SUMMARY OF PRODUCT CHARACTERISTICS
1. Name of the medicinal product
Atarax 25mg Film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 25 mg of hydroxyzine dihydrochloride
3. Pharmaceutical form
White, oblong, film-coated tablet, with a bisect line.
4. Clinical Particulars
4.1 Therapeutic Indications
the symptomatic relief of anxiety in adults,
the symptomatic relief of pruritus,
premedication before surgery.
4.2 Posology and Method of Administration
Atarax should be used at the lowest effective dose and for the shortest possible duration (see Section
Warnings and Precautions).
For oral use.
Adults
In adults and children over 40 kg in weight, the maximum daily dose is 100 mg per day.
For symptomatic treatment of anxiety
50 mg/day in 3 separate administrations of 12.5-12.5-25 mg; in more severe cases doses of up to 100
mg/day can be used.
For symptomatic treatment of pruritus
Starting dose of 25 mg at night, increasing as necessary to 25 mg three or four times daily.
For premedication before surgery
50 to 100 mg/day in 1or 2 administrations: single administration 1 hour before surgery, which may be
preceded by 1 administration the night before anaesthesia.
Children (from 12 months) (see Section Warnings and Precautions)
For symptomatic treatment of pruritus
from 12 months 1 mg/kg/day up to 2 mg/kg/day in divided doses.
In children up to 40 kg in weight, the maximum daily dose is 2 mg/kg/day in divided doses. In children
over 40 kg in weight, the maximum daily dose is 100 mg/day.
For premedication before surgery
Single administration of 1 mg/kg 1 hour before surgery, which may be preceded by 1mg/kg the night
before anaesthesia.
Special Populations
The dosage should be adapted within the recommended dose range accordingly to the patient's response
to therapy.
Elderly
Use of hydroxyzine in the elderly is not recommended. However, if needed, it is advised to start with half
the recommended dose due to a prolonged action.
In the elderly, the maximum daily dose is 50 mg per day (see Sections Warnings and Precautions).
Renal impairment
Dosage should be reduced in patients with moderate or severe renal function impairment due to decreased
excretion of its metabolite cetirizine.
Hepatic impairment
In patients with hepatic dysfunction, it is recommended to reduce the daily dose by 33%.
4.3 Contra-indications
Hydroxyzine is contraindicated in:
patients with a history of hypersensitivity to hydroxyzine or any of the excipients, to cetirizine, to
other piperazine derivatives, to aminophylline, or to ethylenediamine,
pregnancy and lactation (see Section Pregnancy and Lactation),
patients with porphyria,
patients with known acquired or congenital QT interval prolongation,
patients with a known risk factor to QT interval prolongation including a known cardiovascular disease,
significant electrolytes imbalance (hypokalaemia, hypomagnesaemia), family history of sudden cardiac
death, significant bradycardia, concomitant use with drugs known to prolong the QT interval and/or
induce Torsade de Pointes (see Sections: Warnings and Precautions, Interactions).
4.4 Special Warnings and Precautions for Use
Cardiovascular effects
Hydroxyzine 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 or
concomitant treatment that may have been contributory (see Section Adverse Reactions).
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.
Convulsions
Hydroxyzine should be administered cautiously in patients with increased potential for convulsions.
Children
Young children are more susceptible to develop adverse events related to the central nervous system (see
Section Adverse Reactions). In children, convulsions have been more frequently reported than in adults.
Elderly
Hydroxyzine is not recommended in elderly patients because of a decrease of hydroxyzine elimination in
this population as compared to adults and greater risk of adverse reactions (e.g. anticholinergic effects)
(see Section Adverse Reactions).
Hydroxyzine anticholinergic effects
Because of its potential anticholinergic effects, hydroxyzine should be used cautiously in patients
suffering from glaucoma, bladder outflow obstruction, decreased gastro-intestinal motility, myasthenia
gravis, or dementia.
Co- administration with CNS depressants
Dosage adjustments may be required if hydroxyzine is used simultaneously with other central nervous
system depressant drugs or with drugs having anticholinergic properties (see Section Interactions).
Alcohol
The concomitant use of alcohol and hydroxyzine should be avoided (see Section Interactions).
Hepatic and renal impairment
Hydroxyzine dosage should be reduced in patients with hepatic dysfunction and in patients with moderate
or severe renal impairment.
Tablets
Lactose
Hydroxyzine film-coated tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interactions
Associations contraindicated
Co-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 gastrointestinal medicines
(e.g. prucalopride), some medicines used in cancer (e.g. toremifene, vandetanib), methadone, increase the
risk of cardiac arrhythmia. Therefore, the combination is contraindicated (see Section Contraindications).
Associations requiring precaution of use
Caution 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.
CNS depressants
Patients should be informed that hydroxyzine may potentiate the effects of barbiturates, other CNS
depressants or drugs having anticholinergic properties.
Alcohol
Alcohol also potentiates the effects of hydroxyzine.
Betahistine and anticholinesterase drugs
Hydroxyzine antagonises the effects of betahistine and anticholinesterase drugs.
