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.
Hydroxyzine has also been used for the management of agitation caused by acute alcohol withdrawal; to reduce opiate analgesic dosa to control motion sickness; and to control nausea and vomiting of various etiologies (e.g., postoperative). Safe use of hydroxyzine for the prevention and treatment of nausea and vomiting of pregnancy has not been established, and the drug is contraindicated during early pregnancy.
Administration 
Hydroxyzine hydrochloride and hydroxyzine pamoate are administered orally; hydroxyzine hydrochloride may also be administered by IM injection. Because severe adverse effects may occur, the drug must not be administered by subcutaneous, intra-arterial, or IV injection. (See Cautions: Local Effects.) Oral therapy should replace IM therapy as soon as possible.
For IM administration, the commercially available hydroxyzine injection is used without further dilution. The Z-track technique of injection may be used to prevent subcutaneous infiltration. For IM administration in adults, injection should be made preferably deep into the upper outer quadrant of the gluteus maximus or the midlateral thigh. The deltoid area should be used with caution and only if well developed, in order to avoid radial nerve injury. IM injections should not be made into the lower and mid-third of the upper arm. For IM administration in children, injections should be made preferably into the midlateral muscles of the thigh; in infants and small children, the periphery of the upper outer quadrant of the gluteus maximus should be used only when necessary (e.g., burn patients), in order to minimize the possibility of damage to the sciatic nerve.
Dosage
Dosage of hydroxyzine hydrochloride or pamoate is expressed in terms of the hydrochloride. Dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.
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, the usual adult oral dosage of hydroxyzine is 50-100 mg 4 times daily. The usual oral dosage of hydroxyzine for the symptomatic management of anxiety and tension associated with psychoneuroses and as an adjunct in organic disease states in children 6 years of age or older is 50-100 mg daily given in divided doses; for children younger than 6 years of age, the usual oral dosage is 50 mg daily given in divided doses.
For prompt control of acutely disturbed or hysterical patients and for the management of agitation caused by alcohol withdrawal, the usual adult IM dose of hydroxyzine is 50-100 mg. This dose may be repeated every 4-6 hours, as needed to control symptoms.
For the management of pruritus caused by allergic conditions such as chronic urticaria or atopic or contact dermatoses, and in histamine-mediated pruritus, the usual adult oral dosage of hydroxyzine is 25 mg 3 or 4 times daily. The usual oral dosage of hydroxyzine for the management of pruritus caused by allergic conditions in children 6 years of age or older is 50-100 mg daily given in divided doses; for children younger than 6 years of age, the usual oral dosage is 50 mg daily given in divided doses.
For sedation before and following general anesthesia, the usual adult dose of hydroxyzine is 50-100 mg orally or 25-100 mg IM. When used as a sedative before and following general anesthesia in children, the usual dose of hydroxyzine is 0.6 mg/kg orally or 1.1 mg/kg IM.
For control of nausea and vomiting (excluding nausea and vomiting of pregnancy), the usual initial IM dose of hydroxyzine is 25-100 mg in adults and 1.1 mg/kg in children. Subsequent dosage should be adjusted according to individual requirements and response.
For control of emesis, to permit reduction in opiate dosage, or to allay anxiety in prepartum and postpartum states, the usual initial adult IM dose of hydroxyzine is 25-100 mg. Subsequent dosage should be adjusted according to individual requirements and response.
Adverse reactions to hydroxyzine generally involve the CNS and are usually mild, transient, and reversible following discontinuance of the drug.
Nervous System Effects
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.
Local Effects
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.
Following inadvertent intra-arterial injection of hydroxyzine hydrochloride, thrombosis and digital gangrene necessitating amputation have occurred. Phlebitis and hemolysis have been reported following IV administration of the drug. Following inadvertent subcutaneous administration of hydroxyzine hydrochloride, tissue necrosis, tissue slough, swelling, edema, petechial hemorrhage, and abscess have occurred.
Other Adverse Effects
Other adverse effects that have been reported following administration of hydroxyzine include a bitter taste in the mouth, nausea, increased GI peristalsis, flushing, wheezing, and tightness of the chest.
Precautions and Contraindications
Hydroxyzine shares the toxic potentials of the antihistamines, and the usual precautions of antihistamine therapy should be observed.
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.
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). Patients also should be warned that hydroxyzine may enhance their response to alcohol, barbiturates, or other CNS depressants.
Hydroxyzine is contraindicated in patients who are hypersensitive to the drug.
