Hydroxyzine Pamoate

Introduction Overview

Generic Name

Hydroxyzine pamoate

Brand Name

Vistaril, Atarax (related brands)

Dosage Form

Capsule

Drug Class

Antihistamines; Miscellaneous anxiolytics, sedatives and hypnotics

Pharmacokinetics

Absorption:
Hydroxyzine pamoate is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Clinical effects typically manifest within 15 to 30 minutes of dosing. The compound is practically insoluble in water, yet its formulation as a pamoate salt facilitates adequate bioavailability. Food intake has not been shown to significantly alter its absorption kinetics. Pharmacokinetic studies indicate that peak plasma concentrations are reached promptly, enabling prompt onset of anxiolytic, sedative, and antihistaminic effects.

Distribution:
The drug exhibits wide distribution throughout the body, including central nervous system tissues due to its lipophilic nature. Hydroxyzine readily crosses the blood-brain barrier, explaining its CNS depressant effects such as sedation and anxiolysis. It is also bound moderately to plasma proteins, influencing free drug concentrations. The volume of distribution is large, consistent with extensive tissue penetration. Distribution to sites of allergic inflammation supports its efficacy in pruritic and urticarial conditions.

Metabolism:
Hydroxyzine undergoes hepatic biotransformation primarily via oxidation and conjugation pathways. It is metabolized to cetirizine, an active metabolite that possesses selective peripheral H1 antihistaminic activity with minimal sedative effects. The primary enzymes involved are within the cytochrome P450 system, though specific isoenzymes have not been definitively identified. Metabolic clearance contributes significantly to its elimination, and hepatic impairment may alter pharmacokinetics, necessitating cautious dosing.

Elimination:
The elimination of hydroxyzine occurs predominantly through renal excretion of both parent compound and metabolites. The exact extent of renal clearance is not completely quantified, but elderly patients with reduced renal function may exhibit delayed elimination, necessitating dose adjustments. The elimination half-life ranges from approximately 20 to 25 hours, supporting dosing intervals of three to four times daily depending on indication. Hydroxyzine is not significantly removed by hemodialysis. Clinical monitoring is advised in overdose situations given its CNS depressant capacity and potential cardiac effects.

Dosage Forms

Available Dosage Forms:
Hydroxyzine pamoate is available in hard gelatin capsules. The capsules are provided in two strengths:
- 25 mg capsules: green opaque cap and body, imprinted EP 136 in black ink
- 50 mg capsules: white opaque cap, green opaque body, imprinted EP 112 in black ink

Dosages for Adults and Adolescents:
- For symptomatic relief of anxiety and tension associated with psychoneurosis: 50–100 mg administered four times daily.
- For management of pruritus due to allergic conditions: 25 mg three to four times daily.
- As a sedative premedication and post-general anesthesia: 50–100 mg in adults.

Dosages for Pediatric Patients:
- Children under 6 years: 50 mg daily in divided doses for anxiety or pruritus.
- Children over 6 years: 50–100 mg daily in divided doses.
- As a sedative in children: 0.6 mg/kg dosage.

Specific Patient Populations:
Dose adjustments are recommended in elderly patients, starting at the low end of the dosing range due to the potential for increased sedation and altered pharmacokinetics related to hepatic and renal function decline. Careful titration and monitoring are advised.
Capsules should be stored at controlled room temperature (20° to 25°C or 68° to 77°F) and dispensed in tight, light-resistant containers to maintain stability.

Mechanism Of Action

Hydroxyzine pamoate exerts its pharmacological effects primarily through antagonism of peripheral and central histamine H1 receptors. By competitively inhibiting the binding of histamine to these receptors, hydroxyzine effectively mitigates allergic symptoms such as pruritus and urticaria. Moreover, its central H1 receptor blockade is implicated in its sedative and anxiolytic actions.

Beyond antihistaminic properties, hydroxyzine moderates central nervous system activity by depressing subcortical areas, which contributes to its anxiolytic and sedative effects without direct cortical depression. It also induces primary skeletal muscle relaxation, a mechanism verified through experimental models, enhancing its utility in tension and anxiety states.

Furthermore, hydroxyzine exhibits antiemetic effects, mediated potentially through interactions with central chemoreceptor trigger zones, as demonstrated via apomorphine and veriloid tests. Its ability to provide mild bronchodilation and analgesic effects extends its clinical applications beyond simple antihistaminic use.

