4.1. Therapeutic indications

Hydroxyzine Tablets are indicated to assist in the management of anxiety in adults.

Hydroxyzine Tablets are indicated for the management of pruritus associated with acute and chronic urticaria, including cholinergic and physical types, and atopic and contact dermatitis in adults and children.

4.2. Posology and method of administration

Posology

Hydroxyzine Tablets 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 100mg per day.

Anxiety

Adults 50-100mg daily in divided doses

Pruritis

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

Elderly

In the elderly, the maximum daily dose is 50 mg per day (see section 4.4). A reduced dose is advised. This is due to a possible increase in the volume of distribution, prolonged action and the possible effect of age-related changes on pharmacologic functions, including hepatic metabolism and renal excretion (see Section 5.2 'Pharmacokinetic properties')

Paediatric Population

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

From 6 months to 6 years, 5-15mg daily in divided doses adjusted depending on the child's weight.

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

For children over 6 years, starting at 15-25mg and increasing to 50-100mg daily in divided doses adjusted according to the child's weight.

As with all medications, the dosage should be adjusted according to the patient's response to therapy.

Hepatic impairment

The total daily dose should be reduced by 33%. Use in patients with severe liver disease should be avoided (see Section 4.4 'Special Warnings and Precautions for Use').

Renal impairment

For patients with moderate or severe renal impairment, it is recommended that the total daily dosage should be reduced by 50% (see section 4.4 'Special Warnings and Precautions for Use').

Method of administration: Oral

4.3. Contraindications

Hydroxyzine Tablets are contra-indicated in the following:

• patients who have shown previous hypersensitivity to hydroxyzine hydrochloride, cetirizine, other piperazine derivatives, aminophylline or ethylenediamine, or any of the excipients of Hydroxyzine Tablets (for a full list of excipients see section 6.1 'List of excipients')

• 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).

• asthmatics who have previously experienced a serious anti-histamine-induced adverse bronchopulmonary effect

• porphyria

• pregnancy and breast-feeding (see section 4.6 'Fertility, pregnancy and lactation')

Hydroxyzine Tablets contain lactose (see section 6.1). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 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.

Patients with hepatic impairment

Due to its sedative properties, use of hydroxyzine should be avoided in severe liver disease due to an increased risk of coma, and in patients with hepatic failure due to possibility of hepatic encephalopathy.

Hydroxyzine elimination is impaired in patients with hepatic dysfunction secondary to primary biliary cirrhosis. Dosage should be modified for patients with hepatic impairment (see Section 4.2 'Posology and Method of Administration')

Patients with renal impairment

Hydroxyzine Tablets should be used with caution in patients with impaired renal function (see Section 4.2 'Posology and Method of Administration'). It is uncertain whether the drug may accumulate or have other adverse effects in such patients.

Hydroxyzine Tablets are completely metabolised and one of the metabolites is the active metabolite cetirizine. Cetirizine is renally excreted and clearance is reduced in patients with moderate renal impairment and on dialysis compared to normal volunteers.

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). In elderly patients, it is recommended to reduce the dose of hydroxyzine due to a possible increase in the volume of distribution, prolonged action, and the possible effect of agerelated changes on pharmacologic functions, including hepatic metabolism and renal excretion (see Section 4.2 'Posology and Method of Administration' and Section 5.2 'Pharmacokinetic properties')

Because of its potential antimuscarinic actions, Hydroxyzine Tablets should be used with caution in patients suffering from angle-closure glaucoma, urinary retention, prostatic hyperplasia, or pyroduodenal obstruction.

Caution is required in patients suffering the following conditions:

• seizure disorders including epilepsy

• myasthenia gravis

• dementia

• decreased GI motility

• bladder outflow obstruction

• stenosing peptic ulcer

• patients with breathing problems (e.g. emphysema, chronic bronchitis)

• increased intraocular pressure

• hyperthyroidism

• cardiovascular disease

• hypertension

Dosage adjustments may be required if Hydroxyzine Tablets are used simultaneously with other CNS depressants or with drugs having antimuscarinic properties (see section 4.5 'Interaction with other medicinal products and other forms of interaction').

The concomitant use of alcohol and hydroxyzine should be avoided (see section 4.5 'Interaction with other medicinal products and other forms of interaction').

Treatment should be stopped for one week before skin testing for allergy is undertaken, and for 96 hours prior to a methocholine test.

Children and the elderly are more susceptible to side-effects.

Patients should be warned of impaired judgement and dexterity.

4.5. Interaction with other medicinal products and other forms of interaction

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 coadministered with drugs known to be potent inhibitors of these enzymes.

