Hydroxyzine
hydroxyzine hydrochloride (Atarax) · hydroxyzine pamoate (Vistaril)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Anxiety and tension associated with psychoneurosis | Adults and children | Monotherapy or adjunctive | FDA Approved |
| Pruritus due to allergic conditions (chronic urticaria, atopic and contact dermatoses, histamine-mediated pruritus) | Adults and children | Monotherapy | FDA Approved |
| Sedation — pre- and postoperative adjunct | Adults and children | Adjunctive (with analgesics/anesthetics) | FDA Approved |
| Antiemetic (nausea and vomiting, excluding pregnancy) | Adults | Monotherapy or adjunctive | FDA Approved |
Hydroxyzine is one of the oldest anxiolytic agents still in widespread clinical use, approved since 1956. It occupies a unique position as a non-benzodiazepine, non-controlled-substance option for acute anxiety relief, making it particularly useful in patients with substance use histories or when benzodiazepine prescribing is restricted. Its antihistaminic properties give it dual utility for pruritus and anxiety. The FDA label notes that long-term effectiveness beyond 4 months has not been established in systematic studies, and clinicians should periodically reassess ongoing need.
Insomnia — Commonly prescribed at 25–100 mg at bedtime for short-term sleep initiation. A 2023 systematic review found mixed efficacy for sleep onset and maintenance. Evidence quality: Low.
Acute agitation in psychiatric emergencies — Used IM at 50–100 mg as an alternative to benzodiazepines or antipsychotics for acute behavioral disturbance. Evidence quality: Low.
Alcohol withdrawal adjunct — Used as an adjunctive agent to manage anxiety symptoms during alcohol withdrawal protocols; does not prevent withdrawal seizures. Evidence quality: Very low.
Nausea/vomiting of pregnancy — Not approved and contraindicated in early pregnancy by the FDA label due to animal teratogenicity data. Evidence quality: Not recommended.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute anxiety — situational or short-term relief | 25–50 mg | 25–50 mg TID–QID | 100 mg/day (EMA/MHRA); 400 mg/day (US PI) | Onset within 15–30 min; use lowest effective dose EMA limits max to 100 mg/day due to QT risk; US PI permits up to 400 mg/day |
| Generalized anxiety — ongoing management | 25 mg TID | 50–100 mg QID | 100 mg/day (EMA/MHRA); 400 mg/day (US PI) | Not assessed beyond 4 months in controlled studies; reassess periodically Consider transition to first-line agents (SSRIs) for chronic GAD |
| Pruritus — chronic urticaria or allergic dermatoses | 25 mg TID | 25 mg TID–QID | 100 mg/day | Often effective at lower doses than anxiety dosing Second-generation antihistamines preferred for chronic urticaria per guidelines |
| Preoperative / procedural sedation | 50–100 mg | Single dose | 100 mg | Give 30–60 min before procedure Potentiates opioids and barbiturates — reduce their doses by up to 50% |
| Insomnia (off-label) | 25–50 mg | 25–50 mg at bedtime | 100 mg | Short-term only; tolerance to sedation can develop within days Off-label; limited RCT evidence |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Anxiety or pruritus — children <6 years | 12.5 mg BID–TID | 50 mg/day in divided doses | 50 mg/day | Use oral syrup for accurate dosing in young children EMA max: 2 mg/kg/day for children up to 40 kg |
| Anxiety or pruritus — children ≥6 years | 12.5–25 mg TID–QID | 50–100 mg/day in divided doses | 100 mg/day | Shorter half-life (~7 h) in children may require more frequent dosing EMA max: 2 mg/kg/day (up to 40 kg); adult dose for children >40 kg |
| Preoperative sedation — children | 0.6 mg/kg | Single dose | 0.6 mg/kg | Weight-based dosing; administer 30–60 min before procedure |
Special Population Adjustments
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly (≥65 years) | 10–25 mg BID | Lowest effective dose | 50 mg/day (EMA); use caution | Half-life ~29 h in elderly; high anticholinergic burden; Beers Criteria lists as potentially inappropriate EMA/MHRA recommend avoiding in elderly where possible |
| Hepatic impairment | Reduce dose by ~50%; half-life likely prolonged | Extensively hepatically metabolized; use conservatively | ||
| Renal impairment | Reduce dose; extent of renal excretion not determined | Cetirizine (active metabolite) is renally excreted and will accumulate | ||
Hydroxyzine IM injection is strictly intramuscular — it must never be given subcutaneously, intra-arterially, or intravenously. The preferred injection site is the upper outer quadrant of the gluteus maximus or the mid-lateral thigh in children. Tissue necrosis can occur with improper injection technique.
