Hydroxyzine Canon (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

N05BB01 (Hydroxyzine)

Active Substance

Hydroxyzine (Rec.INN registered by WHO)

Dosage Form

Hydroxyzine Canon

Film-coated tablets, 25 mg: 20, 25, 30, or 50 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, with a score; the cross-section is almost white.

Excipients: pregelatinized corn starch – 30 mg, colloidal silicon dioxide – 0.7 mg, magnesium stearate – 1 mg, mannitol – 40 mg, microcrystalline cellulose – 33.3 mg.

10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
25 pcs. – blister packs (1) – cardboard packs.
25 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Anxiolytic agent (tranquilizer)

Pharmacological Action

Hydroxyzine is a first-generation H₁-histamine receptor blocker, a phenothiazine derivative with antimuscarinic and sedative properties and a diphenylmethane, it contributes to the inhibition of activity of certain subcortical zones.

It has H₁-histamine-blocking, bronchodilatory, and antiemetic effects, and has a moderate inhibitory effect on gastric secretion. Hydroxyzine significantly reduces itching in patients with urticaria, eczema, and dermatitis.

Hydroxyzine has a positive effect on cognitive abilities, improving attention and memory. Hydroxyzine does not cause addiction or mental dependence, and no withdrawal syndrome has been noted with prolonged use.
Hydroxyzine is capable of depressing the central nervous system, also has anticholinergic, antihistamine, antispasmodic, local anesthetic, sympatholytic action, and has muscle relaxant activity.

In hepatic insufficiency, the H₁-histamine-blocking effect may be prolonged up to 96 hours after a single dose. It has moderate anxiolytic activity.

Polysomnography in patients with insomnia and anxiety demonstrates an increase in sleep duration and a decrease in the frequency of nocturnal awakenings after a single or repeated dose of hydroxyzine at a dose of 50 mg. A reduction in muscle tension in patients with anxiety was noted when taking the drug at a dose of 50 mg 3 times a day.

The H₁-histamine-blocking effect occurs approximately 1 hour after oral administration of the tablets. The sedative effect appears after 30-45 minutes.

Pharmacokinetics

Absorption

Absorption is high. T_max after oral administration is 2 hours. After an average dose of 50 mg, C_max in adults is 70 mg/ml.

Distribution

The volume of distribution is 7-16 L/kg in adults. Hydroxyzine penetrates the blood-brain barrier and placenta, concentrating to a greater extent in fetal tissues than in maternal tissues. After oral administration, Hydroxyzine penetrates well into the skin, with hydroxyzine concentrations in the skin far exceeding serum concentrations both after a single dose and after multiple doses. Plasma concentration of hydroxyzine does not necessarily reflect its tissue binding or distribution in skin receptors. It affects skin inflammation depending on serum concentration.

Metabolism

Hydroxyzine is metabolized in the liver. Cetirizine – the main metabolite (45%) is an H₁-histamine receptor blocker. Metabolites are found in breast milk.

Excretion

T_1/2 in adults is 14 hours (range: 7-20 hours). The total clearance of hydroxyzine is 13 ml/min/kg. About 0.8% of hydroxyzine is excreted unchanged by the kidneys. The main metabolite cetirizine is excreted mainly in the urine, also unchanged (25% of the administered dose of hydroxyzine).

Pharmacokinetics in special patient groups

In elderly patients

In elderly patients, T_1/2 was 29 hours. The volume of distribution is 22.5 L/kg. A reduction in the daily dose of hydroxyzine is recommended when prescribed to elderly patients.

Children under 1 year

In children, total clearance is 2.5 times higher than in adults. The dose should be adjusted. T_1/2 is 4 hours.

Children from 1 year to 14 years

T_1/2 is 11 hours.

In patients with hepatic impairment

In patients with secondary liver dysfunction due to primary biliary cirrhosis, total clearance was approximately 66% of the value recorded in healthy volunteers. In patients with liver disease, T_1/2 increased to 37 hours, and serum metabolite concentrations were higher than in young patients with normal liver function. Patients with hepatic impairment are recommended to reduce the daily dose or frequency of administration.

In patients with renal impairment

The pharmacokinetics of hydroxyzine were studied in 8 patients with severe renal impairment (creatinine clearance 24±7 ml/min). The duration of exposure to hydroxyzine did not change significantly, while the duration of exposure to cetirizine was increased. To avoid any significant accumulation of the metabolite cetirizine after multiple administrations of hydroxyzine in patients with impaired renal function, the daily dose of hydroxyzine should be reduced.

Indications

• Symptomatic treatment of anxiety in adults;
• As a sedative during premedication;
• Symptomatic treatment of itching of allergic origin.

ICD codes

Dosage Regimen

The drug is administered orally.

Children

For symptomatic treatment of itching of allergic origin

Aged 3 to 6 years from 1.0 mg/kg/day to 2.5 mg/kg/day in several doses.

Aged 6 years and older from 1.0 mg/kg/day to 2.0 mg/kg/day in several doses.

For premedication 1 mg/kg at night before anesthesia.

