Atarax 25mg Film-coated tablets

Hydroxyzine hydrochloride 25mg

Excipient(s) with known effect:

Lactose (anhydrous) 118.25mg

For the full list of excipients, see section 6.1

25mg film-coated tablets, coloured green and coded on one side with 'AX'.

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

Atarax is 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.

Method of administration: oral.

Dosage:

Anxiety

Adults 50-100mg four times daily.

Pruritus

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

Use in the elderly 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')

Use in children From 6 months to 6 years 5-15mg rising to 50mg daily in divided doses and for children over 6 years, 15-25mg rising to 50-100mg daily in divided doses.

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').

Atarax is 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 Atarax (for a full list of excipients see section 6.1 'List of excipients')

• 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')

Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Atarax 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. Atarax is 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

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 age-related 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, Atarax 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:

• patients with a predisposition to cardiac dysrhythmias, with susceptibility to QT-interval prolongation or who are concomitantly treated with a potentially arrhythmogenic drug. All antihistamines should be screened for cardiotoxicity, as some patients may be poor metabolizers or may be susceptible to plasma concentrations near to the usual therapeutic range

• 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 Atarax is 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.

Atarax may have the following interactions:

Pregnancy

Atarax 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.

The following events were observed in a neonate whose mother received high dose (600mg per day) hydroxyzine during pregnancy; hypotonia, movement disorders including extrapyramidal disorders, clonic movements, tachypnea and poor feeding.

Lactation

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

Patients should be warned that Atarax 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).

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.

Undesirable effects are listed by MedDRA System Organ Classes.

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

Very common: 1/10

Common: 1/100 to <1/10

Uncommon: 1/1,000 to <1/100

Rare: 1/10,000 to <1/1,000

Very rare: <1/10,000

Not known: cannot be estimated from the available data

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.

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 Atarax. 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 life-threatening 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.

Pharmacotherapeutic group: Anxiolytics

ATC code: N05B B01

Atarax is unrelated chemically to benzodiazepines, phenothiazines, reserpine and meprobamate.

Mechanism of action

Hydroxyzine is a first generation antihistamine, a piperazine derivative, with antimuscarinic and sedative properties.

Antihistamines act as competitive antagonists of histamine at H₁ histamine receptors, thus inhibiting H₁ receptor-mediated reactions, such as vasodilation, flare and itch reactions and sneezing.

First-generation H₁ antagonists easily cross the blood-brain barrier, consequently producing well-documented sedative and anticholinergic effects.

First-generation antihistamines also have affinity for 5-HT receptors, alpha-adrenoreceptors, and muscarinic receptors. They also reduce cyclic GMP concentrations, increase atrioventricular nodal conduction, and inhibit activation of airway vagal afferent nerves.

Pharmacodynamic effects

Hydroxyzine has CNS depressant, anticholinergic, antispasmodic, and local anaesthetic activity, in addition to antihistaminic effects. The drug also has sedative, antiemetic and primary skeletal muscle relaxant activity.

An onset of sedative action of hydroxyzine is usually noted within 15 to 30 minutes after oral administration. Sedative effects persist for 4-6 hours following administration of a single dose.

Hydroxyzine suppresses the inflammatory response (wheal and flare reaction) and pruritus for up to 4 days after intradermal skin tests with allergens and histamine.

The therapeutic range for plasma hydroxyzine concentrations and the relationship of plasma concentration to clinical response or toxicity have not been established.

Hydroxyzine does not appear to increase gastric secretions or acidity, and usually has mild antisecretory effects.

It induces a calming effect in anxious tense adults. It is not a cortical depressant, but its action may be due to a suppression of activity in certain key regions of the subcortical area of the central nervous system.

Clinical efficacy and safety

Atarax has been shown clinically to be a rapid-acting anxiolytic with a wide margin of safety.

Antihistamine effects have been demonstrated experimentally and confirmed clinically; it is highly effective in alleviating pruritus.

Paediatric population

The pharmacokinetics and antipruritic effects of hydroxyzine were studied in 12 children (mean age 6.1 +/- 4.6 years) with severe atopic dermatitis, each given a single 0.7 mg/kg oral dose. Pruritis was significantly suppressed from 1 to 24 hours after the administration of the dose, with greater than 85% suppression from 2 to 12 hours. The potent antipruritic effect persists even when serum concentrations of the drug are low (only 10% of the maximum levels achieved). In children, the biologic effects of hydroxyzine appear to be much more prolonged than would be predicted from the half life values.

Absorption

Hydroxyzine is rapidly absorbed from the gastrointestinal tract.

After a single oral dose of hydroxyzine, 0.7 mg/kg (mean dose 39.0 +/- 5.4 mg) a mean maximum serum hydroxyzine concentration of 72.5 +/- 11.1 ng/ml has been shown to occur at a mean time of 2.1 +/- 0.4 hours.

Distribution

Distribution of hydroxyzine into human body tissues and fluids has not been fully characterised. Following administration of hydroxyzine to animals, the drug is widely distributed into most body tissues and fluids with highest concentrations in the liver, lungs, spleen, kidneys, and adipose tissue. The drug is also distributed into bile in animals.

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

Serum hydroxyzine concentrations do not necessarily reflect hydroxyzine tissue binding or distribution to skin receptor sites. Suppression of wheals, flares, and associated pruritis has been shown to persist even when serum hydroxyzine concentrations are low.

First-generation H₁ antagonists easily cross the blood-brain barrier.