Pharmacology
Mechanism of Action
Hydroxyzine is a first-generation piperazine-class antihistamine that exerts its effects through competitive antagonism at peripheral and central histamine H1 receptors. Its anxiolytic effect is thought to arise primarily from suppression of subcortical neuronal activity rather than cortical depression, distinguishing it mechanistically from benzodiazepines. Hydroxyzine has no activity at GABAA-benzodiazepine receptors. It also possesses significant anticholinergic (muscarinic), antiserotonergic, and weak antidopaminergic activity. The muscarinic antagonism accounts for the dry mouth and other anticholinergic effects, while central H1 blockade produces sedation. Hydroxyzine additionally demonstrates bronchodilator, antiemetic, and skeletal muscle relaxant properties in experimental models. Its principal active metabolite, cetirizine, is a second-generation antihistamine with minimal CNS penetration and accounts for a substantial portion of the sustained antihistaminic effect in vivo.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed from GI tract; clinical effects within 15–30 min; Tmax ~2 h | Fast onset makes it suitable for PRN use in acute anxiety; rapid relief comparable to benzodiazepines |
| Distribution | Protein binding ~93%; Vd ~22.5 L/kg (elderly); crosses blood-brain barrier readily | High CNS penetration underlies both sedative efficacy and drowsiness liability; large Vd means tissue accumulation |
| Metabolism | Hepatic via CYP3A4/3A5; primary active metabolite cetirizine (t½ ~8 h); N-dealkylated and O-dealkylated metabolites also produced | CYP3A4 substrate — potential for interaction with strong inhibitors/inducers; cetirizine provides sustained peripheral antihistaminic activity |
| Elimination | t½ ~14–20 h (adults), ~7 h (children), ~29 h (elderly); primarily biliary/fecal in animal studies; renal excretion of parent drug not well characterized | Long half-life in adults and elderly supports once- or twice-daily dosing for pruritus but increases accumulation risk in elderly; cetirizine is renally eliminated |
Side Effects
Hydroxyzine was approved in 1956, before modern adverse-event reporting standards. The FDA PI does not contain structured placebo-controlled incidence tables. The frequencies below draw on the FDA label, postmarketing reports, published clinical studies, and systematic reviews.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Drowsiness / somnolence | Up to ~14% | Most common effect; usually transient, often resolving within days of continued therapy or with dose reduction; dose-related |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dry mouth | ~5–10% | Anticholinergic mechanism; manage with oral hydration, sugar-free gum; assess dental risk in long-term use |
| Headache | ~5–7% | Reported in clinical studies; usually mild and self-limiting |
| Fatigue / tiredness | ~3–5% | Related to central H1 blockade; may overlap with drowsiness |
| Dizziness | ~2–4% | Falls risk especially in elderly; postmarketing syncope reports |
| Constipation | ~1–3% | Anticholinergic effect; increase dietary fiber and fluids |
| Blurred vision | ~1–2% | Anticholinergic effect on ciliary muscle; usually resolves with dose reduction |
| Urinary retention | ~1–2% | Greater risk in elderly men with benign prostatic hyperplasia; postmarketing reports |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QT prolongation / Torsade de Pointes | Rare (conditional risk) | Variable; most cases in patients with risk factors | Obtain baseline ECG in at-risk patients; discontinue if QTc prolonged; correct electrolytes; avoid co-prescription with QT-prolonging drugs |
| Seizures / convulsions | Rare (usually at supratherapeutic doses) | Variable; more common in overdose | Discontinue hydroxyzine; manage seizure per protocol; neurological evaluation |
| Acute generalized exanthematous pustulosis (AGEP) | Very rare (postmarketing) | Hours to days after exposure | Discontinue immediately; do not rechallenge; avoid cetirizine and levocetirizine (cross-sensitivity risk) |
| Fixed drug eruption | Very rare (postmarketing) | Hours to days | Discontinue; document reaction site; avoid re-exposure |
| Severe hypersedation / respiratory depression | Rare (mainly with CNS depressant co-use) | Within hours of combined administration | Supportive care; airway management; reduce CNS depressant doses by up to 50% when co-administered |
| Involuntary motor activity / dystonia / dyskinesia | Very rare (postmarketing) | Variable; case reports after prolonged use | Discontinue; consider anticholinergic treatment for acute dystonia; neurological review |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Excessive sedation | Most common | Usually early in treatment; often resolves with continued use or dose reduction |
| Anticholinergic effects (dry mouth, constipation, urinary retention) | Infrequent | More problematic in elderly; consider anticholinergic burden with other medications |
Drowsiness is the most impactful clinical side effect, though the FDA PI states it is “usually transitory and may disappear in a few days of continued therapy or upon reduction of dose.” To manage: start at the lowest effective dose (25 mg), give the largest portion of the daily dose at bedtime, and titrate slowly. Warn patients to avoid driving and operating machinery until they know how hydroxyzine affects them. In elderly patients, even low doses can cause excessive sedation and increase fall risk.