Tests results
The treatment should be stopped at least 5 days before allergy testing or methacholine bronchial
challenge, to avoid effects on the test results.
Monoamine oxidase inhibitors
Simultaneous administration of hydroxyzine with monoamine oxidase inhibitors should be avoided.
Epinephrine
Hydroxyzine counteracts the pressor action of epinephrine.
Phenytoin
In rats, hydroxyzine antagonised the anticonvulsant action of phenytoin.
Cimetidine
Cimetidine 600 mg b.i.d. has been shown to increase the serum concentrations of hydroxyzine by 36%
and to decrease peak concentrations of the metabolite cetirizine by 20%.
CYP2D6 substrates
Hydroxyzine is an inhibitor of cytochrome P450 2D6 (Ki : 3.9 µM ; 1.7 µg/ml) and may cause at high
doses drug-drug interactions with CYP2D6 substrates.
Effect on other drug metabolism
Hydroxyzine has no inhibitory effect at 100 µM on UDP-glucuronyl transferase isoforms 1A1 and 1A6 in
human liver microsomes. It inhibits cytochrome P450 2C9/C10, 2C19 and 3A4 isoforms at concentrations
(IC50 : 19 to 140 µM ; 7 to 52 µg/ml) well above peak plasma concentrations.
The metabolite cetirizine at 100 µM has no inhibitory effect on human liver cytochrome P450 (1A2, 2A6,
2C9/C10, 2C19, 2D6, 2E1 and 3A4) and UDP-glucuronyl transferase isoforms. Therefore, hydroxyzine is
unlikely to impair the metabolism of drugs which are substrates for these enzymes.
4.6 Pregnancy and lactation
Fertility
There are no relevant data available.
Pregnancy
Hydroxyzine is contraindicated during pregnancy (see Section Contraindications).
Animal studies have shown reproductive toxicity.
Hydroxyzine crosses the placental barrier leading to higher foetal than maternal concentrations.
To date, no relevant epidemiological data are available relating to exposure to hydroxyzine during
pregnancy.
In neonates whose mothers received hydroxyzine during late pregnancy and/or labour, the following
events were observed immediately or only a few hours after birth: hypotonia, movement disorders
including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic conditions, or
urinary retention.
Lactation
Hydroxyzine is contraindicated during lactation (see Section Contraindications). Breast-feeding should be
stopped if hydroxyzine therapy is needed.
Cetirizine, the principal metabolite of hydroxyzine, is excreted in human milk.
Although no formal studies have been performed on the excretion of hydroxyzine in human milk, severe
adverse effects have been shown in breastfed newborns/infants of hydroxyzine treated mothers.
4.7 Effects on Ability to Drive and Use Machines
Hydroxyzine may impair the ability to react and to concentrate. Patients should be warned of this
possibility and cautioned against driving a car or operating machinery. Concomitant use of hydroxyzine
with alcohol or other sedative drugs should be avoided as it aggravates these effects.
4.8 Undesirable Effects
Undesirable effects are mainly related to CNS depressant or paradoxical CNS stimulation effects, to
anticholinergic activity, or to hypersensitivity reactions.
Adverse reactions are ranked under headings of frequency using the following convention:
Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1000 to <1/100
Rare ≥1/10000 to <1/1000
Very rare <1/10000
Not known (cannot be estimated from the available data).
Clinical Trial Data
The following undesirable effects were reported in placebo-controlled clinical trials for hydroxyzine and
including 735 subjects exposed to hydroxyzine up to 50 mg daily.
Nervous system disorders
Very common: somnolence
Common: headache
Uncommon: dizziness, insomnia, disturbance in attention
Gastrointestinal disorders
Common: dry mouth
Uncommon: constipation, nausea
General disorders and administration site conditions
Common: fatigue
Uncommon: asthenia
Post Marketing Data
Immune system disorders
Not known: hypersensitivity, anaphylactic shock
Psychiatric disorders
Not known: agitation, confusion, disorientation, hallucination
Nervous system disorders
Not known: sedation, tremor, convulsions, dyskinesia
Eye disorders
Not known: accommodation disorder, vision blurred
Cardiac disorders
Not known: tachycardia, QT interval prolongation, venticular arrhythmias (e.g. Torsade de Pointes) (see
Section Warnings and Precautions)
Vascular disorders
Not known: hypotension
Respiratory, thoracic and mediastinal disorders
Not known: bronchospasm
Gastrointestinal disorders
Not known: vomiting
Hepatobiliary disorders
Not known: liver function tests abnormal
Skin and subcutaneous tissue disorders
Not known: pruritus, erythematous rash, maculo-papular rash, urticaria, dermatitis, angioneurotic oedema,
hyperhidrosis, fixed drug eruption, acute generalized exanthematous pustulosis, erythema multiforme,
Stevens-Johnson syndrome
Renal and urinary disorders
Not known: urinary retention
General disorders and administration site conditions
Not known: malaise, pyrexia
The following adverse reactions have been observed with cetirizine, the principal metabolite of
hydroxyzine: thrombocytopenia, aggression, depression, tic, dystonia, paraesthesia, oculogyric crisis,
diarrhoea, dysuria, enuresis, asthenia, oedema, weight increased and could potentially occur with
hydroxyzine.