Comparatively, unlike benzodiazepines or barbiturates, hydroxyzine does not bind to GABA receptors; instead, its mechanism focuses on histaminergic pathways and modulation of subcortical neural activity. This difference underscores hydroxyzine’s unique profile as a non-benzodiazepine anxiolytic with added antihistaminic benefits. Clinical studies have confirmed rapid onset of action with oral administration and significant symptom relief in anxiety, pruritus, and sedation contexts.

Pharmacological Actions

Selective antagonism of central and peripheral histamine H1 receptors resulting in antihistaminic activity.
Central nervous system depressant effects via suppression of subcortical CNS regions causing sedation and anxiolysis.
Primary skeletal muscle relaxation demonstrated experimentally and clinically.
Bronchodilator effects, beneficial in allergic respiratory conditions.
Analgesic properties through poorly defined central mechanisms.
Antiemetic activity via interaction with central emetic pathways.
Mild antisecretory effect on gastric secretions, without increasing acidity.
Potentiation of other CNS depressants when co-administered (e.g., barbiturates, meperidine).
Rapid gastrointestinal absorption enabling prompt therapeutic effects.
Minimal cortical depression distinguishing it from benzodiazepines and barbiturates.

Therapeutic Or Clinical Uses

Symptomatic relief of anxiety and tension associated with psychoneurosis.
Adjunct therapy in organic disease states presenting with anxiety symptoms.
Management of pruritus arising from allergic conditions including chronic urticaria, atopic dermatitis, and contact dermatoses.
Treatment of histamine-mediated pruritus of various etiologies.
Sedative premedication prior to surgical procedures and following general anesthesia.
Adjunct to other CNS depressants to enhance sedation if used cautiously.
Off-label usage as an antiemetic in some clinical scenarios.
Relief of anxiety-related insomnia due to sedative properties.

Side Or Adverse Effects

Common transitory drowsiness, which generally diminishes with continued therapy or dose adjustment.
Dry mouth due to anticholinergic effects.
Rare involuntary motor activities including tremors and convulsions particularly at doses higher than recommended.
QT interval prolongation and potential for Torsade de Pointes arrhythmia reported post-marketing.
Skin reactions including pruritus, rash, urticaria, and rare acute generalized exanthematous pustulosis (AGEP).
Occasional headache and hallucinations reported in post-marketing surveillance.
Allergic reactions consisting of hypersensitivity manifestations.
Potential for over sedation especially when combined with other CNS depressants.
Nausea and vomiting primarily observed in overdose cases.
Respiratory depression not clinically significant at recommended dosages.
Transient CNS effects such as dizziness and fatigue.
Possible exacerbation of pre-existing skin conditions due to hypersensitivity.

Precautions

Concomitant administration with other CNS depressants (e.g., narcotics, barbiturates) requires dose adjustment due to potentiation of sedative effects.
Patients should be warned of possible drowsiness and cautioned against driving or operating heavy machinery while taking hydroxyzine.
Alcohol consumption may potentiate CNS depressant effects and should be avoided or minimized.
Use with caution in elderly patients due to increased risk of sedation, confusion, and decreased hepatic/renal function.
QT prolongation risk necessitates careful use in patients with congenital long QT syndrome or other predisposing cardiac conditions.
Avoid use in patients with known hypersensitivity to hydroxyzine or related compounds cetirizine and levocetirizine due to cross-reactivity.
Pregnancy: contraindicated in early pregnancy due to teratogenic effects demonstrated in animal studies; safety in human pregnancy not established.
Nursing mothers should avoid hydroxyzine due to potential secretion in breast milk and unknown infant effects.
Monitor patients for skin reactions, discontinuing drug at first signs of rash or hypersensitivity.
Caution in patients with bradyarrhythmias, recent myocardial infarction, or uncompensated heart failure.
Dose adjustments advised in patients with compromised renal function.
Use with caution when co-administered with other QT-prolonging agents such as certain antiarrhythmics, antipsychotics, antidepressants, and antibiotics.

