Hydroxyzine-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HYDROXYZINE-ZN (HYDROXYZINE-ZN)

Composition:

Active substance: hydroxyzine;

1 tablet contains hydroxyzine hydrochloride 25 mg;

Excipients: celactose 80 [a mixture of monohydrate lactose and powdered cellulose (75 : 25)], colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol 400, titanium dioxide (E 171).

Medicinal form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, nearly white, round cylindrical in shape with two convex surfaces and a dividing line on one side.

Pharmacotherapeutic group. Anxiolytics. Diphenylmethane derivatives.

ATC code N05BB01.

Pharmacological properties.

Pharmacodynamics.

Hydroxyzine hydrochloride is a derivative substance, a diphenylmethane compound, chemically unrelated to phenothiazines, reserpine, meprobamate, or benzodiazepines.

Mechanism of action

Hydroxyzine hydrochloride is not a depressant of the cerebral cortex, but its action may be related to suppression of activity in certain key subcortical areas of the central nervous system.

Pharmacodynamic effects

Antihistaminic and bronchodilating effects have been demonstrated experimentally and confirmed clinically. The antiemetic effect has been demonstrated in both apomorphine- and veratrole-induced tests. Pharmacological and clinical studies indicate that hydroxyzine, at therapeutic doses, does not increase gastric secretion or acidity and in most cases exhibits mild antisecretory activity. Reduction of wheals and erythema has been demonstrated in healthy adult volunteers and in children following intradermal injections of histamine or antigens. Hydroxyzine has also shown efficacy in relieving pruritus associated with various forms of urticaria, eczema, and dermatitis.

In patients with hepatic impairment, the antihistaminic effect of a single dose may be prolonged up to 96 hours after administration.

EEG data in healthy volunteers demonstrate an anxiolytic-sedative profile of the drug. The anxiolytic effect has been confirmed in patients using various classical psychometric tests. Polysomnographic data in anxious patients and in patients suffering from insomnia indicate an increase in total sleep time, reduction in total nighttime awakenings, and reduction in sleep latency after single or repeated daily doses of 50 mg. Reduction in muscle tone has been demonstrated in anxious patients receiving a daily dose of 3 × 50 mg.

No memory impairments were observed. No withdrawal symptoms or signs were reported after 4 weeks of treatment in anxious patients.

When oral pharmaceutical forms are used, the antihistaminic effect begins approximately 1 hour after administration. The sedative effect begins 5–10 minutes after administration of oral liquid forms and 30–45 minutes after tablet administration. Hydroxyzine also exhibits spasmolytic and sympatholytic effects. It has weak affinity for muscarinic receptors. Hydroxyzine exerts mild analgesic activity.

Pharmacokinetics.

Absorption. Hydroxyzine is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration (C_max) is reached approximately 2 hours after oral administration. After single oral doses of 25 mg and 50 mg in adults, C_max concentrations are typically 30 and 70 ng/mL, respectively. After repeated once-daily administration, concentrations increase by 30%. The bioavailability of hydroxyzine after oral administration, compared to intramuscular (i.m.) administration, is approximately 80%.

Distribution. Hydroxyzine is widely distributed throughout the body and generally achieves higher tissue concentrations than in plasma. In adults, the apparent volume of distribution ranges from 7 to 16 L/kg. Hydroxyzine penetrates into the skin after oral administration. Both after single and multiple doses, hydroxyzine concentrations in the skin are higher than in blood serum. Hydroxyzine crosses the blood-brain and placental barriers, resulting in higher concentrations in the fetus than in the pregnant mother.

Biological transformation. Hydroxyzine undergoes extensive metabolism. The formation of the main metabolite—cetirizine, a carboxylic acid metabolite (approximately 45% of the oral dose)—is catalyzed by alcohol dehydrogenase. This metabolite is a potent peripheral H₁-antagonist. Other identified metabolites include N-dealkylated and O-dealkylated metabolites, with a half-life of 59 hours. These metabolic pathways are primarily mediated by CYP3A4/5.

