(±)-Hydroxyzine

374.90428

374.90

200-693-1

4000

169188

DTXSID8023137

Oil

N05BB01|N - Nervous system

2933599090

35.9

2.7

Solid

1.1020 (rough estimate)

190°C

250 °C @ Press: 0.1 Torr

9.14e-02 g/L

Commercially available preparations of hydroxyzine should be stored in tight, light-resistant containers at a temperature less than 40 deg C, preferably at 15 - 30 deg C; freezing of the oral solution, oral suspension, or injection should be avoided.

1.17X10-11 mm Hg at 25 deg C (est)

LD50 oral in rat: 840mg/kg

Henry's Law constant = 3.86X10-17 atm-cu m/mol at 25 °C (est)

pKa1 = 2.47 (amine); pKa2 = 6.95 (amine) (est)

197.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Crystals; mw 763.27; practically insoluble in water /Hydroxyzine pamoate/|Hydroxyl radical reaction rate constant = 2.48X10-10 cu cm/molec-sec at 25 °C (est)

1106

R11:Highly Flammable. R20/22:Harmful by inhalation and if swallowed . R35:Causes severe burns.

S3:Keep in a cool place . S16:Keep away from sources of ignition - No smoking . S23:Do not breathe gas/fumes/vapor/spray (appropriate wording to be specified by the manufacturer) . S26:In case of contact with eyes, rinse immediately with plenty of water an

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl hydroxyzine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Hydroxyzine hydrochloride/|The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl hydroxyzine pamoate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Hydroxyzine pamoate/

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P281, P285, P301+P312, P304+P340, P304+P341, P308+P313, P312, P314, P330, P342+P311, P403+P233, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The oral LD50 is 840 mg/kg in rats and 400 mg/kg in mice. Overdose from hydroxyzine is most commonly characterized by hypersedation, but may also manifest as convulsions, stupor, nausea, and vomiting. In cases of overdose, consider the induction of vomiting and the use of gastric lavage. Other treatment should involve general symptomatic and supportive care. Hypotension may be controlled by intravenous fluids and pressors, and caffeine and sodium benzoate injection may be used to counteract any observed CNS depressant effects. Hemodialysis is unlikely to provide any benefit in the treatment hydroxyzine overdose.

Despite widespread use, hydroxyzine has not been linked to liver test abnormalities or to clinically apparent liver injury. Indeed, hydroxyzine is commonly used for the pruritus associated with liver disease. The reason for its safety may relate to low daily dose and limited duration of use.

Hydroxyzine has been shown to inhibit and reverse the vasopressor effect of epinephrine. If a vasopressor agent is required in patients receiving hydroxyzine, norepinephrine or metaraminol should be used; epinephrine should not be used.|Additive anticholinergic effects may occur when hydroxyzine is administered concomitantly with other anticholinergic agents.|Hydroxyzine may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. When hydroxyzine is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation, and the manufacturers recommend that dosage of the CNS depressant be reduced by up to 50%.|Mechanism of a rise of blood hydroxyzine concentrations due to ethanol administration was investigated used rabbits. When 10 mg/kg hydroxyzine dihydrochloride were orally administered together with 10 mL/kg of 1 to 15% ethanol solution, blood hydroxyzine concentrations rised in all rabbits given ethanol solution more than 10%. When 10 mL/kg of 15% ethanol solution were orally administered at 1, 2 or 3 hours before oral administration of hydroxyzine, blood hydroxyzine concentrations rised markedly in all cases. Blood hydroxyzine concentrations rised little or a little when hydroxyzine were orally administered immediately after intravenous administration of 5 mL/kg of 20% ethanol solution. It was considered that the main mechanism of a rise of blood hydroxyzine concentration was not metabolic interaction between hydroxyzine and ethanol, but an enhancement of intestinal absorption of hydroxyzine due to ethanol. It was also found that hydroxyzine in blood distributed rapidly into bodily tissues.

LD50 Rat oral 840 mg/kg|LD50 Rat ip 160 mg/kg|LD50 Rat iv 45 mg/kg|LD50 Mouse oral 480 mg/kg|For more Non-Human Toxicity Values (Complete) data for HYDROXYZINE (6 total), please visit the HSDB record page.

Hydroxyzine has been shown to bind to human albumin _in vitro_, but the extent of protein binding in plasma has not been evaluated.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,362 workers (719 of these were female) were potentially exposed to hydroxyzine in the US(1).

