Source: Υπουργείο Υγείας (CY) Revision Year: 2023 Publisher: UCB Pharma S.A., 60 ALLÉE DE LA RECHERCHE, BRUSSELS, 1070
Hydroxyzine should be administered with caution 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 with caution 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).
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.
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). In elderly patients, it is recommended to initiate treatment with half the recommended dose due to prolonged effect (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).
The tablets include lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose mal-absorption should not take this medicine (see section 6.1).
This medicine contains 4.75 mg of alcohol (ethanol) in each 5 ml, which is equivalent to 0.95 mg/ml (0.095% w/v). The amount in 5 ml of this medicine is equivalent to less than 2 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.
The syrup includes 0.75 g of sucrose per ml. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
At a dose higher than 6.5 ml of the 2 mg/ml syrup, the sucrose content should be taken into consideration in patients with diabetes mellitus. Sucrose may be harmful to the teeth (see section 6.1).
This medicine contains 1.5 mg of sodium benzoate in each 5 ml which is equivalent to 0.3 mg/ml.
This medicine contains less than 1 mmol sodium (23 mg) per 5 ml, that is to say essentially 'sodium-free'.
The potentiating action of hydroxyzine must be considered when the drug is used in conjunction with drugs having central nervous system depressant properties or anticholinergic properties, and dosage should be adapted on an individual basis. 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 adrenaline 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 CYP2D6 (Ki: 3.9 μM; 1.7 μg/ml) and may cause at high doses drug-drug interactions with CYP2D6 substrates.
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, 2C19 and 3A4 isoforms at concentrations (IC50: 103 to 140 μM; 46 to 52 μg/ml) well above peak plasma concentrations. Therefore, hydroxyzine is unlikely to impair the metabolism of drugs which are substrates for these enzymes. The metabolite cetirizine at 100 μM has no inhibitory effect on human liver cytochrome P450 (1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) and UDP-glucuronyl transferase isoforms.
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.
However, when only one pathway of metabolism is inhibited, the other pathway may partially compensate.
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 and hydroxychloroquine), 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).
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.
Therefore, hydroxyzine is contra-indicated during pregnancy.
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.
Hydroxyzine is therefore contra-indicated during lactation. Breast-feeding should be stopped if hydroxyzine therapy is needed.
No data are available on fertility in humans. Animal studies do not indicate impaired fertility due to hydroxyzine dihyrochloride.
Women of childbearing potential should use adequate contraception to prevent pregnancy during treatment with hydroxyzine.
No studies on the effects on the ability to drive and use machine have been performed. Hydroxyzine may cause tiredness, dizziness, sedation, visual disturbances and thereby may have moderate to major influence, in particular at higher doses and/or if alcohol or sedative drugs are co-administered, on 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.
Undesirable effects are mainly related to CNS depressant or paradoxical CNS stimulation effects, to anticholinergic activity, or to hypersensibility reactions.
Hydroxyzine oral administration: The following table lists the undesirable effects reported in placebo-controlled clinical trials at rates of at least 1% for hydroxyzine and including 735 subjects exposed to hydroxyzine up to 50 mg daily and 630 subjects exposed to placebo.
Post-marketing experience The following lists, per body system and per frequency category, the undesirable adverse reactions during marketed use of the drug. The frequency has been estimated using the following definitions: very common (≥1/10); common (≥1/100 to <1/10; uncommon (≥1/1000 to <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), not known (cannot be estimated from the available date).
| Adverse Events (PT) | Frequency class (% of AE) Hydroxyzine | Frequency class (% of AE) Placebo |
| Nervous system disorders | ||
| Somnolence | Very common (13.74) | Common (2.70) |
| Headache | Common (1.63) | Common (1.90) |
| Gastrointestinal disorders | ||
| Dry mouth | Common (1.22) | Uncommon (0.63) |
| General disorders and administration site conditions | ||
| Fatigue | Common (1.36) | Uncommon (0.63) |
Rare: tachycardia
Not known: ventricular arrhythmias (e.g. Torsade de Pointes), QT interval prolongation (see section 4.4).
Rare: accommodation disorder, vision blurred
Uncommon: nausea
Rare: constipation, vomiting
Uncommon: malaise, pyrexia
Rare: hypersensitivity
Very rare: anaphylactic shock
Common: sedation
Uncommon: dizziness, insomnia, tremor
Rare: convulsions, dyskinesia
Not known: loss of consciousness (syncope)
Uncommon: agitation, confusion
Rare: disorientation, hallucination
Rare: urinary retention
Very rare: bronchospasm
Rare: Pruritus, rash rrythematous, rash maculo-papular, urticaria, dermatitis
Very rare: Angioneurotic oedema, sweating increased, fixed drug eruption, acute generalized exanthematous pustulosis erythema multiforme, Stevens-Johnson syndrome
Not known: bullous conditions (for example toxic epidermal necrolysis, pemphigoid)
Rare: hypotension
Rare: liver function test abnormal
Not known: hepatitis
Not known: Weight increased
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.
Reporting suspected adverse reactions after authorization 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 reaction via Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22 608649.
Not applicable.
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