HYDROXYZINE HYDROCHLORIDE 10 MG FILM-COATED TABLETS, ATARAX 10 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Atarax 10mg Film-coated tablets

Hydroxyzine hydrochloride 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Hydroxyzine hydrochloride 10mg

Excipient(s) with known effect:

Lactose (anhydrous) 47.3mg

Sunset Yellow (E110) 0.24mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

10mg film-coated tablets, coloured orange and coded on one side with ‘AX’.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

To assist in the management of anxiety in adults.

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 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 (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

Patients who have shown previous hypersensitivity to hydroxyzine hydrochloride, cetirizine, other piperazine derivatives, aminophylline or ethylenediamine, or any of the excipients of this medicinal product (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’)

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

4.6 Fertility, pregnancy and lactation

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.

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.

In neonates whose mothers received hydroxizine 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.

Lactation

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

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 gastrointestinal 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 co-administered with drugs known to be potent inhibitors of these enzymes.

Hydroxyzine may also have the following interactions:

4.6 Fertility, 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.

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 hydroxyzine may be excreted into breast milk. The effects on the nursing infant are unknown. Hydroxyzine should not be given to nursing mothers (see section 4.3 ‘Contraindica­tions’).

4.7 Effects on ability to drive and use machines

Patients should be warned that hydroxyzine 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.

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

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anxiolytics

ATC code: N05B B01

Hydroxyzine 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, alphaadrenore­ceptors, 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

Hydroxyzine 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.

5.2 Pharmacokinetic properties

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 halflife 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 (t1/2 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’)

5.3 Preclinical safety data

None stated.

6.1 List of excipients

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).

6.2 Incompatibilities

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.

6.3

24 Months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

DHP Healthcare Limited

26 Pickering Street

Maidstone

Kent ME15 9RS

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00111/0206