Drug Interactions
Hydroxyzine is metabolized by CYP3A4/3A5. Its most clinically important interactions involve additive CNS depression with other sedating agents and pharmacodynamic QT-prolongation risk when combined with other QT-prolonging drugs. The FDA PI explicitly warns that hydroxyzine potentiates opioids and barbiturates, and their doses should be reduced when given concomitantly.
Monitoring
The FDA PI does not recommend specific laboratory tests. Monitoring focuses on clinical response, sedation level, cardiac rhythm in at-risk patients, and anticholinergic burden assessment in the elderly.
-
ECG / QTc interval
Baseline in at-risk patients; repeat if dose increased or QT drug added
Trigger-based Obtain baseline ECG in patients with pre-existing heart disease, congenital long QT, electrolyte abnormalities, or concurrent QT-prolonging medications. Hydroxyzine is contraindicated if QTc is already prolonged. -
Sedation level
Each visit; first 1–2 weeks especially
Routine Assess for excessive drowsiness, falls risk, and functional impairment. Particularly important in elderly patients who may experience confusion and over-sedation. -
Anticholinergic burden
At initiation and medication review
Routine Use the Anticholinergic Burden Scale or equivalent tool to assess cumulative anticholinergic load, especially in elderly patients on multiple medications. Monitor for dry mouth, constipation, urinary retention, confusion. -
Electrolytes (K+, Mg2+)
Baseline if cardiac risk; repeat with diuretics
Trigger-based Hypokalemia and hypomagnesemia increase QT-prolongation risk. Correct electrolyte abnormalities before starting hydroxyzine in at-risk patients. -
Skin reactions
Each visit
Trigger-based Monitor for AGEP (fever, sterile pustules on erythematous skin) and fixed drug eruptions. Discontinue immediately if skin rash appears or pre-existing skin conditions worsen. -
Ongoing need
Every 3–4 months
Routine Effectiveness beyond 4 months not established in systematic clinical studies (FDA PI). Periodically reassess whether continued treatment is warranted; consider transition to evidence-based first-line anxiolytics.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to hydroxyzine, cetirizine, or levocetirizine — cross-sensitivity exists between hydroxyzine and its metabolite cetirizine; also avoid levocetirizine.
- Prolonged QT interval — hydroxyzine inhibits hERG channels and poses conditional risk for TdP (FDA PI, EMA review).
- Early pregnancy — animal studies showed fetal abnormalities in rats and mice at supratherapeutic doses; the FDA PI explicitly contraindicated in early pregnancy.
Relative Contraindications (Specialist Input Recommended)
- Significant hepatic impairment — hydroxyzine is extensively hepatically metabolized; half-life prolongation likely; reduce dose substantially.
- Significant renal impairment — cetirizine (active metabolite) is renally eliminated; accumulation expected.
- Elderly patients (≥65 years) — the American Geriatrics Society Beers Criteria lists hydroxyzine as potentially inappropriate due to strong anticholinergic properties and sedation risk. The EMA/MHRA recommends avoiding in the elderly where possible.
- Risk factors for QT prolongation — congenital long QT syndrome, family history, recent MI, heart failure, bradyarrhythmias, electrolyte imbalances, concomitant QT-prolonging drugs.
Use with Caution
- Concurrent CNS depressants — reduce doses of opioids, barbiturates, benzodiazepines, and other sedating agents by up to 50%.
- Patients with seizure history — involuntary motor activity and convulsions reported, usually at supratherapeutic doses.
- Patients with narrow-angle glaucoma — anticholinergic effects may worsen intraocular pressure.
- Patients with urinary obstruction / prostatic hypertrophy — anticholinergic effects may worsen urinary retention.
- Driving and operating machinery — avoid until the patient knows how hydroxyzine affects their alertness.
- IM injection technique — strictly intramuscular; never subcutaneous, intra-arterial, or intravenous.