The dosage is calculated by the doctor individually depending on the child’s body weight in accordance with the recommended doses, taking into account that the minimum obtainable dosage, after dividing the tablet, is 12.5 mg.

Adults

For symptomatic treatment of anxiety the standard dose is 50 mg per day, divided into 3 doses (1/2 tablet (12.5 mg) in the morning, 1/2 tablet (12.5 mg) in the afternoon and 1 tablet (25 mg at night). For severe anxiety, the drug is used at a dose of 50-100 mg 4 times a day.

For symptomatic treatment of itching of allergic origin the initial dose is 1 tablet (25 mg) at bedtime, if necessary the dose can be increased to 1 tablet (25 mg) 3-4 times a day.

For premedication in surgical practice 2-8 tablets (50-200 mg) at night before anesthesia.

A single maximum dose for an adult should not exceed 8 tablets (200 mg), the maximum daily dose is no more than 12 tablets (300 mg).

Use in special patient groups

When used in the elderly, the dose is selected individually, taking into account concomitant diseases within the range of recommended doses (see the Pharmacokinetics section).

Use in patients with renal impairment and hepatic impairment

Patients with severe and moderate renal impairment, as well as hepatic impairment, require a dose reduction. In patients with hepatic impairment, it is recommended to reduce the daily dose by 33%. In patients with severe and moderate renal impairment, the drug is used at half the dose due to reduced excretion of the main metabolite of hydroxyzine – cetirizine.

Adverse Reactions

Possible side effects are listed below by body system and frequency of occurrence.

WHO classification of the frequency of side effects

Very common – ≥1/10 prescriptions (>10 %)

Common – from ≥1/100 to < 1/10 prescriptions (>1 % and <10 %)

Uncommon – from ≥ 1/1000 to <1/100 prescriptions (>0.1 % and <1 %)

Rare – from ≥ 1/10000 to <1/1000 prescriptions (>0.01 % and <0.1 %)

Very rare – <1/10000 prescriptions (<0.01 %)

The most frequent adverse reactions were drowsiness, headache, lethargy, dry mouth, and fatigue.

Immune system disorders

Rare: hypersensitivity;

Very rare: anaphylactic shock.

Nervous system disorders

Uncommon: dizziness, insomnia, tremor;

Rare: convulsions, dyskinesia.

Uncommon: agitation, confusion;

Rare: hallucinations, disorientation.

Eye disorders

Rare: accommodation disorder, vision disorder.

Cardiac disorders

Rare: tachycardia;

Frequency unknown: QT interval prolongation on electrocardiogram, torsades de pointes ventricular tachycardia.

Vascular disorders

Rare: decreased blood pressure.

Respiratory, thoracic and mediastinal disorders

Very rare: bronchospasm.

Gastrointestinal disorders:

Uncommon: nausea; rare: vomiting, constipation.

Hepatobiliary disorders:

Rare: abnormal liver function tests;

Frequency unknown: hepatitis.

Renal and urinary disorders

Rare: urinary retention.

Skin and subcutaneous tissue disorders

Rare: itching, rash (erythematous, maculopapular), urticaria, dermatitis;

Very rare: angioedema, increased sweating, acute generalized exanthematous pustulosis, erythema multiforme, Stevens-Johnson syndrome.

General disorders

Rare: hyperthermia, malaise.

The following side effects were observed with cetirizine – the main metabolite of hydroxyzine: thrombocytopenia, aggression, depression, tic, dystonia, paresthesia, oculogyric crisis, diarrhea, dysuria, enuresis, asthenia, edema, weight gain and may be observed when taking hydroxyzine.

Contraindications

• Hypersensitivity to any component of the drug, cetirizine and other piperazine derivatives, aminophylline or ethylenediamine;
• Porphyria;
• Children under 3 years of age;
• Pregnancy, childbirth and breastfeeding.

With caution in myasthenia gravis, prostatic hyperplasia with clinical manifestations, difficulty urinating, constipation, with glaucoma, dementia, seizure disorders, including epilepsy, with a tendency to arrhythmia, including electrolyte imbalance (hypokalemia, hypomagnesemia), in patients with a history of heart disease (with heart failure and arterial hypertension) or when using drugs that can cause arrhythmia, with hyperthyroidism. Hydroxyzine contributes to a decrease in gastrointestinal motility, the development of a stenosing peptic ulcer, and impaired breathing.

Use in Pregnancy and Lactation

Hydroxyzine Canon is contraindicated during pregnancy, childbirth and breastfeeding.

Use in Hepatic Impairment

Patients with hepatic impairment require a dose reduction. In patients with hepatic impairment, it is recommended to reduce the daily dose by 33%.

Use in Renal Impairment

Patients with severe and moderate renal impairment require a dose reduction. In patients with severe and moderate renal impairment, the drug is used at half the dose due to reduced excretion of the main metabolite of hydroxyzine – cetirizine.

Pediatric Use

Contraindicated in children under 3 years of age.

Geriatric Use

When used in the elderly, the dose is selected individually, taking into account concomitant diseases within the range of recommended doses (see the Pharmacokinetics section).