Pregnancy and Lactation
Pregnancy
Although there are no adequate and controlled studies to date in humans, hydroxyzine has been shown to be teratogenic in mice, rats, and rabbits when given at dosages substantially greater than the therapeutic human dosage. Pending accumulation of further data regarding safety in pregnant women, hydroxyzine is contraindicated during early pregnancy.
Lactation
It is not known whether hydroxyzine is distributed into milk. The manufacturers recommend that hydroxyzine not be given to nursing women.
CNS Depressants
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%.
Anticholinergic Agents
Additive anticholinergic effects may occur when hydroxyzine is administered concomitantly with other anticholinergic agents.
Epinephrine
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.
Laboratory Test Interferences
Hydroxyzine has been reported to cause falsely elevated urinary concentrations of 17-hydroxycorticosteroids when the Porter-Silber reaction or the Glenn-Nelson method is used.
Acute Toxicity
Limited information is available on the acute toxicity of hydroxyzine. The acute lethal dose of hydroxyzine in humans is not known. In addition, there is no clearly defined relationship between plasma hydroxyzine concentration and severity of intoxication.
Manifestations
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.
Treatment
Treatment of hydroxyzine overdosage generally involves symptomatic and supportive care; there is no specific antidote for hydroxyzine intoxication. Following acute ingestion of the drug, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Appropriate therapy should be instituted if hypotension or excessive sedation occurs. If hypotension occurs, it may be controlled with IV fluids and norepinephrine or metaraminol; epinephrine should not be used. Although one manufacturer states that caffeine and sodium benzoate may be used to counteract CNS depressant effects of the drug, most authorities believe caffeine and other analeptics should not be used in overdosage resulting from CNS depressants. Although hemodialysis or peritoneal dialysis is probably not effective in enhancing elimination of hydroxyzine, if other agents (e.g., barbiturates) have been ingested concomitantly, dialysis may be indicated.
Pharmacology
The principal pharmacologic effects of hydroxyzine are similar to those of other antihistamines. (see Antihistamines General Statement 4:00)
Nervous System Effects
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.
Like many other centrally acting agents, hydroxyzine exhibits analgesic activity in a variety of analgesic test systems; this effect may be related to its sedative activity. Hydroxyzine also has primary skeletal muscle relaxant activity.
GI Effects
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.
Cardiovascular Effects
Although hydroxyzine does not appear to have clinically important antiarrhythmic properties, mild antiarrhythmic activity has been observed in some experimentally induced ventricular arrhythmias. Therapeutic dosages of hydroxyzine produce only minimal effects on blood pressure; however, hypotension may occur following overdosage.
Other Effects
Hydroxyzine has been shown to produce bronchodilation in healthy individuals and in patients with chronic obstructive pulmonary disease.
Pharmacokinetics
Absorption
Hydroxyzine is rapidly absorbed from the GI tract following oral administration.
The onset of sedative action of hydroxyzine is 15-30 minutes following oral administration. Sedative effects persist for 4-6 hours following administration of a single dose. Hydroxyzine suppresses the inflammatory response (wheal and flare reaction) and pruritus for up to 4 days after intradermal skin tests with allergens and histamine.
The therapeutic range for plasma hydroxyzine concentrations and the relationship of plasma concentration to clinical response or toxicity have not been established.
Distribution
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.
It is not known if hydroxyzine crosses the placenta or is distributed into milk.
Elimination
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 (Zyrtec®, Pfizer), is a long-acting antihistamine.
Chemistry and Stability
Chemistry
Hydroxyzine is a piperazine-derivative antihistamine that is structurally similar to meclizine. Hydroxyzine is chemically unrelated to reserpine, meprobamate, benzodiazepines, or phenothiazines. Hydroxyzine is commercially available as the hydrochloride and pamoate salts.
Hydroxyzine hydrochloride occurs as a white, odorless powder and is very soluble in water and freely soluble in alcohol. The drug has pKas of 2.6 and 7.0. Hydroxyzine hydrochloride injection is a sterile solution of the drug in water for injection. Sodium hydroxide is added during manufacture of the injection to adjust the pH to 3.5-6. The commercially available injection also contains benzyl alcohol as a preservative.
Hydroxyzine pamoate occurs as a light yellow, practically odorless powder and is practically insoluble in water and in alcohol. The commercially available hydroxyzine pamoate oral suspension has a pH of 4.5-7.
Stability
Commercially available preparations of hydroxyzine should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably at 15-30°C; freezing of the oral solution, oral suspension, or injection should be avoided.
Hydroxyzine hydrochloride injection is physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.