4.9 Overdose
Symptoms and signs
Symptoms observed after an important overdose are mainly associated with excessive anticholinergic
load, Central Nervous System (CNS) depression or CNS paradoxical stimulation. They include nausea,
vomiting, tachycardia, pyrexia, somnolence, impaired pupillary reflex, tremor, confusion, or
hallucination. This may be followed by depressed level of consciousness, respiratory depression,
convulsions, hypotension, or cardiac arrhythmia. Deepening coma and cardiorespiratory collapse may
ensue.
Treatment
Airway, breathing and circulatory status must be closely monitored with continuous ECG recording and
an adequate oxygen supply should be available. Cardiac and blood pressure monitoring should be
maintained until the patient is free of symptoms for 24 hours. Patients with altered mental status should
be checked for simultaneous intake of other drugs or alcohol and should be given oxygen, naloxone,
glucose, and thiamine if deemed necessary.
Norepinephrine or metaraminol should be used if vasopressor is needed. Epinephrine should not be used.
Syrup of ipecac should not be administered in symptomatic patients or those who could rapidly become
obtunded, comatose or convulsing, as this could lead to aspiration pneumonitis. Activated charcoal may
be left in the stomach but there are scant data to support its efficacy.
It is doubtful that haemodialysis or haemoperfusion would be of any value.
There is no specific antidote.
Literature data indicate that, in the presence of severe, life-threatening, intractable anticholinergic effects
unresponsive to other agents, a therapeutic trial dose of physostigmine may be useful. Physostigmine
should not be used just to keep the patient awake. If cyclic antidepressants have been co-ingested, use of
physostigmine may precipitate seizures and intractable cardiac arrest. Also avoid physostigmine in
patients with cardiac conduction defects.
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Phramacotherapeutic group Anxiolytics; Diphenylmethane derivatives
ATC Code N05BB01
Mechanism of Action
Hydroxyzine is a first generation antihistamine that crosses the blood/brain barrier extensively and has a
high affinity for histaminic receptors into the brain, thereby producing sedative-anxiolytic effects.
Pharmacodynamic effects
Antihistaminic and bronchodilator 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.
Onset of action
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 a weak affinity for muscarinic receptors.
5.2 Pharmacokinetic Properties
Absorption
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, C max
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.
Distribution
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.
Metabolism
Hydroxyzine is extensively metabolised. 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.
Elimination
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).
Special patient populations
Children
The pharmacokinetics of hydroxyzine was evaluated in 12 paediatric patients (mean 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 Dosage and Administration).
Elderly
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 by
half the daily dose of hydroxyzine in elderly patients (see Section Dosage and Administration).
Renal impairment
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 haemodialysis. 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 Dosage and Administration).
Hepatic impairment
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 Dosage and Administration).
Clinical Studies
Not relevant for this product.
5.3 Preclinical Safety Data
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 intra venous (i.v.).
Single oral doses of 80 mg/kg and above induced signs of depression, ataxia, convulsions and tremors in
dogs. In monkeys, at oral doses exceeding 50 mg/kg, some vomiting occurred without any other signs up
to 400 mg/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 lead to important local tissue lesions in
rabbits.
In isolated canine Purkinje fibres, hydroxyzine at 3µM increased action potential duration suggesting that
there was an interaction with potassium channels involved with the repolarisation phase. At a higher
concentration, 30µM, there was a marked decrease in the action potential duration suggesting a possible
interaction with calcium and/or sodium currents. 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 0.62µM, a concentration that is between 10 and 60-fold higher than therapeutic concentrations.
Moreover, the hydroxyzine concentrations required to produce effects on cardiac electrophysiology are 10
to 100-fold higher than those required to block H1 and 5-HT2 receptors. 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 po) 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 os.
Chronic toxicity was tested in rats at oral doses up to 50 mg/day in 100 g 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 tumorgenic risk during several decades of
clinical use.
6 Pharmaceutical Particulars
6.1 Excipients
Tablet core:
Lactose monohydrate 54,80 mg
Microcrystalline cellulose 28,00 mg
Magnesium stearate 1,50 mg
Colloidal anhydrous silica 0,70 mg
Tablet coating:
Opadry® Y-1-7000 3,30 mg (titane dioxyde 0,21 mg, Hypromellose 2,06 mg,
macrogol 400 1,03 mg).
6.2 Incompatibilities
There are no relevant data available.
6.3 Shelf life
60 months
6.4 Storage conditions
Store in dry place, below 25°C
6.5 Nature and contents of container
25 tablets in PVC - aluminium foil blister. 1 blister with leaflet insert inside of carton.
6.6 Special precautions for disposal
There are no special requirements for use or handling of this product.
7 Manufacturer (name, address, company)
UCB Pharma S. A., Chemin du Foriest, B-1420 Braine-I’Alleud, Belgium
8 Marketing Authorisation Holder
GlaxoSmithKline Export Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK
9. Date of final revision of the text
Version number: 03
Version date: 28 July 2015
