Each film-coated tablet contains:

active ingredient: hydroxyzine hydrochloride – 25 mg;

excipients: tablet core – microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate, sodium starch glycolate, povidone, magnesium stearate,aerosil;
tablet coating – hypromellose, titanium dioxide, propylene glycol, talc purified.

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.

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 .

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

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.

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.

Use in children From 3 years 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 .

Renal impairment For patients with moderate or severe renal impairment, it is recommended that the total daily dosage should be reduced by 50% .

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.

Blood and lymphatic system disorders
Not known: blood disorders, including agranulocytosis, leucopenia, haemolytic anaemia, and thrombocytopenia.

Immune system disorders
Not known: hypersensitivity reactions, anaphylaxis, angioedema.

Metabolic and nutritional disorders
Not known: porphyria, anorexia.

Psychiatric disorders
Not known: agitation, confusion, disorientation, hallucinations, sleep disturbances, depression, increased anxiety, nightmares.

Nervous system disorders
Not known: 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.

Eye disorders
Not known: accommodation disorder, blurred vision.

Ear and labyrinth disorders
Not known: tinnitus, labrynthitis, vertigo.

Cardiac disorders
Not known: tachycardia, palpitation.

Vascular disorders
Not known: hypotension, flushing.

Respiratory, thoracic and mediastinal disorders
Not known: bronchospasm, thickened respiratory tract secretions, wheezing, nasal stuffiness, dryness of throat.

Gastrointestinal disorders
Not known: constipation, dryness of the mouth, nausea, vomiting, increased gastric reflux, diarrhoea, epigastric pain, increased GI peristalsis.

Hepatobiliary disorders
Not known: liver dysfunction.

Skin and subcutaneous tissue disorders
Not known: dermatitis, fixed drug eruption, pruritis, erythema, papular rash, sweating increased, urticaria, hair loss, eczema.

Muscoskeletal and connective tissue disorders
Not known: myalgia.

Renal and urinary disorders
Not known: urinary retention, dysuria.

Reproductive system and breast disorders
Not known: priapism, impotence, early menses.

General disorders and administration site conditions
Not known: fatigue, malaise, lassitude, pyrexia, dryness of respiratory mucosae, asthenia, tightness of chest, irritability, chills.

Investigations
Not known: liver function tests abnormal.

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.

There is no specific antidote. It is doubtful whether haemodialysis or peritoneal dialysis has any value in the treatment of overdosage with La-Son. 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.

• patients who have shown previous hypersensitivity to hydroxyzine hydrochloride, cetirizine, other piperazine derivatives, aminophylline or ethylenediamine, or any of the excipients of La-Son.
• asthmatics who have previously experienced a serious anti-histamine-induced adverse bronchopulmonary effect
• porphyria
• pregnancy and breast-feeding
• children under 3 years
• QT- interval prolongation in history.

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.

Patients with renal impairment

La-Son should be used with caution in patients with impaired renal function. It is uncertain whether the drug may accumulate or have other adverse effects in such patients. La-Son 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.

Because of its potential antimuscarinic actions, La-Son 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 La-Son is used simultaneously with other CNS depressants or with drugs having antimuscarinic properties.
The concomitant use of alcohol and hydroxyzine should be avoided.
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.

Pregnancy:

La-Son 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.

Breast-feeding:
It is expected that La-Son may be excreted into breast milk. The effects on the nursing infant are unknown. La-Son should not be given to nursing mothers.

Lа-Son may 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.

Skin testing for allergy: treatment should be stopped at least one week before skin testing for allergy to avoid effects on the test results.

CNS depressants: patients should be warned that La-Son 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.

Antimuscarinics: antimuscarinic side effects (both peripheral and central) may be increased if La-Son is given with antimuscarinics such as atropine and some antidepressants (both tricyclics and MAOIs).

Adrenaline: hydroxyzine has been shown to inhibit and reverse the vasopressor effect of adrenaline.

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.

2 blister packets with 10 tablets in each and leaflet inserted in the cardboard box.

2 years. Do not use after the expiration date.

To be dispensed with prescription.

Store at a room temperature, in a dry place, out of the reach of children. Protect from light.