Hydroxyzine

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

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. The concomitant use of alcohol and hydroxyzine should be avoided.

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.

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

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.

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

Refer to the following table and adjust the dose as indicated.

Dosing adjustments for adult patients with impaired renal function:

Caution with bradycardia and hypokalaemia-inducing drugs.

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.

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 counteracts the adrenaline pressor action.

In rats, hydroxyzine antagonised the anticonvulsant action of phenytoin.

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from bladder outflow obstruction.

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from glaucoma.

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from decreased gastro-intestinal motility.

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from prostatic hyperplasia.

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from dementia.

Caution in administration of hydroxyzine is required in patients suffering from stenosing peptic ulcer.

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

Because of its potential anticholinergic effects, hydroxyzine should be used with caution in patients suffering from myasthenia gravis.

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.

Fertility

No data are available on fertility in humans. Animal studies do not indicate impaired fertility due to hydroxyzine dihyrochloride.

Women of childbearing potential / Contraception in males and females

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.

Clinical Trials

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).

Cardiac disorders

Rare: tachycardia

Not known: ventricular arrhythmias (e.g. Torsade de Pointes), QT interval prolongation.

Eye disorders

Rare: accommodation disorder, vision blurred

Gastrointestinal system disorders

Uncommon: nausea

Rare: constipation, vomiting

General disorders and administration site conditions

Uncommon: malaise, pyrexia

Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactic shock

Nervous system disorders

Common: sedation

Uncommon: dizziness, insomnia, tremor

Rare: convulsions, dyskinesia

Not known: loss of consciousness (syncope)

Psychiatric disorders

Uncommon: agitation, confusion

Rare: disorientation, hallucination

Renal and urinary disorders

Rare: urinary retention

Respiratory, thoracic and mediastinal disorders

Very rare: bronchospasm

Skin and subcutaneous tissue disorders

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)

Vascular disorders

Rare: hypotension

Hepatobiliary disorders

Rare: liver function test abnormal

Not known: hepatitis

Investigations

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.