Elimination. The elimination half-life of hydroxyzine in adults is approximately 14 hours (range: 7–20 hours). The apparent total body clearance, calculated during studies, is 13 mL/min/kg. Only 0.8% of the dose is excreted unchanged in urine. The main metabolite, cetirizine, is primarily excreted unchanged in urine (25% of orally administered hydroxyzine).

Special populations

Elderly patients. The pharmacokinetics of hydroxyzine were studied in 9 healthy elderly volunteers (69.5 ± 3.7 years) after a single 0.7 mg/kg dose. The elimination half-life of hydroxyzine was prolonged to 29 hours, and the apparent volume of distribution increased to 22.5 L/kg. A reduced daily dose of hydroxyzine is recommended for elderly patients (see section "Dosage and administration").

Children. The pharmacokinetics of hydroxyzine were evaluated in 12 children (6.1 ± 4.6 years; 22 ± 12 kg) after a single 0.7 mg/kg dose. The apparent plasma clearance was approximately 2.5 times higher than in adults. The elimination half-life was shorter than in adults—about 4 hours in 1-year-old patients and 11 hours in 14-year-old patients. The dose should be adjusted when administered to children (see section "Dosage and administration").

Hepatic impairment. In patients with secondary hepatic dysfunction due to primary biliary cirrhosis, total clearance was approximately 66% of that in healthy volunteers. The elimination half-life increased to 37 hours, and serum concentrations of the carboxylic acid metabolite cetirizine were higher than in young patients with normal liver function. The daily dose or frequency of administration should be reduced in patients with impaired liver function (see section "Dosage and administration").

Renal impairment. The pharmacokinetics of hydroxyzine were studied in 8 patients with severe renal impairment (creatinine clearance 24 ± 7 mL/min). The AUC (area under the pharmacokinetic curve) for hydroxyzine did not change significantly, whereas the AUC for the carboxylic acid metabolite cetirizine was increased. This metabolite is not effectively removed by hemodialysis.

To avoid any significant accumulation of the cetirizine metabolite after multiple doses of hydroxyzine, the daily dose of hydroxyzine should be reduced in patients with impaired renal function (see section "Dosage and administration").

Clinical characteristics.

Indications.

Due to its sedative, anxiolytic, and antihistaminic properties, hydroxyzine is indicated for:

• symptomatic treatment of anxiety states in adults;
• symptomatic therapy of allergic pruritus.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the preparation, cetirizine, other piperazine derivatives, aminophylline, or ethylenediamine;

• porphyria;

• diagnosed acquired or congenital QT interval prolongation;

• presence of risk factors for QT interval prolongation, including diagnosed cardiovascular diseases, significant electrolyte imbalances (hypokalemia, hypomagnesemia), sudden cardiac death in family history, marked bradycardia, concomitant use with drugs that prolong the QT interval and/or induce polymorphic ventricular tachycardia of the torsades de pointes type (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");

• pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

Concomitant administration of hydroxyzine with medicinal products that prolong the QT interval and/or induce polymorphic ventricular tachycardia of the torsades de pointes type, such as class IA (e.g., quinidine, disopyramide) and class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antihistamines, certain neuroleptics (e.g., haloperidol), certain antidepressants (e.g., citalopram, escitalopram), certain antimalarial drugs (e.g., mefloquine, hydroxychloroquine), certain antibiotics (e.g., erythromycin, levofloxacin, moxifloxacin), certain antifungal agents (e.g., pentamidine), certain gastrointestinal drugs (e.g., prucalopride), certain anticancer drugs (e.g., toremifene, vandetanib), and methadone, increases the risk of developing cardiac arrhythmia. Therefore, such combinations are contraindicated (see section "Contraindications").

Combinations requiring precautions

Medicinal products causing hypokalemia should be used with caution in case of bradycardia.

Hydroxyzine should be used with caution at doses exceeding the recommended ones when co-administered with drugs capable of inducing cardiac arrhythmia, such as quinidine, lithium, thioridazine, tricyclic antidepressants, atropine, and similar agents.