Warnings

Hydroxyzine is contraindicated in patients with a known prolonged QT interval due to risk of arrhythmias.
Potential for acute generalized exanthematous pustulosis (AGEP), a serious skin reaction; patients should be informed and monitored for rash.
Not recommended for use in early pregnancy given evidence of fetal abnormalities in animal studies.
Should not be used during lactation because of unknown effects in nursing infants.
Risk of potentiating CNS depressants requires close monitoring when used concomitantly with other sedatives or narcotics.
QT prolongation and Torsade de Pointes have been reported in post-marketing settings; caution in patients with cardiac risk factors.
Avoid concurrent use with drugs known to prolong QT interval, including Class 1A and III antiarrhythmics, certain antipsychotics, some antidepressants, macrolide antibiotics, and others.
Elderly patients have increased susceptibility to sedative and anticholinergic adverse reactions; dosing should be cautious and monitored closely.
Discontinue drug at signs of hypersensitivity or worsening skin manifestations, especially if AGEP suspected.
Hydroxyzine may impair mental and physical abilities; patients should be advised accordingly to prevent accidents.
Overdose management requires supportive care; no specific antidote is available.

Contraindication

Known hypersensitivity to hydroxyzine or any components of the formulation.
Hypersensitivity to related antihistamines such as cetirizine hydrochloride or levocetirizine hydrochloride.
Patients with congenital or acquired prolonged QT interval.
Pregnancy, particularly during early stages, due to teratogenic risk demonstrated in animal studies.
Use in individuals with known hypersensitivity reactions to similar piperazine derivatives.
Patients with history of severe allergic reactions to hydroxyzine or excipients.
Use contraindicated in patients with a history of Torsade de Pointes or ventricular arrhythmias.
Avoid in patients taking other medications known to cause QT prolongation without rigorous medical supervision.

Drug Interactions

Enhanced sedative effects when combined with central nervous system depressants such as narcotics, barbiturates, and non-narcotic analgesics.
Potentiation of CNS depression by alcohol consumption.
Hydroxyzine may antagonize pressor effects of epinephrine; avoid epinephrine for hypotension management in overdosage.
Caution when combined with other QT-prolonging drugs including Class 1A (quinidine, procainamide) and Class III (amiodarone, sotalol) antiarrhythmics.
Potential additive QT prolongation with antipsychotics such as ziprasidone, iloperidone, clozapine, quetiapine, chlorpromazine.
Interactions with certain antidepressants including citalopram and fluoxetine can increase risk of cardiac arrhythmias.
Macrolide antibiotics (azithromycin, erythromycin, clarithromycin) may exacerbate QT prolongation.
Other drugs posing QT prolongation risk include gatifloxacin, moxifloxacin, pentamidine, methadone, ondansetron, droperidol.
No known interference with digitalis drugs.
Concurrent use with belladonna alkaloids (e.g., atropine) does not affect their activity.
No significant interaction with antihistamine-related medications except cross-sensitivity considerations.
Use caution and monitor patients for enhanced sedation or cardiac effects during polypharmacy.
Potential altered metabolism if co-administered with drugs affecting cytochrome P450 enzymes though no specific isoenzymes have been definitively implicated.

Preparations Of The Drug

Hydroxyzine pamoate hard gelatin capsules available in 25 mg strength (green opaque capsules, imprinted EP 136).
Hydroxyzine pamoate hard gelatin capsules available in 50 mg strength (white opaque cap, green opaque body, imprinted EP 112).
Capsules contain inactive ingredients including microcrystalline cellulose, corn starch, sodium lauryl sulfate, sodium starch glycolate potato type A, magnesium stearate, D&C Yellow No. 10, FD&C Red No. 40, FD&C Blue No. 1, titanium dioxide, gelatin, shellac, ferrosoferric oxide, butyl alcohol, isopropyl alcohol, propylene glycol, and ammonia.
Supplied in bottles containing 100 or 500 capsules per container.
Stored at controlled room temperature (20° to 25°C or 68° to 77°F), protected from light and moisture.
Dispensed in tight, light-resistant containers adhering to USP standards.
Distributed by Avet Pharmaceuticals Inc., East Brunswick, NJ.
Manufacturing includes packaging, analysis, and labeling under regulated facility conditions.
No chewable or liquid formulations of hydroxyzine pamoate are included; other salt formulations (hydrochloride) may offer different dosage forms.
Packaging includes clear imprint codes for dose identification.
Approved via ANDA with application number ANDA201507 since 2013.