Hydroxyzine Tablets may also have the following interactions:

Methocholine test

Treatment should be stopped for 96 hours prior to a methocholine test, to avoid effects on the test results (see section 4.4 'Special warnings and precautions for use')

Skin testing for allergy

Treatment should be stopped at least one week before skin testing for allergy to avoid effects on the test results (see section 4.4 'Special warnings and precautions for use')

CNS depressants

Patients should be warned that Hydroxyzine Tablets may enhance their response to alcohol, barbiturates, benzodiazepines, hypnotics, opioids, anxiolytics, antipsychotics, antidepressents, antiemetics, antiepileptics, other antihistamines, skeletal muscle relaxants, sedatives, anaesthetics and other CNS depressants (see section 4.4 'Special warnings and precautions for use')

Antimuscarinics

Antimuscarinic side effects (both peripheral and central) may be increased if Hydroxyzine Tablets are given with antimuscarinics such as atropine and some antidepressants (both tricyclics and MAOIs) (see section 4.4 'Special warnings and precautions for use')

Adrenaline

Hydroxyzine has been shown to inhibit and reverse the vasopressor effect of adrenaline (see Section 4.9 'Overdose')

Anticholinergic agents

Additive anticholinergic effects may occur if hydroxyzine is administered concomitantly with other anticholinergic agents

Anticholinesterase drugs

Hydroxyzine may antagonise the effects of anticholinesterase drugs

Betahistine

Hydroxyzine may antagonise the effects of betahistine

Cimetidine

Cimetidine, 600mg twice a day, has been shown to increase the serum concentrations of hydroxyzine and to decrease peak concentrations of the metabolite cetirizine

CYP2D6 & cytochrome P450

Hydroxyzine is an inhibitor of CYP2D6 and may cause drug-drug interactions with CYP2D6 substrates. Cetirizine does not interact with other drug substances via cytochrome P450

Drugs which have effects on the brain

Drugs which have effects on the brain will interact with antihistamines

Drugs that affect the hepatic microsomal enzyme system

Metabolism may be reduced in patients concomitantly receiving drugs that affect the hepatic microsomal enzyme system. Decreased metabolism may result in accumulation of potentially toxic concentrations of unchanged antihistamine

Ototoxic drugs

It has been suggested that some sedating antihistamines could mask the warning signs of damage caused by ototoxic drugs such as aminoglycoside antibiotics

Porter-Silber reaction or the Glenn-Nelson method

Hydroxyzine has been reported to cause falsely elevated urinary concentrations of 17-hydroxycorticosteroids when the Porter-Silber reaction or the Glenn-Nelson method is used

4.6. Pregnancy and lactation

Pregnancy

Hydroxyzine Tablets should not be used during pregnancy (see section 4.3 'Contraindications').

Clinical data in humans are inadequate to establish safety in early pregnancy.

The use of sedating antihistamines in the latter part of the third trimester may cause adverse effects in neonates such as irritability, paradoxical excitability, and tremor.

Animal studies have shown reproductive toxicity. Foetal abnormalities have been reported when hydroxyzine was administered, at doses substantially above the human therapeutic dose, to the pregnant mouse, rat and rabbit.

Hydroxyzine crosses the placental barrier which may lead to higher foetal than maternal concentrations.

In neonates whose mothers received Hydroxyzine Tablets 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.

Breast-feeding

It is expected that Hydroxyzine Tablets may be excreted into breast milk. The effects on the nursing infant are unknown. Hydroxyzine Tablets should not be given to nursing mothers (see section 4.3 'Contraindications').

Fertility

No human data on the effect of hydroxyzine on fertility are available.

4.7. Effects on ability to drive and use machines

Patients should be warned that Hydroxyzine Tablets may impair their ability to perform activities requiring mental alertness or physical co-ordination such as operating machinery or driving a vehicle. Concomitant use of hydroxyzine with alcohol or other CNS depressants should be avoided as this may aggravate these effects (see section 4.5 'Interaction with other medicinal products and other forms of interaction).

4.8. Undesirable effects

The most common adverse effect of the sedating antihistamines is CNS depression. Effects vary from slight drowsiness to deep sleep, and include lassitude, dizziness, and incoordination. Paradoxical stimulation may occasionally occur, especially at high doses and in children and the elderly. If sedative effects occur, they may diminish after a few days of treatment. Other common adverse effects include headache, psychomotor impairment and antimuscarinic effects.

Adverse events are listed below by system Organ Class and frequency.

Assessment of undesirable effects is based on the following frequency groupings:

Very common: ≥1/10

Common: ≥1/100 to <1/10

Uncommon: ≥1/1000 to <1/100

Rare: ≥1/10,000 to <1/1000

Very rare: <1/10,000

Not known: cannot be estimated from the available data

System Organ Class

Undesirable Effect

Frequency

Blood and lymphatic system disorders

blood disorders, including agranulocytosis, leucopenia, haemolytic anaemia, and thrombocytopenia

Not known

Immune system disorders

Hypersensitivity reactions, anaphylaxis, angioedema

Not known

Metabolic and nutritional disorders

porphyria, anorexia

Not known

Psychiatric disorders

agitation, confusion, disorientation, hallucinations, sleep disturbances, depression, increased anxiety, nightmares

