SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ucerax 25 mg film-coated Tablets

2 Qualitative and quantitative composition

Each film-coated tablet contains 25 mg of hydroxyzine dihydrochloride For the full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

White oblong, film-coated tablet with a bisect line

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ucerax is indicated to assist in the management of anxiety in adults.

Ucerax is indicated to assist in the management of pruritus associated with acute and chronic urticaria, including cholinergic and physical types, and in atopic and contact dermatosis in adults and children.

4.2    Posology and method of administration

Posology

Ucerax should be used at the lowest effective dose and for the shortest possible duration. In adults and children over 40 kg in weight, the maximum daily dose is 100 mg per day. Anxiety.

50 mg/day in 3 separate administrations of 12.5-12.5-25mg. In more severe cases, doses up to 100mg/day can be used.

Pruritus.

Starting dose of 25 mg at night, increasing as necessary to 25 mg three or four times daily.

Special populations

The dosage should be adjusted according to the patient’s response to therapy.

Older People

In the elderly, it is advised to start with half the recommended dose due to the prolonged action.

In the elderly, the maximum daily dose is 50 mg per day (see section 4.4).

Patients with hepatic impairment

In patients with hepatic dysfunction, it is recommended to reduce the daily dose by 33%. Patients with renal impairment

Dosage should be reduced in patients with moderate or severe renal impairment due to decreased excretion of its metabolite cetirizine.

Paediatric population:

In children up to 40 kg in weight, the maximum daily dose is 2 mg/kg/day.

In children over 40 kg in weight, the maximum daily dose is 100 mg per day .

Children aged from 12 months: 1mg/kg/day up to 2mg/kg/day in divided doses.

4.3 Contra-indications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, to cetirizine, to other piperazine derivatives, to aminophylline, or to ethylenediamine. Patients suffering from porphyria.

Pregnancy and lactation (see section 4.6).

Patients with a 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 4.4 and 4.5).

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose mal-absorption should not take this medicine.

4.4 Special warnings and precautions for use

Hydroxyzine should be administered cautiously in patients with increased potential for convulsions.

Young children are more susceptible to develop adverse events related to the central nervous system (see section 4.8). In children, convulsions have been more frequently reported than in adults.

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.

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 4.5).

The concomitant use of alcohol and hydroxyzine should be avoided (see section 4.5).

Caution is needed in patients who have a known predisposing factor to cardiac arrhythmia, including electrolytes imbalance (hypokalemia, hypomagnesaemia), who have pre-existing heart disease, or who are concomitantly treated with a potentially arrhythmogenic drug. In those patients, use of alternative treatments is to be considered.

In the elderl y, it is advised to start with half the recommended dose due to a prolonged action (See section 4.2).

Dosage should be reduced in patients with hepatic dysfunction and in patients with moderate or severe renal impairment (see section 4.2).

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 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 patients

Hydroxyzine 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.

4.5 Interaction with other medicinal products and other forms of interactions

Patients should be informed that hydroxyzine may potentiate the effects of barbiturates, other CNS depressants or drugs having anticholinergic properties.

Alcohol also potentiates the effects of hydroxyzine.

Hydroxyzine antagonizes the effects of betahistine, and of anticholinesterase drugs.

The treatment should be stopped at least 5 days before allergy testing or methacholine bronchial challenge, to avoid effects on the test results.

Simultaneous administration of hydroxyzine with monoamine oxidase inhibitors should be avoided.

Hydroxyzine counteracts the epinephrine pressor action.

In rats, hydroxyzine antagonised the anticonvulsant action of phenytoin.

Cimetidine 600 mg bid has been shown to increase the serum concentrations of hydroxyzine by 36% and to decrease peak concentrations of the metabolite cetirizine by 20%.

Hydroxyzine is an inhibitor of cytochrome P450 2D6 (Ki: 3.9 gM ; 1.7 gg/ml) and may cause at high doses drug-drug interactions with CYP2D6 substrates.

Hydroxyzine has no inhibitory effect at 100 gM 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 gM ; 7 to 52 gg/ml) well above peak plasma concentrations.