Hydroxyzine is indicated for the symptomatic relief of anxiety and tension associated with psychoneuroses, and as an adjunct in organic disease states in which anxiety is manifested. It is also indicated in the treatment of histamine-mediated pruritus and pruritus due to allergic conditions such as chronic urticaria. Canadian labeling states that hydroxyzine is also indicated in adults and children as a premedication prior to medical procedures, such as dental surgery. It is also used in the control of nausea and vomiting, excluding nausea and vomiting of pregnancy.

Hydroxyzine is a first generation antihistamine that is used largely for symptoms of itching, nausea, anxiety and tension. Hydroxyzine has not been linked to instances of clinically apparent acute liver injury.

Antihistamines

Anti-Anxiety Agents; Antiemetics; Antipruritics; Histamine H1 Antagonists; Sedatives, Nonbarbiturate|MEDICATION (VET): The efficacy of antihistamines for the treatment of pruritus is highly variable. The most commonly used antihistamines include hydroxyzine hydrochloride ...|MEDICATION (VET): In chronic urticaria, antihistamines such as hydroxyzine may be useful ... in horses ... .|Hydroxyzine has also been used for the management of agitation caused by acute alcohol withdrawal; to reduce opiate analgesic dosage; to control motion sickness; and to control nausea and vomiting of various etiologies (e.g., postoperative). /Included in US product label/|Hydroxyzine is used for the symptomatic management of anxiety and tension associated with psychoneuroses and as an adjunct in patients with organic disease states who have associated anxiety; for the management of pruritus caused by allergic conditions such as chronic urticaria or atopic or contact dermatoses, and in histamine-mediated pruritus; and for its sedative effects before and after general anesthesia. The efficacy of hydroxyzine as an anxiolytic agent during long-term administration (i.e., longer than 4 months) has not been established; most clinicians believe that benzodiazepines, barbiturates, and meprobamate are more effective than hydroxyzine for anxiety. Patients with a history of long-term therapy with hydroxyzine should be evaluated periodically to determine the efficacy and need for further treatment. Hydroxyzine should not be used as the sole agent for the treatment of depression or psychoses. /Included in US product label/

Marked local discomfort, sterile abcesses, erythema, local irritation, and tissue necrosis may occur at the site of IM injection, and marked localized subcutaneous tissue induration has been reported as a result of extravasation of the drug.|The most frequent adverse effects of hydroxyzine are drowsiness and dry mouth. Drowsiness usually diminishes with continued therapy or reduction in dosage. Other less frequent adverse nervous system effects of hydroxyzine include dizziness, ataxia, weakness, slurred speech, headache, agitation, and increased anxiety. Involuntary motor activity, including tremor and seizures, has occurred rarely, usually in patients receiving higher than recommended dosages of the drug.|Patients should be warned that hydroxyzine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).|Because of the risk of adverse local effects, which may be severe (e.g., gangrene, thrombosis), IM administration of hydroxyzine should be performed with caution to avoid extravasation or inadvertent subcutaneous, IV, or intra-arterial injection.|For more Drug Warnings (Complete) data for HYDROXYZINE (11 total), please visit the HSDB record page.

Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation.

Drugs that selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions of endogenous histamine. Included here are the classical antihistaminics that antagonize or prevent the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and some other smooth muscles, and are used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce somnolence. The effects of blocking central nervous system H1 receptors are not as well understood. (See all compounds classified as Histamine H1 Antagonists.)|Agents, usually topical, that relieve itching (pruritus). (See all compounds classified as Antipruritics.)

