and do not restart it if AGEP is suspected.

What about older adults?

The 2023 Beers Criteria advise avoiding hydroxyzine in older adults: it is strongly anticholinergic and its clearance falls with age. The European Medicines Agency does not recommend it in older adults.

Beers lists first-generation antihistamines, including hydroxyzine, as drugs to avoid (moderate evidence, strong recommendation), and notes that cumulative anticholinergic exposure is associated with falls, delirium and dementia. It also advises avoiding more than one drug with anticholinergic properties. The US label lists dry mouth as its only anticholinergic adverse reaction, which is one reason the risk is missed. In an older adult, confusion, constipation, urinary retention or a fall after starting hydroxyzine is a reason to review it, not to call it aging.

What does this look like in practice?

Usually like this: an older patient, a QT-prolonging antidepressant, a diuretic, and hydroxyzine added for anxiety.

The case from Chapter 13: a 71-year-old woman with generalized anxiety takes citalopram and was started on hydroxyzine 25 mg three times a day a month ago. She also takes furosemide, and her potassium last week was 3.2 mmol/L. Her daughter says she has been confused in the evenings and nearly fell getting up at night. She has had no fainting or palpitations.

1. Her age. Beers advises avoiding hydroxyzine; the European Medicines Agency does not recommend it in older adults, and allows at most 50 mg a day if it is used. She takes 75 mg.
2. Citalopram. It is named in the US label as a QT-prolonging drug. Under the European restrictions, the combination is a contraindication.
3. Her potassium. Low potassium is a QT risk factor that needs correcting.
4. Her confusion and near-fall. They fit the label's warning that sedating drugs may cause confusion and oversedation in the elderly.

In the chapter, hydroxyzine is stopped. An ECG is checked, her potassium and magnesium are measured and corrected if low with her primary care clinician, her other medicines are reviewed for anticholinergic and QT effects, and her anxiety treatment is reviewed without adding another anticholinergic or sedating drug.

Is there a catch?

Four. The regulators differ, neither sets a routine ECG schedule, long-term effectiveness has not been systematically assessed beyond four months, and neither gives tapering instructions.

1. The two regulators read the same risk differently. The US label asks for caution with other QT-prolonging drugs; the European Medicines Agency contraindicates the combination. The European limit does not bind US prescribing. Using it as the ceiling is our view, not a US rule.
2. Neither source sets a routine ECG schedule. Checking an ECG and electrolytes before prescribing to a patient with a risk factor or another QT-prolonging drug is our approach, not a regulatory requirement.
3. Long-term effectiveness has not been assessed. The US label says its effectiveness as an anxiolytic for more than 4 months has not been assessed in systematic clinical studies, and its usefulness should be reassessed periodically.
4. There are no tapering instructions. Neither the label nor the European Medicines Agency says how to stop it, so how to stop it is clinical judgment.