In a study group of healthy adults, the mean apparent volume of distribution has been found to be 16.0 +/- 3.0 L/kg.

Biotransformation

Hydroxyzine is metabolised in the liver. Metabolites include cetirizine, which has antihistaminic activity. Cetirizine is formed from hydroxyzine via an oxidative biotransformation step.

Elimination

An elimination half life of 20.0 +/- 4.1 hours and of 14.0 hours has been reported for hydroxyzine.

Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg.

Hydroxyzine is eliminated by hepatic metabolism in humans. Cetirizine is mainly renally excreted.

Special populations

Elderly patients

The pharmacokinetics of hydroxyzine were studied in nine healthy elderly (mean age 69.5 +/- 3.7 years) subjects who ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). The mean serum elimination half life value of hydroxyzine in this elderly group was 29.3 +/-10.1 hours (range 20.2 to 53.3 hours), which was significantly longer than that reported in younger subjects. The mean apparent volume of distribution of hydroxyzine in this elderly group was 22.5 +/- 6.3 L/kg (range 13.4 to 30.7L/kg), which was significantly larger than that reported to be found in young adults. Hydroxyzine has a long mean serum elimination half life value, a large volume of distribution and a prolonged pharmacodynamic effect (suppressive effect on wheal and flare response to histamine) in the elderly.

In the elderly a number of age-related biological and physiological changes may have an effect on the pharmacology of hydroxyzine and its metabolite, cetirizine. These changes may impact upon the pharmacologic functions of absorption, distribution, metabolism, excretion, and receptor sensitivity.

Dosage reduction may be appropriate in elderly patients (see section 4.2 'Posology and Method of Administration')

Paediatric patients

The pharmacokinetics and antipruritic effects of hydroxyzine hydrochloride was studied in 12 children aged 1 to 14 years (mean age 6.1 +/- 4.6 years) with severe atopic dermatitis. The children were given a single orally administered dose of 0.7 mg/kg hydroxyzine. The mean peak serum concentration of 47.4 +/- 17.3 ng/ml occurred at a mean time of 2.0 +/- 0.9 hours. Terminal elimination half life was shorter in children than in adults, at a mean of 7.1+/- 2.3 hours. This resulted from a larger clearance rate in children of 32.08 +/- 11.05 ml/min/kg. The elimination half-life values increased with increasing age. Half life values were approximately 4 hours in the 1 year old patients and 11 hours in the 14 year old patient.

Dosage should be adjusted in the paediatric population (see section 4.2 'Posology and Method of Administration')

Hepatic impairment

The pharmacokinetics and pharmacodynamics of hydroxyzine were studied in eight patients (mean age 53.4 +/- SD11.2 years) with primary biliary cirrhosis, given a single dose of 0.7 mg/kg (mean dose 43.9 +/- 6.6mg) hydroxyzine. All patients had abnormal liver biochemistry tests, all had biopsies compatible with primary biliary cirrhosis, and seven of eight had positive tests for antimitochondrial antibodies.

Hydroxyzine elimination was found to be impaired in patients with primary biliary cirrhosis. Mean peak hydroxyzine levels occurring at 2.3 +/- 0.7 hours were found to be 116.5 +/- 60.6 ng/ml, which was significantly higher than in other patient groups studied previously. Mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, which was significantly longer than in patients with normal hepatic function studied previously.

Dosage should be adjusted in patients with hepatic impairment (see section 4.2 'Posology and Method of Administration')

Renal impairment

The pharmacokinetics of hydroxyzine and of its active metabolite cetirizine were studied in patients with reduced kidney function. Eight healthy volunteers and eight patients with renal insufficiency received a single peroral dose of 50 mg hydroxyzine.

With regards to hydroxyzine, results showed moderate elevation of the average terminal half-life in the patients group (t_1/2 14 vs. 23 h). The areas under the concentration-time curves (AUC) were 996 ng·h·ml^-1 in the healthy volunteers group and 1621 ng·h·ml^-1 in the patients group. For cetirizine, AUC measured 6036 ng·h·ml^-1 in the healthy volunteers group and 31635 ng·h·ml^-1 in the patients group. The study concluded that the reduced renal clearance of cetirizine may be of clinical importance in patients with renal failure.

Dosage should be adjusted in patients with renal impairment (see section 4.2 'Posology and Method of Administration')

None stated.

Tablet core:

• Lactose (anhydrous)

• Calcium Hydrogen Phosphate Anhydrous

• Starch, Pregelatinised.

• Magnesium Stearate

• Sodium Laurilsulphate

• Silica, colloidal anhydrous.

Tablet coating:

Opadry II Green 85G21674 (25mg only) -contains:

• Poly (vinyl alcohol)

• Talc

• Macrogol 3350

• Quinoline yellow (E104)

• Titanium dioxide (E171)

• Brilliant blue (E133)

• Indigo carmine ( E132)

• Lecithin (E322).

Hydroxyzine hydrochloride has been reported to be incompatible with aminophylline, benzylpenicillin salts, chloramphenicol sodium succinate, dimenhydrinate, doxorubicin hydrochloride (in a liposomal formulation), thioridazine, and some soluble barbiturates.

24 Months.

Do not store above 25°C.

White opaque 250/5/120 micron PVC/TE/PVdC - 20 micron aluminium foil blister strips containing 28 x 25mg tablets (2 blister strips per carton).

No special requirements.

Alliance Pharmaceuticals Limited

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

United Kingdom

PL 16853/0095

24 July 1985/24 July 2002

24^th April 2012