Atarax (PSYCHOANALEPTICS)

Atarax 10mg Film-coated tablets

Hydroxyzine hydrochloride 10mg

Excipient(s) with known effect:

10mg film-coated tablets, coloured orange 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.

Posology

Atarax 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

Adults 50-100mg daily in divided doses

Pruritus

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.'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%.'Special Warnings and Precautions for Use')

Renal impairment

Method of administration: oral.

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

Renal impairment

Method of administration: oral.

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

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.

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.'Posology and Method of Administration')

Patients with renal impairment

Elderly patients

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 10mg Film-coated tablets contain Sunset Yellow (E110) which may cause allergic reactions.

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 10mg Film-coated tablets contain Sunset Yellow (E110) which may cause allergic reactions.

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.

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.

Atarax may also have the following interactions:

Pregnancy

Atarax should not be used during pregnancy.

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.

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.'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.

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.

Overdosage with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects.'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).'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.'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.'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.'Posology and Method of Administration')

None stated.

Tablet core:

- Lactose anhydrous

- Calcium Phosphate Dibasic Anhydrous

- Pregelatinised Starch

- Magnesium Stearate

- Sodium Lauryl Sulfate

- Silicon dioxide

Tablet coating:

Opadry II Orange 85G23730 (10mg only) - contains:

- Poly (vinyl alcohol)

- Talc

- Macrogol 3350

- Sunset yellow (E110)

- Titanium dioxide (E171)

- Iron oxide yellow (E172)

- Quinoline yellow (E104)

- 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.

Do not store above 25°C.

White opaque 250/51 micron PVC/PCTFE (Aclar) - 20 micron aluminium foil blister strips containing 84 x 10mg tablets, (6 blister strips per carton)

No special requirements.

Alliance Pharmaceuticals Limited

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

United Kingdom

PL 16853/0094

27 April 1987/30 July 1997

20 June 2016