- hydroxyzine dihydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
Cardiovascular effectsHydroxyzine has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been cases of QT interval prolongation and torsade de pointes in patients taking hydroxyzine. Most of these patients had other risk factors, electrolyte abnormalities and concomitant treatment that may have been contributory (see section 4.8).Hydroxyzine should be used at the lowest effective dose and for the shortest possible duration.Treatment with hydroxyzine should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should seek immediate medical attention.Patients should be advised to promptly report any cardiac symptoms.
Elderly patientsHydroxyzine is not recommended in elderly patients because of a decrease of hydroxyzine elimination in this population as compared to adults and the greater risk of adverse reactions (e.g. anticholinergic effects) (see sections 4.2 and 4.8).Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Associations contraindicatedCo-administration of hydroxyzine with drugs known to prolong the QT interval and/or induce Torsade de Pointes e.g. class IA (e.g. quinidine, disopyramide) and III antiarrhythmics (e.g. amiodarone, sotalol), some antihistamines, some antipsychotics (e.g. haloperidol), some antidepressants (e.g. citalopram, escitalopram), some antimalarial drugs (e.g. mefloquine), some antibiotics (e.g. erythromycin, levofloxacin, moxifloxacin), some antifungal agents (e.g. pentamidine), some gastro-intestinal medicines (e.g. prucalopride), some medicines used in cancer (e.g., toremifene, vandetanib), methadone, increase the risk of cardiac arrhythmia. Therefore, the combination is contra-indicated (see section 4.3).
Associations requiring precaution of useCaution with bradycardia and hypokalaemia-inducing drugs.Hydroxyzine is metabolized by alcohol dehydrogenase and CYP3A4/5 and an increase in hydroxyzine blood concentrations may be expected when hydroxyzine is co-administered with drugs known to be potent inhibitors of these enzymes.
|System Organ Class||Adverse event preferred term||Frequency|
|Nervous system disorders||Somnolence||Very common|
|Disturbance in attention||Uncommon|
|Gastrointestinal disorders||Dry mouth||Common|
|General disorders and administration site conditions||Fatigue||Common|
Immune system disorders :Hypersensitivity, anaphylactic shockPsychiatric disorders :Agitation, confusion, disorientation, hallucination
Nervous system disorders :Sedation, tremor, convulsions, dyskinesia
Eye disorders :Accommodation disorder, vision blurred
Cardiac disorders :Tachycardia, QT interval prolongation (see section 4.4), ventricular arrhythmias (e.g. Torsade de Pointes)
Vascular disorders :Hypotension
Respiratory, thoracic and mediastinal disorders :Bronchospasm
Gastrointestinal disorders :Vomiting
Skin and subcutaneous tissue disorders :Pruritus, erythematous rash, maculo-papular rash, urticaria, dermatitis, angioneurotic oedema, sweating increased, fixed drug eruption, acute generalized exanthematous pustulosis, erythema multiforme, Stevens-Johnson syndrome
Renal and urinary disorders :Urinary retention
General disorders and administration site conditions :Malaise, pyrexia
Investigations :Liver function tests abnormal
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard .
Mechanism of actionHydroxyzine is a first generation antihistamine that crosses extensively the blood/brain barrier and has a high affinity for histaminic receptors into the brain, thereby producing sedative-anxiolytic effects.Pharmacodynamic effects 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. Hydroxyzine was studied in eight patients with primary biliary cirrhosis. All had abnormal liver biochemistry tests, all had biopsies compatible with primary cirrhosis, and seven of eight had positive tests for antimitochodrial antibodies. The patients received a single dose of hydroxyzine (0.7mg/kg mean does 43.9 ± 6.6 mg). In these subjects with hepatic dysfunction secondary to primary cirrhosis, total body clearance was approximately 66% that of normal subjects (8.65 ± 7.46 ml/min/kg versus 10 ml/min/kg for normal subjects). The half-life was increased to 37 hours and the serum concentrations of the carboxylic metabolite, cetirizine (500.4 ± 302.0 mg/ml), were higher than in young patients with a normal liver function. As hydroxyzine elimination is impaired in patients with hepatic dysfunction, daily dose or dose frequency should be reduced in patients with impaired liver function.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.
Onset of actionThe 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 a weak affinity for muscarinic receptors.
AbsorptionHydroxyzine 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 65 ng/ml.
DistributionHydroxyzine 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 fetal than maternal concentrations.
BiotransformationHydroxyzine 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. An elimination half-life for cetirizine of about 20 hours has been reported. 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.
EliminationAcross studies, the half life (t½) of hydroxyzine in adults is 12 ± 5 hrs (range 7 20 hrs). Across studies the apparent plasma clearance (CL/F) of hydroxyzine is 14 ± 4 ml/min/kg (range 9.4-17.5 ml/min/kg). 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).After a single dose of 50 mg hydroxyzine, the Cmax of cetirizine (261 ng/ml) was comparable to that after a single dose of 10 mg cetirizine (282 ng/ml) but the AUC was similar to that after a single dose of 20 mg cetirizine.
Older PeopleThe 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± 10 hrs (range 20-53 hrs) and the apparent volume of distribution was increased to 22 ± 6 l/kg (range 13 -31 l/kg). In view of the longer t½ and of the prolonged Pharmacodynamic effect (suppression of the wheal and flare response to histamine), it is advised to start with half the recommended dose (see section 4.2).
Paediatric populationThe pharmacokinetics of hydroxyzine was evaluated in 12 paediatric patients aged 1 to 14 years (mean 6.1 ± 4.6 yrs) with severe atopic dermatitis. A 0.7 mg/kg single dose of hydroxyzine was administered orally. The mean peak serum concentration was 47 ± 17 ng/ml and occurred at a mean time of 2.0 ± 0.9h after the dose. The mean plasma clearance was higher than in adults (32 ± 11 ml/min/kg). The half-life was shorter than in adults and increased with age from 4 hrs at 1 year of age to 11 hrs at 14 years of age. No data was available regarding the metabolite cetirizine.Like in adults, the antipruritic effect lasted longer than anticipated for the half-life as pruritus was significantly suppressed from 1 to 24 hrs post-dose with >85% suppression from 2 to 12 hrs.Dosage should be adjusted in paediatric population (see section 4.2).
Hepatic impairmentHydroxyzine was studied in eight patients with primary biliary cirrhosis. All had abnormal liver biochemistry tests, all had biopsies compatible with primary cirrhosis, and seven of eight had positive tests for antimitochodrial antibodies. The patients received a single dose of hydroxyzine (0.7mg/kg mean does 43.9 ± 6.6 mg).In these subjects with hepatic dysfunction secondary to primary cirrhosis, total body clearance was approximately 66% that of normal subjects (8.65 ± 7.46 ml/min/kg versus 10 ml/min/kg for normal subjects). The half-life was increased to 37 hours and the serum concentrations of the carboxylic metabolite, cetirizine (500.4 ± 302.0 mg/ml), were higher than in young patients with a normal liver function. As hydroxyzine elimination is impaired in patients with hepatic dysfunction, daily dose or dose frequency should be reduced in patients with impaired liver function (see section 4.2).
Renal impairmentThe 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).
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