Special Precautions

When used concomitantly with drugs that have m-cholinolytic properties and drugs that depress the CNS, the dose of hydroxyzine must be reduced.

Hydroxyzine may lead to QT interval prolongation on the electrocardiogram, so concomitant use with other drugs that can impair cardiac activity may increase the risk of arrhythmias. It is assumed that other drugs that cause changes on the electrocardiogram (atropine, antiparkinsonian drugs, lithium carbonate, quinidine, phenothiazines, procainamide, tricyclic antidepressants, thioridazine) may aggravate and enhance the changes that may be caused by hydroxyzine, and increase the risk of sudden death. The simultaneous use of two or more drugs that prolong the QT interval should be avoided due to the danger of additive effects that can cause potentially life-threatening and severe cardiac arrhythmias.

In renal and/or hepatic impairment, doses should be reduced.

In the elderly, the dosage should be selected individually, starting with half the minimum dose, and adjusted within the range of recommended doses. If it is necessary to perform allergy tests or a methacholine test, the use of Hydroxyzine Canon should be discontinued 5 days before the study to prevent distorted data.

During treatment with Hydroxyzine Canon, alcohol consumption should be avoided.

Effect on ability to drive vehicles and operate machinery

Hydroxyzine Canon may impair the ability to concentrate and the speed of psychomotor reactions. Taking other sedative medications may enhance this effect. Therefore, one should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms of CNS toxicity are associated with excessive m-cholinolytic action, depression or paradoxical stimulation of the CNS. These symptoms include nausea, vomiting, tachycardia, hyperthermia, drowsiness, impaired pupillary reflex, tremor, confusion or hallucinations. Subsequently, depression of consciousness, respiration, convulsions, decreased blood pressure, and arrhythmia may develop. Aggravation of coma and cardiopulmonary collapse is possible.

Treatment It is necessary to monitor the condition of the airways, respiration and circulation using Electrocardiographic (ECG) monitoring, and ensure adequate oxygenation. Cardiac activity and blood pressure should be monitored for 24 hours after the symptoms disappear.

In large doses, Hydroxyzine can lead to QT interval prolongation and obvious changes on the electrocardiogram.

In case of impaired mental status, the use of other drugs or alcohol should be ruled out; if necessary, the patient should be given oxygen inhalation, naloxone, dextrose (glucose) and thiamine should be administered. The use of analeptics is not permissible.

If a vasopressor effect is necessary, norepinephrine or metaraminol is prescribed. Epinephrine should not be used. In case of oral intake of a significant amount of the drug, gastric lavage with prior endotracheal intubation can be performed. The use of activated charcoal is possible, but there is insufficient data on its effectiveness. There is no specific antidote. Hemodialysis is not effective.

Literature data indicate that in the case of severe, life-threatening, difficult-to-treat m-cholinolytic effects not relieved by other drugs, the use of a therapeutic dose of physostigmine is possible. Physostigmine should not be used solely to bring the patient to consciousness. If the patient has taken tricyclic antidepressants, the use of physostigmine may provoke seizures and irreversible cardiac arrest. The use of physostigmine should also be avoided in patients with cardiac conduction disorders.

Drug Interactions

The potentiating effect of hydroxyzine should be taken into account when used concomitantly with drugs that depress the central nervous system (CNS), such as narcotic analgesics, barbiturates, tranquilizers, hypnotics, and alcohol. In this case, their doses should be selected individually. Concomitant use with MAO inhibitors (MAOIs) and anticholinergics should be avoided. The drug counteracts the pressor effect of epinephrine and the anticonvulsant activity of phenytoin, and also counteracts the action of betahistine and cholinesterase inhibitor drugs.

It has been established that the use of cimetidine at a dose of 600 mg twice a day increases the serum concentration of hydroxyzine by 36% and reduces the maximum concentration of the metabolite cetirizine by 20%.

The effect of atropine, belladonna alkaloids, cardiac glycosides, antihypertensive agents, H₂-histamine receptor blockers is not altered by hydroxyzine. Hydroxyzine is an inhibitor of the CYP2D6 isoenzyme and in high doses may be the cause of drug interactions with CYP2D6 substrates. Since Hydroxyzine is metabolized in the liver, an increase in its plasma concentration can be expected with simultaneous use with inhibitors of liver microsomal enzymes. Since Hydroxyzine is metabolized by alcohol dehydrogenase and the CYP3A4/5 isoenzyme, an increase in the plasma concentration of hydroxyzine is possible with simultaneous use with drugs that potentially inhibit the CYP3A4/5 isoenzyme (telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and some HIV protease inhibitors, including atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, lopinavir/ritonavir, saquinavir/ritonavir and tipranavir/ritonavir). However, inhibition of one metabolic pathway may be partially compensated by the work of another. Concomitant use of hydroxyzine with drugs that can potentially cause arrhythmia may increase the risk of QT interval prolongation and torsades de pointes ventricular tachycardia.

Concomitant use of the drug with agents possessing an ototoxic effect, such as gentamicin, may mask symptoms of ototoxicity like dizziness.

The drug should be discontinued 3 days prior to planned skin tests with allergens.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.