Enhanced effects of hydroxyzine should be considered when used concomitantly with medicinal products that depress the central nervous system or have anticholinergic properties. In such cases, dosage should be individually adjusted. Alcohol also potentiates the effects of the medicinal product.

Concomitant administration with monoamine oxidase inhibitors (MAO inhibitors) should be avoided.

In patients treated with anticoagulants, hemostasis should be checked prior to initiating therapy.

The medicinal product interferes with the pressor effect of adrenaline, acts as an antagonist of phenytoin's anticonvulsant activity in rats, and also interferes with the action of betahistine and cholinesterase inhibitor drugs. If allergic testing or methacholine bronchial challenge testing is required, the drug should be discontinued at least 5 days before the tests to prevent interference with test results.

Administration of hydroxyzine may interfere with the determination of 17-hydroxycorticosteroids in urine.

Cimetidine 600 mg twice daily increased serum concentrations of hydroxyzine by 36% and reduced peak concentrations of the metabolite cetirizine by 20%.

Hydroxyzine is an inhibitor of CYP2D6 (Ki: 3.9 µmol; 1.7 µg/mL) and at high doses may cause drug interactions with CYP2D6 substrates (metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, aripiprazole, codeine, dextromethorphan, duloxetine, flecainide, mexiletine, ondansetron, tamoxifen, tramadol, venlafaxine).

The medicinal product has no inhibitory effect at a concentration of 100 µmol on UDP-glucuronosyltransferase isoforms 1A1 and 1A6 in human liver microsomes. It inhibits cytochrome P450 isoforms 2C9/C10, 2C19, and 3A4 at concentrations exceeding peak plasma concentrations (IC50 (IC50): 103–140 µmol; 46–52 µg/mL). Therefore, it is unlikely that the medicinal product will interfere with the metabolism of drugs that are substrates for these enzymes.

The metabolite cetirizine at a concentration of 100 µmol does not exhibit inhibitory effects on human liver cytochrome P450 (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1, and 3A4) or UDP-glucuronosyltransferase isoforms.

Hydroxyzine is metabolized by alcohol dehydrogenase and CYP3A4/5. Increased blood concentrations of hydroxyzine may be expected when hydroxyzine is co-administered with drugs known as potent inhibitors of these enzymes (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, when only one metabolic pathway is inhibited, other pathways may partially compensate for this.

Special precautions for use.

Hydroxyzine should be administered with caution to patients prone to seizures.

Due to the anticholinergic effect of the drug, it should be prescribed with caution to patients with glaucoma, prostatic hyperplasia, urinary retention, decreased gastrointestinal motility, myasthenia gravis, or dementia.

Dosage adjustment is required in patients receiving concomitant treatment with other central nervous system (CNS) depressants or anticholinergic agents (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol intake or concomitant use of other sedative drugs should be avoided during hydroxyzine treatment (see section "Interaction with other medicinal products and other forms of interaction").

Effect on the cardiovascular system

Hydroxyzine has been associated with QT interval prolongation on ECG. During post-marketing surveillance, cases of QT interval prolongation and polymorphic ventricular tachycardia of the torsades de pointes type have been reported in patients taking hydroxyzine. Most of these patients had additional risk factors, including electrolyte imbalances and concomitant medications, which may have contributed to the development of these symptoms (see section "Adverse reactions").

Hydroxyzine should be used at the lowest effective dose and for the shortest possible duration. If signs or symptoms suggestive of cardiac arrhythmia occur, hydroxyzine therapy should be discontinued immediately, and patients should seek medical advice without delay.

Patients should be advised to report any cardiac symptoms immediately.

Skin reactions

Life-threatening skin and immunological reactions, such as Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema, have been reported during treatment with this medicinal product.

Patients should be informed about these signs and symptoms, and careful monitoring for the development of skin and immunological reactions is required. The highest risk of developing Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema occurs within the first few days to several weeks after initiating treatment.

