Is it safe to give hydroxyzine and doxepin together?

Safety of Combining Hydroxyzine and Doxepin

Combining hydroxyzine and doxepin requires significant caution due to additive CNS depression, anticholinergic effects, and potential cardiac risks including QT prolongation—this combination should generally be avoided unless absolutely necessary with close monitoring. 1, 2

Primary Safety Concerns

Cardiac Risk - QT Prolongation

• Both medications can prolong the QT interval, and their combination significantly increases the risk of dangerous cardiac arrhythmias including Torsade de Pointes. 1, 2, 3
• The British Journal of Dermatology specifically warns that mizolastine (another antihistamine) should not be taken concurrently with tricyclic antidepressants like doxepin due to arrhythmic properties. 1
• The FDA label for hydroxyzine explicitly cautions against concomitant use with drugs known to prolong QT interval, specifically listing tricyclic antidepressants. 2
• Historical cardiac monitoring data shows hydroxyzine can produce abnormal ventricular repolarization, which tricyclic antidepressants like doxepin may augment, increasing risk of dysrhythmias and sudden death. 3

Central Nervous System Depression

• The FDA mandates that when hydroxyzine is used with CNS depressants, dosages must be reduced due to potentiating effects. 2
• Both drugs cause significant sedation, and their combination produces additive drowsiness that impairs driving ability and increases fall risk, particularly in elderly patients. 1, 2
• The Journal of Clinical Sleep Medicine notes that combining sedating medications requires careful monitoring for excessive daytime sedation. 1

Anticholinergic Effects

• Both hydroxyzine and doxepin have anticholinergic properties that are additive when combined. 1, 2
• This increases risk of confusion, urinary retention, constipation, dry mouth, and blurred vision—especially problematic in elderly patients. 1, 2

Clinical Context Where This Combination Might Arise

Pruritus Management

• Research comparing these medications for sulfur mustard-induced pruritus found both effective as monotherapy (hydroxyzine 25 mg/day vs doxepin 10 mg/day showed equivalent efficacy). 4, 5
• There is no evidence supporting the need to combine these medications—they work equally well individually. 4, 5
• The British Journal of Dermatology recommends using hydroxyzine 10-50 mg at night as an adjunct to non-sedating antihistamines during the day, not in combination with other sedating agents. 1

Insomnia with Comorbid Anxiety

• The Journal of Clinical Sleep Medicine notes that while combination therapy with different drug classes may improve efficacy, it emphasizes general safety of BzRA + antidepressant combinations—not antihistamine + antidepressant combinations. 1
• If sedation is needed, choose one agent, not both. 1

High-Risk Populations Requiring Absolute Avoidance

• Elderly patients: Both medications are sedating and anticholinergic; elderly should start with low doses of single agents and be observed closely for confusion and oversedation. 2
• Patients with cardiac disease: Pre-existing heart disease, electrolyte imbalances, recent MI, uncompensated heart failure, or bradyarrhythmias are contraindications to this combination. 2
• Patients with renal impairment: Hydroxyzine dose should be halved in moderate renal impairment; adding doxepin increases toxicity risk. 1
• Patients with hepatic disease: Both drugs should be avoided in severe liver disease. 1
• Patients taking other QT-prolonging medications: Including Class 1A or III antiarrhythmics, certain antipsychotics, antibiotics (macrolides, fluoroquinolones), or methadone. 2

If Combination Is Absolutely Necessary (Rare Circumstances)

• Obtain baseline ECG and monitor QT interval regularly. 2
• Reduce doses of both medications significantly below standard monotherapy doses. 2
• Monitor electrolytes (potassium, magnesium) and correct abnormalities. 2
• Warn patients explicitly about increased sedation, fall risk, and prohibition of alcohol or other CNS depressants. 2
• Avoid in patients driving or operating machinery. 2
• Consider alternative: Use a single agent (either hydroxyzine OR doxepin, not both) as they have equivalent efficacy for pruritus. 4, 5

Preferred Alternative Approaches

• For pruritus: Use hydroxyzine 10-50 mg at night with a non-sedating antihistamine (cetirizine, fexofenadine, loratadine) during the day. 1
• For insomnia with pruritus: Use hydroxyzine alone at bedtime (10-50 mg). 1
• For depression with pruritus: Use doxepin alone at low doses (10 mg) for its antihistaminic properties. 1, 4