Source: Υπουργείο Υγείας (CY) Revision Year: 2023 Publisher: UCB Pharma S.A., 60 ALLÉE DE LA RECHERCHE, BRUSSELS, 1070
Pharmacotherapeutic group:
ATC code: N05BB01
Hydroxyzine is a psycholeptic and anxiolytic agent (ataractic).
The active substance, hydroxyzine dihydrochloride, is a diphenylmethane derivative, chemically unrelated to the phenothiazines, reserpine, meprobamate or the benzodiazepines.
Hydroxyzine dihydrochloride is not a cortical depressant, but its action may be due to a suppression of activity in certain key regions of the subcortical area of the central nervous system.
Antihistaminic and bronchodilatator activities have been demonstrated experimentally and confirmed clinically. An antiemetic effect, both by the apomorphine test and the veriloid test, has been demonstrated. Pharmacological and clinical studies indicate that hydroxyzine at therapeutic dosage does not increase gastric secretion or acidity and in most cases has mild antisecretory activity. Wheal and flare reduction have been demonstrated in adult healthy volunteers and in children after intradermal injections of histamine or antigens. Hydroxyzine has also revealed its efficacy in relieving pruritus in various forms of urticaria, eczema and dermatitis.
In hepatic function impairment, the antihistaminic effect of one single dose can be prolonged up to 96 hours after intake.
EEG recordings in healthy volunteers show an anxiolytic-sedative profile. Anxiolytic effect was confirmed in patients by the use of various classical psychometric tests. Polysomnographic recordings in anxious and insomniac patients have evidenced an increase in total sleep time, a reduction of total time of night awakenings and a reduction of sleep latency either after single or repeated daily doses of 50 mg. A reduction of the muscular tension was demonstrated in anxious patients at a daily dose of 3 x 50 mg. No memory deficiency has been observed. No withdrawal signs or symptoms have appeared after 4-week treatment in anxious patients.
The antihistaminic effect begins approximately after 1 hour with oral pharmaceutical forms. The sedative effect starts after 5-10 minutes with oral liquid and after 30-45 minutes with tablets.
Hydroxyzine has also spasmolytic and sympatolytic effects. It has a weak affinity for muscarinic receptors. Hydroxyzine shows a mild analgesic activity.
Hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The peak plasma level (Cmax) is reached approximately two hours after oral intake. After single oral doses of 25 mg and 50 mg in adults, Cmax concentrations are typically 30 and 70 ng/ml, respectively. The rate and extent of exposure to hydroxyzine is very similar when given as tablet or as a syrup. Following repeat administration once a day, concentrations are increased by 30%. The oral bioavailability of hydroxyzine with respect to intramuscular (IM) administration is about 80%. After a single 50 mg IM dose, Cmax concentrations are typically 65ng/ml.
Hydroxyzine is widely distributed in the body and generally more concentrated in the tissues than in plasma. The apparent volume of distribution is 7 to 16 l/kg in adults. Hydroxyzine enters the skin following oral administration. Skin concentrations of hydroxyzine are higher than serum concentrations, following both single and multiple administration. Hydroxyzine crosses the blood-brain and placental barriers leading to higher foetal than maternal concentrations.
Hydroxyzine is extensively metabolized. The formation of the major metabolite, cetirizine, a carboxylic acid metabolite (approximately 45% of the oral dose) is mediated by alcohol dehydrogenase. This metabolite has significant peripheral H1- antagonist properties. The other metabolites identified include a N-dealkylated metabolite and an O-dealkylated metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4/5.
Hydroxyzine half-life in adults is approximately 14 hours (range: 7-20 hrs). The apparent total body clearance calculated across studies is 13 ml/min/kg. Only 0.8% of the dose is excreted unchanged in urine. The major metabolite cetirizine is excreted mainly unchanged in urine (25% and 16% of the hydroxyzine oral and IM dose, respectively).
The pharmacokinetics of hydroxyzine was investigated in 9 healthy elderly subjects (69.5 ± 3.7 years) following a single 0.7 mg/kg oral dose. The elimination half-life of hydroxyzine was prolonged to 29 hours and the apparent volume of distribution was increased to 22.5 l/kg. It is recommended to reduce the daily dose of hydroxyzine in elderly patients (see section 4.2).