Cases of QT prolongation and Torsade de Pointes have been reported during postmarketing use of hydroxyzine. The majority of cases occurred in patients with additional risk factors: pre-existing heart disease, electrolyte imbalances, or concurrent use of arrhythmogenic drugs. Following an EMA safety review in 2015, the maximum recommended adult daily dose was reduced to 100 mg in European markets (50 mg in the elderly), and hydroxyzine was contraindicated in patients with a prolonged QT interval. These restrictions are reflected in the current US labeling as well. Clinicians should assess cardiac risk before prescribing hydroxyzine and monitor ECG in at-risk patients.
Patient Counselling
Purpose of Therapy
Hydroxyzine is an antihistamine that helps relieve anxiety, itching, and nausea. Unlike benzodiazepines, it is not a controlled substance, does not carry abuse potential, and does not produce physical dependence. It works quickly — typically within 15 to 30 minutes — making it useful for short-term or as-needed relief.
How to Take
Take hydroxyzine exactly as prescribed. It may be taken with or without food. If using the oral liquid, measure with an accurate device (not a household spoon). Shaking the Vistaril suspension thoroughly before each dose ensures accurate measurement. The largest portion of the daily dose can be taken at bedtime to manage daytime drowsiness.
Sources
- Hydroxyzine hydrochloride tablets USP prescribing information. Teva Pharmaceuticals USA. Revised April 2014. FDA Label (PDF) Primary source for oral HCl formulation — dosing, indications, contraindications, and adverse reactions.
- Vistaril (hydroxyzine pamoate) capsules and oral suspension prescribing information. Pfizer. Revised 2016. FDA Label (PDF) Source for pamoate formulation with updated QT prolongation warnings and AGEP risk information.
- Hydroxyzine hydrochloride tablets prescribing information. DailyMed / NLM. Updated September 2024. DailyMed Current generic labeling with QT prolongation precautions and AGEP warning.
- Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database Syst Rev. 2010;(12):CD006815. doi:10.1002/14651858.CD006815.pub2 Cochrane review of 5 RCTs (884 patients) confirming hydroxyzine’s efficacy over placebo for GAD with higher drowsiness rates than active comparators.
- Clark JE, Oswald AH, McCoy CE. Efficacy and safety of hydroxyzine for sleep in adults: systematic review. J Am Pharm Assoc. 2023;63(3):815-823. doi:10.1016/j.japh.2023.01.010 Systematic review of 5 studies (207 patients) with mixed evidence for hydroxyzine as a sleep aid in adults.
- Medicines and Healthcare products Regulatory Agency (MHRA). Hydroxyzine (Atarax, Ucerax): risk of QT interval prolongation and Torsade de Pointes. Drug Safety Update. April 2015. GOV.UK Key regulatory safety communication reducing maximum daily dose to 100 mg and advising caution in the elderly.
- American Geriatrics Society 2023 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372 Lists first-generation antihistamines including hydroxyzine as potentially inappropriate in elderly due to anticholinergic and sedative properties.
- Schlit AF, Delaunois A, Colomar A, et al. Risk of QT prolongation and torsade de pointes associated with exposure to hydroxyzine: re-evaluation of an established drug. Pharmacol Res Perspect. 2017;5(3):e00309. doi:10.1002/prp2.309 Comprehensive cardiac safety re-evaluation including pharmacovigilance review of 59 QT/TdP reports and in vitro hERG channel inhibition data.
- Simons FER. Advances in H1-antihistamines. N Engl J Med. 2004;351(21):2203-2217. doi:10.1056/NEJMra033121 Landmark review of antihistamine pharmacology including hydroxyzine-cetirizine relationship and CNS penetration differences.
- Simons FER, Simons KJ, Frith EM. The pharmacokinetics and antihistaminic effects of hydroxyzine in patients with primary biliary cirrhosis. J Clin Pharmacol. 1989;29(9):809-815. doi:10.1002/j.1552-4604.1989.tb03420.x Demonstrates prolonged hydroxyzine half-life in liver disease patients, informing hepatic dose adjustments.
- Simons FER, Simons KJ, Becker AB, Haydey RP. Pharmacokinetics and antipruritic effects of hydroxyzine in children with atopic dermatitis. J Pediatr. 1984;104(1):123-127. doi:10.1016/S0022-3476(84)80608-3 Source for pediatric half-life (~7 hours) and cetirizine generation kinetics in children.
- Simons FER, Simons KJ, Frith EM. Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther. 1989;45(1):9-14. doi:10.1038/clpt.1989.2 Key source for elderly pharmacokinetics — half-life 29.3 hours, Vd 22.5 L/kg — informing dose reduction recommendations.