Hydroxyzine

Indications

• FDA-approved for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease with anxiety.
• FDA-approved for pruritus due to allergic conditions including chronic urticaria and atopic or contact dermatoses.
• FDA-approved as a sedative for premedication before and following general anesthesia, and the intramuscular form as an antiemetic.
• The intramuscular hydrochloride salt is labeled as adjunctive therapy in acute alcoholism with delirium tremens or hallucinosis.
• Off-label but widely used as a scheduled or as-needed anxiolytic in patients with substance use disorder, since it is not controlled.
• Off-label for insomnia; a Cochrane review found modest short-term anxiolytic benefit in generalized anxiety but no long-term data.

Mechanism of action

• Potent inverse agonist at the histamine H1 receptor, and central H1 blockade is the source of both sedation and anxiolysis.
• Blocks 5-HT2A and dopamine D2 receptors weakly, and has modest anticholinergic activity that contributes to dry mouth and confusion.
• It has no activity at GABA-A receptors, which is why it produces no tolerance, no physical dependence and no withdrawal syndrome.
• Blocks the cardiac hERG potassium channel at higher concentrations, the mechanism behind QT prolongation and rare torsades de pointes.
• Its active metabolite cetirizine is a peripherally selective H1 antagonist that carries the antihistaminic but not the sedating effect.

Pharmacokinetics

• Rapidly absorbed with clinical effect within 15-30 minutes and peak plasma concentrations at about 2 hours after an oral dose.
• Elimination half-life is roughly 20 hours in healthy adults, lengthening to about 29 hours in older patients.
• Metabolized principally by alcohol dehydrogenase to cetirizine, an active metabolite, with additional CYP3A4 and CYP3A5 oxidation.
• Half-life extends to about 37 hours in primary biliary cirrhosis, so dose reduction is appropriate in significant hepatic impairment.
• Cetirizine is renally cleared, so accumulation and prolonged antihistaminic effects occur in advanced renal impairment.

Dosing

• Anxiety in practice: 25-50 mg PO three or four times daily or as needed; the older label lists 50-100 mg four times daily, which is rarely used.
• European regulators cap total daily dosing at 100 mg/day in adults and 50 mg/day in older adults because of QT prolongation risk.
• Pruritus: 25 mg PO three or four times daily; premedication before anesthesia 50-100 mg PO or 25-100 mg intramuscularly.
• Children under 6 years: 50 mg/day in divided doses; children over 6 years: 50-100 mg/day in divided doses for anxiety or pruritus.
• The intramuscular route only; hydroxyzine must never be given intravenously, subcutaneously or intra-arterially because of tissue necrosis and hemolysis.
• No taper is required on discontinuation, and there is no withdrawal syndrome, which is a major practical advantage over benzodiazepines.

Adverse effects

• Sedation is the most common effect and is dose-related, along with dry mouth, dizziness, blurred vision and constipation.
• Anticholinergic burden causing urinary retention, confusion and worsened cognition, which is the main limit in older adults.
• QT prolongation and rare torsades de pointes, more likely at higher doses, with hypokalemia, or alongside other QT-prolonging drugs.
• Rare acute generalized exanthematous pustulosis and fixed drug eruption, and hypersensitivity in patients allergic to cetirizine.
• Paradoxical CNS stimulation, tremor and rarely seizures, described more often in children and at higher doses.
• Intramuscular injection can cause marked local pain, sterile abscess and tissue necrosis if given by any other route.

Monitoring

• Obtain a baseline ECG when the dose exceeds 50 mg/day, in older adults, or when other QT-prolonging medications are in use.
• Check potassium and magnesium in patients on diuretics or with vomiting or diarrhea, since hypokalemia amplifies torsades risk.
• Assess daytime sedation, cognition, falls and anticholinergic symptoms at follow-up, particularly in patients over 65.
• Reassess whether as-needed dosing is actually reducing anxiety, since tolerance to sedation can be mistaken for loss of anxiolysis.
• No routine laboratory monitoring is otherwise required and no controlled substance monitoring applies, since it is not scheduled.

Interactions

• Contraindicated with other QT-prolonging drugs where possible, including citalopram at higher doses, methadone, ondansetron and antipsychotics.
• Additive sedation and psychomotor impairment with opioids, alcohol, benzodiazepines, gabapentinoids and other CNS depressants.
• Additive anticholinergic burden with tricyclic antidepressants, oxybutynin, benztropine, paroxetine and low-potency antipsychotics.
• Contraindicated in known hypersensitivity to hydroxyzine, cetirizine or levocetirizine, and in patients with congenital long QT syndrome.
• The label contraindicates use in early pregnancy, and it may mask the cutaneous response in allergy skin testing for several days.

Special populations

• Pregnancy: contraindicated in early pregnancy per the label; later use is sometimes accepted for nausea but should be individualized.
• Lactation: hydroxyzine and cetirizine pass into breast milk and infant sedation is possible; monitor feeding and alertness.
• Pediatrics: dosing is established from infancy for pruritus and anxiety, though paradoxical stimulation is more common in children.
• Older adults: the AGS Beers Criteria advise avoiding first-generation antihistamines including hydroxyzine due to anticholinergic effects and delirium.
• Hepatic and renal impairment: reduce the dose in cirrhosis given the prolonged half-life, and in renal impairment where cetirizine accumulates.

Clinical pearls

• Not scheduled and not habit forming, so it is a first choice when a benzodiazepine is unwise.
• Get an ECG above 50 mg/day or in older adults; hERG blockade prolongs QT dose-dependently.
• Give intramuscularly or orally only; intravenous or subcutaneous routes cause tissue necrosis.