The pharmacokinetics of hydroxyzine was evaluated in 12 paediatric patients (6.1 ± 4.6 yrs; 22.0 ± 12.0 kg) following a single oral dose of 0.7 mg/kg. The apparent plasma clearance was approximately 2.5 times that in adults. The half-life was shorter than in adults. It was approximately 4 hours in the 1 year-old patients and 11 hours in the 14 year-old-patients. Dosage should be adjusted in paediatric population (see section 4.2).
In subjects with hepatic dysfunction secondary to primary biliary cirrhosis, total body clearance was approximately 66% that of normal subjects. The half-life was increased to 37 hours and the serum concentrations of the carboxylic metabolite, cetirizine, were higher than in young patients with a normal liver function. Daily dose or dose frequency should be reduced in patients with impaired liver function (see section 4.2).
The pharmacokinetics of hydroxyzine was studied in 8 severe renally impaired subjects (Creatinine clearance: 24 ± 7 ml/min). The extent of exposure (AUC) to hydroxyzine was not altered in a relevant manner while that to the carboxylic metabolite, cetirizine, was increased. This metabolite is not removed efficiently by hemodialysis. In order to avoid any important accumulation of the cetirizine metabolite following multiple doses of hydroxyzine, the daily dose of hydroxyzine should be reduced in subjects with impaired renal function (see section 4.2).
None stated.The safety pharmacology, acute, sub-acute and chronic toxicity studies did not raise significant safety concerns from data in rodents, dogs and monkeys. Lethal doses 50 (LD50) in rats and mice are respectively 690 and 550 mg/kg per os whereas these are 81 and 56 mg/kg I.V.
Single oral doses of 80 mg/kg and above induced signs of depression, ataxia, convulsions and tremor in dogs. In monkeys, at oral doses exceeding 50 mg/kg, some vomiting occurred without any other signs up to 400mg/kg, whereas i.v. doses of 15 mg/kg caused transient ataxia and convulsions, with complete recovery within 5 minutes after dosing. Intra-arterial injections led to important local tissue lesions in rabbits.
Hydroxyzine produced inhibition of the potassium (Ikr) current in human ether-a-go-go-related gene (hERG) channels expressed in mammalian cells, with an IC50 of 0.39 μM, a concentration that is 40-fold higher than the free therapeutic plasma concentration at the dose of 50 mg. In isolated canine Purkinje fibres hydroxyzine at 3 μM increased action potential duration suggesting that there was an interaction with potassium channels involved with the repolarisation phase. At a higher concentration of 30 μM , there was a marked decrease in the action potential duration suggesting a possible interaction with calcium and/or sodium currents. This was confirmed in a multi-ion cardiac channel assay, showing that hydroxyzine inhibits Nav 1.5 and Cav 1.2 channels at such concentrations. In unrestrained conscious dogs monitored by telemetry, hydroxyzine and its enantiomers produced similar cardiovascular profiles though there were some minor differences. In a first dog telemetry study, hydroxyzine (21 mg/kg p.o.) slightly increased heart rate and shortened PR and QT intervals. There was no effect on QRS and QTc intervals and thus at normal therapeutic doses these slight changes are unlikely to be of clinical concern. Similar effects on heart rate and PR interval were observed in a second dog telemetry study, where the absence of effects of hydroxyzine on QTc interval was confirmed up to a single oral dose of 36 mg/kg.
In rats, hydroxyzine administered for 30 days was well tolerated at 20 mg/kg/day s.c., but some mortalities occurred at 200 mg/kg/day per o.s.
Chronic toxicity was tested in rats at oral doses up to 50 mg/day in 100g food for 24 weeks without clinical signs or histopathological abnormalities. Doses of 10 mg/kg/day for 70 days reduced the concentration and the viability of spermatocytes in male rats. In dogs, oral doses up to 20 mg/kg/day during 6 months were not associated with any histopathological changes.
Teratogenicity was assessed in pregnant rodents: foetal malformations and foetal abortions were associated with doses over 50 mg/kg of hydroxyzine, this being due to the accumulation of norchlorcyclizine metabolite. Teratogenic doses are much higher than those used in man for therapeutic purpose. No mutagenic activity was shown in the Ames test. A mouse lymphoma study showed marginal increases in mutations of low magnitude in the presence of S9 at ≥15 μg/ml. This was close to the maximum level of toxicity for this study. A study for micronuclei induction in rats was negative. As only very marginal effects were noted in the in vitro study and the in vivo study was negative, it is considered that hydroxyzine is not a mutagen.
Animal carcinogenicity studies have not been undertaken with hydroxyzine. However, the drug is not mutagenic and has not been associated with any overt increased tumourigenic risk during several decades of clinical use.
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