Can hydroxyzine cause QT interval prolongation and arrhythmias, particularly in elderly patients or those with pre‑existing cardiac disease, electrolyte disturbances, or concomitant QT‑prolonging medications?

Hydroxyzine and Cardiac Risk

Yes, hydroxyzine can cause QT interval prolongation and torsade de pointes (TdP), particularly in patients with underlying risk factors, and should be used with extreme caution or avoided entirely in elderly patients, those with pre-existing cardiac disease, electrolyte disturbances, or concomitant QT-prolonging medications. 1

FDA Warning and Mechanism

The FDA drug label explicitly warns that cases of QT prolongation and torsade de pointes have been reported during post-marketing use of hydroxyzine, with the majority occurring in patients with other risk factors for QT prolongation or TdP (pre-existing heart disease, electrolyte imbalances, or concomitant arrhythmogenic drug use). 1

Hydroxyzine blocks human ether-a-go-go-related gene (hERG) potassium channels in a concentration-dependent manner, the same mechanism responsible for QT prolongation with Class IA and III antiarrhythmic drugs. 2, 3 This inhibition of cardiac repolarization directly prolongs the QT interval and creates substrate for life-threatening arrhythmias. 2

High-Risk Patient Populations Requiring Extreme Caution

Hydroxyzine should be used with caution (or avoided) in patients with:

• Congenital long QT syndrome or family history of long QT syndrome 1
• Recent myocardial infarction, uncompensated heart failure, or bradyarrhythmias 1
• Pre-existing heart disease or baseline QT prolongation 1, 2
• Electrolyte imbalances (hypokalemia, hypomagnesemia, hypocalcemia) 1, 2
• Elderly patients, who are more susceptible to sedation and cardiac effects 1
• Complete atrioventricular block or significant bradycardia 4

The combination of cardiovascular disorders plus concomitant treatment with drugs known to induce arrhythmia represents the greatest combined risk factor for hydroxyzine-induced cardiac events. 2

Critical Drug Interactions

Caution is mandatory during concomitant use of drugs known to prolong the QT interval, including: 1

• Class IA antiarrhythmics (quinidine, procainamide) 1
• Class III antiarrhythmics (amiodarone, sotalol) 1
• Certain antipsychotics (ziprasidone, iloperidone, clozapine, quetiapine, chlorpromazine) 1
• Certain antidepressants (citalopram, fluoxetine) 1
• Macrolide antibiotics (azithromycin, erythromycin, clarithromycin) 1
• Fluoroquinolones (gatifloxacin, moxifloxacin) 1
• Other QT-prolonging agents (pentamidine, methadone, ondansetron, droperidol) 1

Clinical Evidence of Harm

Real-world pharmacovigilance data identified 59 reports of QT prolongation and/or TdP potentially linked to hydroxyzine use between 1955 and 2016. 2 Aside from intentional overdose, all cases involved underlying medical conditions or concomitant medications that constituted at least one additional risk factor. 2

Case reports document TdP occurring even with small doses (12.5 mg) in high-risk patients, such as an 82-year-old woman with complete atrioventricular block who developed TdP during pacemaker implantation after hydroxyzine administration for sedation. 4 Another case involved a 58-year-old male with an ICD who developed refractory TdP after receiving 50 mg hydroxyzine for opioid withdrawal symptoms. 5

A particularly instructive case involved a 34-year-old woman with an undiagnosed HERG mutation who experienced repetitive syncope after taking 75 mg hydroxyzine for several days, with QTc prolonging to 630 ms. 3 The QTc shortened to 464 ms after drug cessation, demonstrating the direct causal relationship. 3

Risk Classification

Based on pharmacovigilance analysis and electrophysiological studies, hydroxyzine is appropriately listed as a drug with "conditional risk of TdP", meaning the risk is substantially elevated in patients with underlying risk factors. 2 This classification aligns with American Heart Association guidance that distinguishes between high-risk drugs (which may cause TdP even without additional risk factors) and conditional-risk drugs (which require other risk factors to manifest arrhythmia). 6

Clinical Recommendations

Before prescribing hydroxyzine:

• Obtain baseline ECG to measure QTc interval, particularly in elderly patients or those with cardiac risk factors 6, 1
• Check and correct electrolyte abnormalities (maintain potassium 4.5-5.0 mEq/L, magnesium >2.0 mg/dL) 6
• Review all concomitant medications for QT-prolonging potential 1
• Consider alternative agents in patients with baseline QTc >450 ms (men) or >470 ms (women) 7

During hydroxyzine therapy:

• Use the lowest effective dose 5
• Monitor for symptoms of arrhythmia (palpitations, dizziness, syncope) 8
• Discontinue immediately if QTc exceeds 500 ms or increases >60 ms from baseline 6

Common Pitfalls to Avoid

The most dangerous pitfall is administering hydroxyzine to elderly patients with multiple cardiac risk factors without ECG screening. 1 The sedating properties may mask early warning symptoms of arrhythmia in this population. 1

Another critical error is combining hydroxyzine with other QT-prolonging medications (particularly macrolide antibiotics, antipsychotics, or antiarrhythmics) without cardiac monitoring. 1, 2

Never assume that low doses are safe in high-risk patients—case reports document TdP with doses as low as 12.5 mg in patients with bradycardia or conduction abnormalities. 4