Not known

Nervous system disorders

Dyskinesia4, insomnia, sedation, drowsiness, dizziness, weakness, headache, tremor1, convulsions2, psychomotor impairment, paraesthesias, extrapyramidal effects, seizure, coma, somnolence, disturbance in attention, involuntary motor activity3, ataxia, slurred speech, bitter taste in mouth, faintness

Not known

Eye disorders

Accommodation disorder, blurred vision

Not known

Ear and labyrinth disorders

tinnitus, labrynthitis, vertigo

Not known

Cardiac disorders

Ventricular arrhythmias (e.g. Torsade de Pointes), QT interval prolongation (see section 4.4), tachycardia, palpitation

Not known

Vascular disorders

hypotension, flushing

Not known

Respiratory, thoracic and mediastinal disorders

bronchospasm, thickened respiratory tract secretions, wheezing, nasal stuffiness, dryness of throat

Not known

Gastrointestinal disorders

constipation, dryness of the mouth, nausea, vomiting, increased gastric reflux, diarrhoea, epigastric pain, increased GI peristalsis

Not known

Hepatobiliary disorders

liver dysfunction

Not known

Skin and subcutaneous tissue disorders

dermatitis, fixed drug eruption, pruritis, erythema, papular rash, sweating increased, urticaria, hair loss, eczema, acute generalised exanthematous pustulosis (AGEP), toxic epidermal necrolysis Stevens-Johnson syndrome, erythema multiforme

Very rare

Muscoskeletal and connective tissue disorders

myalgia

Not known

Renal and urinary disorders

urinary retention, dysuria

Not known

Reproductive system and breast disorders

priapism, impotence, early menses

Not known

General disorders and administration site conditions

fatigue, malaise, lassitude, pyrexia, dryness of respiratory mucosae, asthenia, tightness of chest, irritability, chills

Not known

Investigations

liver function tests abnormal, weight increased

Not known

Footnotes

1,2, 3 reported usually with doses considerably higher than those recommended.

Continuous therapy with over 1g/day has been employed in some patients without these effects having been encountered.

4 dyskinesia may follow termination of prolonged antihistamine therapy.

Children and the elderly are more susceptible to side-effects.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdosage with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects. If CNS stimulation predominates over CNS depression, ataxia, excitement, seizures, tremors, psychoses, hallucinations, convulsions and hyperpyrexia can occur. Coma and cardiorespiratory collapse may follow. CNS stimulation is more likely in children and elderly. In adults, CNS depression is more common with drowsiness, postictal depression, coma, and convulsions, progressing to respiratory failure and cardiovascular collapse. In children and adults, cerebral oedema and upper nephron nephrosis, a deepening coma, tachycardia, QRS widening, heart block, cardiorespiratory collapse/arrest, cardiogenic shock, and death may occur.

Common features include excessive sedation, nausea, vomiting, flushing, dilated pupils, dry mouth and tongue, hot dry skin, fever, sinus tachycardia, hypertension, ataxia, nystagmus, delirium, agitation, psychosis and visual hallucinations. Uncommon systemic features include myoclonic jerking, muscle rigidity, coma, convulsions, cardiac conduction abnormalities, QT prolongation and arrhythmias, cardiovascular collapse, paralytic ileus, urinary retention, hyperkalaemia, metabolic acidosis and rhabdomyolysis.

Peak concentrations occur approximately two hours post ingestion, and elimination half-life has been reported approximately 14 hours and 20 hours post ingestion (see section 5.2 'Pharmacokinetic properties').

There is no specific antidote. It is doubtful whether haemodialysis or peritoneal dialysis has any value in the treatment of overdosage with Hydroxyzine Tablets. However, if other agents such as barbiturates have been ingested concomitantly, dialysis may be indicated.

Consider activated charcoal only if the patient presents within 1 hour of ingestion of a potentially toxic amount. Gastric lavage is rarely required; for substances that cannot be removed effectively by other means, it should be considered only if a lifethreatening amount has been ingested within the previous hour. It should be carried out only if the airway can be protected adequately. Induction of emesis is not recommended.

General supportive care, including frequent monitoring of the vital signs and close observation of the patient is indicated. Clear airways should be maintained, and there should be adequate ventilation. Assisted ventilation is indicated if hypercapnia is present. Observation for 6 hours after ingestion, without any other specific treatment, will be sufficient for the majority of patients. Monitor BP, pulse and body temperature. In symptomatic patients measure U&Es and creatine kinase. Perform a 12-lead ECG and monitor cardiac rhythm. Patients who have been unconscious may be hypothermic.

Hypotension, though unlikely, may be controlled with intravenous fluids. In adults, if severe hypotension persists, determine the cause and consider treatment with the following; if hypotension is mainly due to decreased systemic vascular resistance, drugs such as noradrenaline or high dose dopamine may be beneficial, if hypotension is due to reduced cardiac output dobutamine, or in severe cases adrenaline may be beneficial. However it should be noted that hydroxyzine has been shown to inhibit and reverse the vasopressor effect of adrenaline.

Analeptic agents should not be used since they may cause seizures.

As in the management of overdosage with any drug, it should be borne in mind that

multiple agents may have been taken.