If symptoms or signs of Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema (e.g., progressive skin rash, often accompanied by pain, blistering, mucosal lesions, and sometimes fever) occur, the drug should be discontinued immediately and medical help should be sought.

Best outcomes in treating Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema are achieved through early diagnosis and treatment, as well as immediate discontinuation of the suspected drug. Early withdrawal of the drug is associated with a better prognosis.

If a patient develops Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema while taking this drug, the drug must never be used again in this patient.

Elderly patients

Hydroxyzine is not recommended for use in elderly patients due to reduced clearance of hydroxyzine in this population compared to younger patients and an increased risk of adverse reactions (e.g., anticholinergic effects) (see sections "Dosage and administration" and "Adverse reactions").

Hepatic and/or renal impairment

Dosage reduction is required in patients with hepatic impairment or with moderate to severe renal impairment (see section "Dosage and administration").

If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Paediatric population

Young children are more susceptible to central nervous system adverse effects (see section "Adverse reactions"). Seizures have been observed more frequently in children than in adults.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have demonstrated reproductive toxicity of the drug. Hydroxyzine crosses the placental barrier, resulting in higher concentrations in the fetus compared to the maternal organism. Currently, there are no relevant epidemiological data on the effects of hydroxyzine during pregnancy; therefore, the drug is contraindicated during pregnancy.

In newborns whose mothers received the drug during late pregnancy and/or during labor, the following effects have been observed either immediately or several hours after birth: hypotonia, movement disorders including extrapyramidal disorders, clonic movements, central nervous system depression, neonatal hypoxic states, or urinary retention. Therefore, the drug is contraindicated during pregnancy.

Breastfeeding. Cetirizine, the main metabolite of hydroxyzine, is excreted into breast milk.

Although there is no formal study on the excretion of hydroxyzine into breast milk, severe adverse effects have been observed in newborns/infants whose mothers received hydroxyzine treatment.

The drug is contraindicated during breastfeeding. If hydroxyzine treatment is necessary, breastfeeding should be discontinued.

Fertility. There are no adequate data on the effect on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Hydroxyzine may impair the ability to react and concentrate. Patients should be aware of this and exercise caution when driving or operating machinery.

Concomitant use of this medicinal product with alcohol or other sedative drugs should be avoided, as this may enhance the aforementioned effects.

Dosage and Administration

The medicinal product is taken orally.

Hydroxyzine should be used at the lowest effective dose and for the shortest possible duration.

Adults

For symptomatic treatment of anxiety states: 50–100 mg daily, i.e., 2–4 tablets of 25 mg or ½–1 tablet of 100 mg in the evening before bedtime if anxiety develops, particularly when associated with insomnia.

For symptomatic treatment of allergic pruritus: 25–100 mg daily, i.e., 1–4 tablets of 25 mg daily.

The maximum daily dose for adults and children with body weight of 40 kg or more is 100 mg.

The duration of treatment is determined by the physician based on symptoms, and the lowest possible maintenance dose should be prescribed.

Since patient response to hydroxyzine may vary, it is recommended to initiate treatment with low doses and gradually increase the dose until the optimal dose adjusted according to the patient's response to therapy is achieved.

Children

For symptomatic treatment of allergic pruritus:

Children and adolescents aged 12 years and older (body weight over 40 kg): 25–100 mg/day, i.e., 1–4 tablets of 25 mg daily.

Children aged 9 to 12 years (body weight 28–40 kg): 25–75 mg/day, i.e., 1–3 tablets of 25 mg daily.

Children aged 7 to 9 years (body weight 23–28 kg): 25–50 mg/day, i.e., 1–2 tablets of 25 mg daily.

Children aged 4 to 7 years (body weight 17–23 kg): 25–37.5 mg/day, i.e., 1–1½ tablets of 25 mg daily.

Children aged 3 to 4 years (body weight 12.5–17 kg): 12.5–25 mg/day, i.e., ½–1 tablet of 25 mg daily.