The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (T_max) approximately 2 hours following administration.|Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined.|The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma.|Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults.|It is not known if hydroxyzine crosses the placenta or is distributed into milk.|Distribution of hydroxyzine into human body tissues and fluids has not been fully characterized. Following administration of hydroxyzine in animals, the drug is widely distributed into most body tissues and fluids with highest concentrations in the liver, lungs, spleen, kidneys, and adipose tissue. The drug is also distributed into bile in animals.|Hydroxyzine is rapidly absorbed from the GI tract following oral administration.|The distribution into cerebrospinal fluid of 4 structurally similar antihistamines, chlorcyclizine hydrochloride, chlorpheniramine maleate, hydroxyzine hydrochloride (hydroxyzine dihydrochloride), and triprolidine hydrochloride, was studied in Sprague-Dawley rats after the administration of intranasal solutions or intra-arterial injections of solutions of each of the antihistamines; drug concentrations were measured in plasma and cerebrospinal fluid (CSF). Doses of 15.4, 13.3, 8.7, and 16.5 mumol/kg of chlorcyclizine, chlorpheniramine, hydroxyzine, and triprolidine, respectively, were administered. Hydroxyzine plasma and CSF concentrations were significantly greater than most of the other antihistamines. Also, hydroxyzine showed the most rapid absorption into plasma following intranasal administration, and its CSF Cmax values were significantly higher after intranasal administration compared to intra-arterial administration. The ratios of AUC (0-180 min) values for intranasal:intra-arterial administration in CSF and plasma for hydroxyzine were 4 and 0.42 and for triprolidine, the only other antihistamine with measurable CSF concentrations, were 0.54 and 0.66, respectively.|For more Absorption, Distribution and Excretion (Complete) data for HYDROXYZINE (8 total), please visit the HSDB record page.

Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine [cetirizine]. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans.|Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 ug mL(-1) and that of hydroxyzine 0.16 ug mL(-1). The terminal half-life for cetirizine varied between 10 and 11 hr after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 hr, which correlated with a plasma concentration of cetirizine greater than 1.5 ug mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).|Although the exact metabolic fate of hydroxyzine is not clearly established, it appears that the drug is completely metabolized, principally in the liver. In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination. The carboxylic acid metabolite of hydroxyzine, cetirizine, is a long-acting antihistamine.

The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment.|Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. ... The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. ...|... The pharmacokinetics and antipruritic effects of hydroxyzine hydrochloride in 12 children, mean age 6.1 +/- 4.6 years, with severe atopic dermatitis /were examined/. After a single 0.7 mg/kg orally administered dose of the drug, ... . The mean elimination half-life was 7.1 +/- 2.3 hours, ... .|... The changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days /were studied/. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer (p less than 0.05) than that of 2.4 +/- 0.3 hours obtained on day 1. ...|... The pharmacokinetics and the suppression of histamine-induced wheals, flares, and pruritus in the skin after administration of the histamine H1 antagonist hydroxyzine to seven healthy adults /were studied/. After a single oral dose of hydroxyzine, 0.7 mg/kg (mean dose 39.0 +/- 5.4 mg), ... The mean elimination half-life calculated from the terminal linear portion of the serum hydroxyzine concentration vs. time curve was 20.0 +/- 4.1 hr. ...

The H₁ histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H₁ receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H₁-receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets.|Hydroxyzine does not appear to increase gastric secretions or acidity, and usually has mild antisecretory effects. The antispasmodic activity of hydroxyzine is apparently mediated through interference with the mechanism that responds to spasmogenic agents such as acetylcholine, histamine, and serotonin.|Hydroxyzine has CNS depressant, anticholinergic, antispasmodic, and local anesthetic activity, in addition to antihistaminic effects. The drug also has sedative and antiemetic activity. The sedative and tranquilizing effects of hydroxyzine are thought to result principally from suppression of activity at subcortical levels of the CNS; the drug does not have cortical depressant activity. The precise mechanism of antiemetic and antimotion sickness actions of hydroxyzine are unclear, but appear to result, at least in part, from its central anticholinergic and CNS depressant properties.|The effects of the drug hydroxyzine on the activities of the rat liver monoamine oxidases (EC 1.4.3.6; MAO) and the membrane-bound and soluble forms of bovine semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) were studied. Hydroxyzine was found to be a competitive inhibitor of MAO-B (Ki - 38 microM), whereas it had a low potency towards MAO-A (IC50 > 630 microM). Although it was a relatively potent competitive inhibitor of bovine plasma SSAO (Ki approximately 1.5 microM), it was a weak inhibitor of the membrane-bound form of the enzyme from bovine lung (IC50 approximately 1 mM). These findings extend our knowledge of the drug binding capabilities of the amine oxidases and suggest that these interactions may contribute to the complex actions of this drug.