The metabolite cetirizine at 100 gM has no inhibitory effect on human liver cytochrome P₄₅₀ (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1 and 3A4) and UDP-glucuronyl transferase isoforms. Therefore, Ucerax is unlikely to impair the metabolism of drugs which are substrates for these enzymes.

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 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 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.

Fertility, pregnancy and lactation

Pregnancy:

Animal studies have shown reproductive toxicity.

Hydroxyzine crosses the placental barrier leading to higher fetal than maternal concentrations.

To date, no relevant epidemiological data are available relating to exposure to Ucerax during pregnancy.

In neonates whose mothers received Ucerax 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. Therefore, Ucerax should not be used during pregnancy.

Breastfeeding:

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. Ucerax is therefore contraindicated during lactation. Breast-feeding should be stopped if Ucerax therapy is needed.

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.

Clinical trials

The following table lists the relevant undesirable effects reported in placebo-controlled clinical trials for hydroxyzine and including 735 subjects exposed to hydroxyzine up to 50 mg daily. The frequency has been estimated using the following definitions: very common (>1/10); common (>1A00 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).

System Organ Class	Adverse event preferred term	Frequency
Nervous system disorders	Somnolence	Very common
	Headache	Common
	Dizziness	Uncommon
	Insomnia	Uncommon
	Disturbance in attention	Uncommon
Gastrointestinal disorders	Dry mouth	Common
	Constipation	Uncommon
	Nausea	Uncommon
General disorders and administration site conditions	Fatigue	Common
	Asthenia	Uncommon

Post-marketing experience

The following lists, per body system, the additional undesirable adverse reactions reported during marketed use of the drug. No frequency can be estimated from post-marketing reporting of events.

Immune system disorders :

Hypersensitivity, anaphylactic shock

Psychiatric disorders :

Agitation, confusion, disorientation, hallucination

Nervous system disorders :

Sedation, tremor, convulsions, dyskinesia

Eye disorders :

Accommodation disorder, vision blurred Cardiac disorders :

Tachycardia, QT 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 reactions

Reporting 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 .

4.9 Overdose

Symptoms observed after an important overdose are mainly associated with excessive anticholinergic load. 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.

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.gastric lavage with prior endotracheal intubation may be performed if a clinically significant ingestion has occurred. Activated charcoal may be left in the stomach but there are scant data to support its efficacy.

It is doubtful that hemodialysis or hemoperfusion 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 coingested, use of physostigmine may precipitate seizures and intractable cardiac arrest. Also avoid physostigmine in patients with cardiac conduction defects.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hydroxyzine is a psycholeptic and anxiolytic agent (ataractic).

ATC code is N05B B01

The active substance, hydroxyzine dihydrochloride, is a diphnylmethane derivative, chemically unrelated to the phenothiazines, reserpine, meprobamate or benzodiazepines.

Mechanism of action

Hydroxyzine 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 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 (C max ) 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.

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 fetal than maternal concentrations.

Biotransformation

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. 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.

Elimination

Across studies, the half life (t'A) 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.

Special population

Older People

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± 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 t'A 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 population

The 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 impairment

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 (see section 4.2).

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 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).

5.3 Preclinical safety data

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In vivo carcinogenicity studies have not been performed with hydroxyzine.

Hydroxyzine inhibited the potassium (IKr) current in human ether-a-go-go-related gene (hERG) channels expressed in mammalian cells with an IC50 10 times above the free plasma concentrations in humans after administration of the highest recommended dose. In dog cardiovascular studies no effects on QTc intervals were observed at exposures up to 20-fold above the plasma concentrations in humans after administration of the highest recommended dose.

In reproductive toxicity studies in rodents, fetal malformations and fetal abortions were associated with doses above the human therapeutic range and attributed to the accumulation of norchlorcyclizine. Doses of 10 mg/kg/day for 70 days reduced the concentration and the viability of spermatocytes in male rats. The safety margin for this effect is unknown.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of Excipients

Core:

Lactose monohydrate.

Microcrystalline cellulose Magnesium stearate Anhydrous colloidal silica

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/02/2006

DATE OF REVISION OF THE TEXT

25/11/2015