Dose should be calculated based on body weight, ranging from 1 mg/kg/day to a maximum of 2 mg/kg/day, administered in divided doses.

For children with body weight below 40 kg, the maximum daily dose is 2 mg/kg/day. For children with body weight above 40 kg, the maximum daily dose is 100 mg/day.

Special Populations

Elderly Patients

The maximum daily dose for elderly patients is 50 mg daily (see section "Special Warnings and Precautions for Use").

Renal Impairment

If a temporary effect is required, the dose may be reduced by half. This may also apply to patients with renal impairment.

Hepatic Impairment

Patients with impaired liver function are recommended to reduce the daily dose by 33%.

Children

The use of the medicinal product in children is described in detail in the section "Dosage and Administration".

Overdose

Symptoms

Symptoms observed after significant overdose are primarily related to excessive anticholinergic effects, CNS depression, or paradoxical CNS stimulation. Symptoms of significant overdose may include nausea, vomiting, tachycardia, hyperthermia, drowsiness, pupillary reflex disturbances, tremor, confusion, or hallucinations. This may be followed by decreased level of consciousness, respiratory depression, seizures, arterial hypotension, or cardiac arrhythmias, including bradycardia. Increased depth of coma and cardiopulmonary collapse may occur.

Treatment

Careful monitoring of airways, respiration, and circulation with continuous ECG recording and adequate oxygen supply is required. Cardiac monitoring and blood pressure should be continued for 24 hours after symptom resolution.

Patients with altered mental status should be evaluated for concomitant alcohol or other drug use; oxygen, naloxone, glucose, and thiamine may be administered as needed.

If vasopressor support is required, norepinephrine or metharaminol should be administered. Epinephrine should not be used.

Syrup of ipecac should not be administered to patients with symptoms or predisposition to rapid deterioration in consciousness, coma, or seizures, as this may lead to aspiration pneumonia.

In cases of ingestion of a clinically significant amount of the drug, gastric lavage may be performed following endotracheal intubation. Activated charcoal may be used, but data supporting its efficacy are limited. Hemodialysis or hemoperfusion is not indicated. There is no specific antidote.

Published data suggest that in cases of severe, life-threatening anticholinergic effects that are refractory to standard treatments and do not respond to conventional antidotes, trial therapeutic doses of physostigmine may be beneficial. Physostigmine should not be used solely to maintain consciousness. If tricyclic antidepressants have been co-ingested, physostigmine administration may precipitate seizures and cardiac arrest that are difficult to treat. Physostigmine should not be administered in patients with conduction system disorders of the heart.

Adverse Reactions

Adverse effects are mainly related to central nervous system (CNS) depression or paradoxical stimulation of the central nervous system, anticholinergic activity, or hypersensitivity reactions.

The table below lists adverse reactions reported during post-marketing use, as well as those observed in placebo-controlled clinical trials with an incidence of at least 1% for hydroxyzine (735 subjects receiving hydroxyzine at doses up to 50 mg daily and 630 subjects receiving placebo). The frequency of adverse reactions in clinical studies is provided as a percentage where possible; for adverse effects reported during post-marketing use, the frequency cannot be reliably estimated.

The adverse reactions listed below, observed during drug use, are classified by organ system according to MedDRA (Medical Dictionary for Regulatory Activities) and by frequency as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Some adverse reactions were identified during clinical trials with the frequency indicated below. However, certain adverse reactions were reported spontaneously during post-marketing use. When the frequency cannot be estimated from the available data, it is listed as "not known."

Description of individual adverse reactions

The following adverse reactions are associated with cetirizine, the main metabolite of hydroxyzine: thrombocytopenia, aggression, depression, tic, dystonia, paresthesia, oculogyric crisis, diarrhea, dysuria, urinary incontinence, weakness, edema, weight gain—and thus may potentially occur during hydroxyzine use.

Reporting of adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging. 10 tablets in a blister; 1 or 3 blisters per carton. 10 tablets in a blister.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu"".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kuлиkivska Street, 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")