(RS)-1-[(4-clorophenyl)phenylmethyl]piperazine|decloxizine

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hyperthermia, and atypical ventricular tachycardia if they occur. Monitor the patient for at least 6-8 hours after ingestion. /Antihistamines/|Specific drugs and antidotes: There is no specific antidote for antihistamine overdose. ... /Antihistamines/|Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of slowed gastrointestinal motility, gut decontamination procedures may be helpful even in late-presenting patients. /Antihistamines/|Most patients require only symptomatic and supportive care. Treatment is focused on controlling agitation, maintaining airway, reversing hyperthermia, and supporting hemodynamic function. Gastrointestinal decontamination is not essential, but if not more than 1 hour has elapsed since ingestion of the drug, activated charcoal may be considered. In view of the potential cardiac toxicity in addition to maintenance of the airway, breathing, and circulatory status of the patient, observation for dysrhythmia is warranted. Clinical assessment for signs that may indicate impending seizure activity (hypertonicity, hyperreflexia, or myoclonic jerking) is important. Patients with altered mental status, seizure, abnormal vital signs, or dysrhythmia are typically admitted. /Antihistamines/|For more Antidote and Emergency Treatment (Complete) data for HYDROXYZINE (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ In general, overdosage of hydroxyzine may be expected to produce effects that are extensions of common adverse reactions; excessive sedation has been the principal effect reported. Hypotension, although rare, may also occur.|/CASE REPORTS/ A /case of/ neonatal withdrawal syndrome associated with maternal hydroxyzine treatment (150 mg/day) confirmed by measurements of hydroxyzine plasma concentrations in the mother and infant after birth /is reported/. Hydroxyzine plasma concentrations were measured by liquid chromatography-mass spectrometry. Neurological symptoms with low neonatal concentrations of hydroxyzine may be due to a withdrawal syndrome. According to previous observations and this case report, clinicians should be warned of this possible rare neurological complication of hydroxyzine in neonates born from long term treated mothers.|/CASE REPORTS/ A case of hydroxyzine toxicity following accidental ingestion in a 13-month old female infant has been presented. A plasma hydroxyzine concentration 8.5 hours after the acute ingestion was 102.7 ug/mL and toxicity was manifested primarily by generalized seizures and sinus tachycardia. General supportive care and seizure control with physostigmine resulted in complete recovery within 72 hours.|/CASE REPORTS/ ... A case report of neonatal withdrawal of a female infant with Apgar scores of 7 and 9 weighing 2950 g delivered of a mother who had been treated during her entire pregnancy with hydroxyzine 600 mg daily and phenobarbital 60 mg daily. The infant's jitteriness; tachypnea; poor suck and feeding; irritability; clonic movement; and shrill cry are all suggestive of a narcotic withdrawal syndrome. Since the small amount of phenobarbital taken in the weeks preceding delivery would not be expected to result in an early neonatal withdrawal syndrome, it is believed that the patient's symptoms were a result of withdrawal from hydroxyzine.|For more Human Toxicity Excerpts (Complete) data for HYDROXYZINE (8 total), please visit the HSDB record page.

2-(2-(4-((4-Chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)ethanol

Boldenone|Equipoise, Parenabol, Vebonol, dehydrotestosterone|4000|Schedule III - Substances in the DEA Schedule III have a potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence.|No

Table: Hydroxyzine Hydrochloride Preparations [Table#4437]|Table: Hydroxyzine Pamoate Preparations [Table#4438]

Analyte: hydroxyzine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Hydroxyzine hydrochloride/|Analyte: hydroxyzine hydrochloride; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry at 230 nm with comparison to standards /Hydroxyzine hydrochloride/|Analyte: hydroxyzine hydrochloride; matrix: chemical identification; procedure: reaction with nitric acid and silver nitrate; preciptate insoluble in nitric acid but soluble in ammonium hydroxide /Hydroxyzine hydrochloride/|Analyte: hydroxyzine hydrochloride; matrix: chemical purity; procedure: liquid chromatography with ultraviolet detection at 230 nm and comparison to standards /Hydroxyzine hydrochloride/|For more Analytic Laboratory Methods (Complete) data for HYDROXYZINE (13 total), please visit the HSDB record page.

Analyte: hydroxyzine; matrix: pharmaceutical preparation (injection solution); procedure: high-performance liquid chromatography with ultraviolet detection at 257 nm|Analyte: hydroxyzine; matrix: blood (serum); procedure: high-performance liquid chromatography with ultraviolet detection at 229 nm; limit of detection: 3 ng/mL|Analyte: hydroxyzine; matrix: blood (whole), urine; procedure: high-performance liquid chromatography with UV detection at 200.5 nm

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals