Zodac^® (Tablets, Drops) Instructions for Use

ATC Code

R06AE07 (Cetirizine)

Active Substance

Cetirizine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Histamine H₁-receptor blocker. Antiallergic drug

Pharmacotherapeutic Group

Systemic antihistamines; piperazine derivatives

Pharmacological Action

Cetirizine – the active substance of the drug Zodac^® – is a metabolite of hydroxyzine, has an antihistamine effect with an antiallergic action.

Cetirizine belongs to the group of competitive histamine antagonists and blocks histamine H₁-receptors with little effect on other receptors and has practically no anticholinergic and antiserotonin action.

Cetirizine affects the histamine-dependent stage of immediate allergic reactions, and also reduces eosinophil migration and limits the release of mediators in delayed-type allergic reactions.

It practically does not pass through the BBB and, therefore, is almost unable to reach central H₁-receptors.

Pharmacodynamic effects

In studies of the effect of histamine on the skin, the action of cetirizine at a dose of 10 mg started after 1 hour, reached a maximum from the 2nd to the 12th hour and was still observed at statistically significant levels after 24 hours.

In addition to the antihistamine effect, Cetirizine also has an anti-inflammatory effect and thus affects the late phase of the allergic reaction.

• At a dose of 10 mg 1 or 2 times/day inhibits the late phase of eosinophil aggregation in the skin;
• At a dose of 30 mg/day inhibits the release of eosinophils into the bronchoalveolar lavage fluid after allergen-induced bronchial constriction;
• Inhibits kallikrein-induced late inflammatory reaction;
• Suppresses the expression of inflammatory markers such as ICAM-1 or VCAM-1;
• Inhibits the action of histamine liberators such as PAF or substance P.

Clinical studies have shown that Cetirizine begins to act 20 minutes after administration, and its effect lasts up to 24 hours.

Pharmacokinetics

Absorption

After oral administration, the drug is rapidly absorbed from the gastrointestinal tract. C_ss is achieved after 3 days. The pharmacokinetic profile of cetirizine is similar in adults and children.

In children after taking cetirizine at a dose of 5 mg, the concentration of the active substance in the body is the same as in adults after taking 10 mg.

In adults after taking cetirizine at a dose of 10 mg, C_max in plasma is reached after 1-2 hours and is 350 ng/ml.

In children after taking cetirizine at a dose of 5 mg, C_max in plasma is reached after 1 hour and is 275 ng/ml.

When taking cetirizine in the form of drops, C_max in plasma is reached at a higher rate.

Distribution

The volume of distribution after taking 10 mg is 35 L in adults, and plasma protein binding is 93%.

In children, V_d after taking 5 mg is approximately 17 L.

A small amount of cetirizine is excreted in breast milk.

When taking the drug at a daily dose of 10 mg for 10 days, no accumulation of cetirizine was observed.

Metabolism and excretion

In adults, 60% of the dose is excreted from the body unchanged by the kidneys.

After taking 10 mg in adults, the total clearance of cetirizine is 0.60 ml/min/kg; T_1/2 is approximately 10 hours.

Multiple dosing does not change the pharmacokinetic parameters.

After the end of treatment, the plasma level of cetirizine quickly falls below detectable limits.

Repeated allergological tests can be resumed after 3 days.

Linearity (non-linearity)

The pharmacokinetic parameters of cetirizine when used in doses from 5 to 60 mg change linearly.

Pharmacokinetics in special patient groups

Elderly patients. In 16 elderly subjects after a single dose of 10 mg, T_1/2 was 50% higher and the elimination rate was 40% lower compared to the control group.

The decrease in cetirizine clearance in elderly patients is probably associated with a deterioration in renal function in this category of patients.

Children. In children aged 6 to 12 years, 70% of the dose is excreted from the body unchanged by the kidneys.

After taking 5 mg in children, the total clearance of cetirizine is 0.93 ml/min/kg.

T_1/2 in children aged 6 to 12 years is 6 hours, from 2 to 6 years – 5 hours, from 6 months to 2 years – reduced to 3.1 hours.

Patients with renal insufficiency. In patients with mild renal insufficiency (CrCl >50 ml/min), the pharmacokinetic parameters are similar to those in healthy volunteers with normal renal function.

In patients with moderate renal insufficiency (CrCl 30-49 ml/min), T_1/2 is prolonged by 3 times, and total clearance is reduced by 70% compared to healthy volunteers with normal renal function.

In patients on hemodialysis (CrCl <7 ml/min), after oral administration of the drug at a dose of 10 mg, total clearance is reduced by 70% compared to healthy volunteers with normal renal function, and T_1/2 is prolonged by 3 times.

Less than 10% of cetirizine is removed during a standard hemodialysis procedure.

Patients with hepatic insufficiency. In patients with chronic liver diseases (hepatocellular, cholestatic and biliary cirrhosis) after a single dose of 10 or 20 mg, T_1/2 increases by approximately 50%, and clearance decreases by 40% compared to healthy subjects.

Dose adjustment is necessary only if the patient with hepatic insufficiency also has concomitant renal insufficiency.

Indications

For adults and children aged 6 months and older to relieve

• Nasal and ocular symptoms of perennial (persistent) and seasonal (intermittent) allergic rhinitis and allergic conjunctivitis (itching, sneezing, nasal congestion, rhinorrhea, lacrimation, conjunctival hyperemia);
• Symptoms of chronic idiopathic urticaria.

Use in children from 6 to 12 months is possible only as prescribed by a doctor and under strict medical supervision!

ICD codes

Dosage Regimen

Tablets

Orally.

The drug should be taken in the evening, because symptoms become more pronounced in the evening.

The drug Zodac^® should be taken without chewing, it is recommended to drink it with water.

The drug Zodac^® can be taken regardless of meals.

Adults are recommended to take 10 mg (1 tablet) once a day.

Children

Cetirizine in the form of film-coated tablets should not be used in children under 6 years of age due to the inability to provide a dosing regimen for this dosage form.

It is recommended to use the pediatric dosage form (oral drops).

Children from 6 to 12 years old – 10 mg (1 tablet) once a day.

The duration of treatment should not exceed 4 weeks.

Alternatively, the dose can be divided into 2 doses (1/2 tablet in the morning and in the evening).

Children over 12 years old – 10 mg (1 tablet) once a day.

Sometimes an initial dose of 5 mg (1/2 tablet) may be sufficient if this allows for satisfactory control of symptoms.

In children with renal insufficiency, the dose is adjusted taking into account CrCl and body weight.

Elderly patients

Due to possible decreased renal function, the dosage regimen of the drug should be adjusted (see the subsection “Patients with renal insufficiency” in the “Dosage Regimen” section).

Special patient groups

Patients with renal insufficiency. Since the drug Zodac^® is excreted from the body mainly by the kidneys (see the “Pharmacokinetics” section), in the absence of alternative treatment, the dosage regimen of the drug should be adjusted depending on renal function (GFR).

CrCl for men can be calculated based on serum creatinine concentration using the following formula

CrCl for women can be calculated by multiplying the obtained value by a factor of 0.85.

Dosing in adult patients with renal insufficiency

Patients with impaired liver function. In patients with impaired liver function only, no adjustment of the dosage regimen is required.

In patients with both impaired liver and renal function, adjustment of the dosage regimen is recommended (see the table above).

Drops

The drug Zodac^® is intended for oral administration.

The drug should be taken in the evening, because symptoms become more pronounced in the evening.

If necessary, the drug Zodac^® can be washed down with a glass of water.

The drug Zodac^® can be taken regardless of meals.

Adults – 10 mg (20 drops) once a day.

Alternatively, the dose can be divided into two doses (10 drops in the morning and in the evening).

Children

Cetirizine in oral drops should not be prescribed to children (used in children) under 6 months of age.

The safety and efficacy of cetirizine in children aged 0 to 6 months have not been established.

Data are not available.

Children from 6 to 12 months – 2.5 mg (5 drops) once a day; children from 1 to 6 years old – 2.5 mg (5 drops) twice a day in the morning and in the evening.

Use in children from 6 to 12 months is possible only as prescribed by a doctor and under strict medical supervision!

Children from 1 to 6 years old– 2.5 mg (5 drops) twice a day in the morning and in the evening.

The duration of treatment should not exceed 4 weeks.

Children from 6 to 12 years old – 10 mg (20 drops) once a day.

The duration of treatment should not exceed 4 weeks.

Alternatively, the dose can be divided into two doses (10 drops in the morning and in the evening).

Children over 12 years old – 10 mg (20 drops) once a day.

Sometimes an initial dose of 5 mg (10 drops) may be sufficient if this allows for satisfactory control of symptoms.

Children with renal insufficiency the dose is adjusted taking into account CrCl and body weight.

Special patient groups

Elderly patients. Due to possible decreased renal function, the dosage regimen of the drug should be adjusted (see the subsection “Patients with renal insufficiency”).

Patients with renal insufficiency. Since the drug Zodac^® is excreted from the body mainly by the kidneys (see the “Pharmacokinetics” section), in the absence of alternative treatment for patients with renal insufficiency, the dosage regimen of the drug should be adjusted depending on renal function (GFR).

When using the table for dose adjustment, CrCl must be calculated in ml/min.

CrCl for men can be calculated based on serum creatinine concentration using the following formula

CrCl for women can be calculated by multiplying the obtained value by a factor of 0.85.

Dosing in adult patients with renal insufficiency

Patients with impaired liver function. In patients with impaired liver function only, no adjustment of the dosage regimen is required.

In patients with both impaired liver and renal function, adjustment of the dosage regimen is recommended (see the table above).

If after treatment there is no improvement or new symptoms appear, it is necessary to consult a doctor.

The drug should be used only according to the method of application and in the doses indicated in the instructions.

Instructions for opening the bottle

The bottle is closed with a cap with a safety device that prevents it from being opened by children.

The bottle is opened by pressing the cap down firmly and then unscrewing it counterclockwise.

After use, the bottle cap must be screwed back on tightly.

Adverse Reactions

Data obtained from clinical studies

The results of clinical studies have demonstrated that the use of cetirizine in recommended doses leads to the development of minor undesirable effects from the central nervous system, including drowsiness, fatigue, dizziness and headache.

In some cases, paradoxical stimulation of the central nervous system was recorded.

Although Cetirizine is a selective peripheral H₁-receptor blocker and has practically no anticholinergic action, isolated cases of difficulty urinating, accommodation disturbances and dry mouth have been reported.

Liver function disorders accompanied by increased activity of liver enzymes and bilirubin have been reported.

In most cases, adverse events resolved after discontinuation of cetirizine.

List of undesirable adverse reactions

There are data obtained from double-blind controlled clinical studies aimed at comparing cetirizine and placebo or other antihistamine drugs used in recommended doses (10 mg once a day for cetirizine) in more than 3200 patients, on the basis of which a reliable analysis of safety data can be carried out.

According to the results of a pooled analysis, in placebo-controlled studies when using cetirizine at a dose of 10 mg, the following adverse reactions with a frequency of 1% or higher were identified

Although the frequency of drowsiness cases in the cetirizine group was higher than in the placebo group, in most cases this adverse event was mild or moderate in severity.

In objective assessments conducted within the framework of other studies, it was confirmed that the use of cetirizine at the recommended daily dose in healthy young volunteers does not affect their daily activities.

Post-registration experience

In addition to the adverse events identified during clinical studies and described above, the following adverse reactions were observed during the post-registration use of the drug.

Adverse events are presented below by MedDRA system organ class and frequency of occurrence, based on post-registration use data.

The frequency of adverse events was determined as follows: very common (≥10), common (≥1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10000, 1/1000), very rare (<1/10000), frequency not known (due to insufficient data).

Description of selected adverse reactions

Cases of pruritus, including intense pruritus and/or urticaria, have been observed after discontinuation of cetirizine.

If the patient experiences side effects listed in the leaflet, or if they worsen, or if any other side effects not listed in the leaflet occur, it is necessary to inform the doctor.

Children

In placebo-controlled studies in children aged 6 months to 12 years, the following adverse reactions were identified with a frequency of 1% and higher

Contraindications

• Hypersensitivity to cetirizine, hydroxyzine or piperazine derivatives, or to any of the excipients of the drug;
• End-stage renal disease (CrCl <10 ml/min).

With caution

• Chronic renal failure (GFR≥15 ml/min, dose adjustment required);
• Epilepsy and patients with increased seizure predisposition;
• Patients with predisposing factors for urinary retention (see section “Special Precautions”);
• Elderly patients (due to age-related decrease in GFR);
• Concomitant use with alcohol or drugs that depress the CNS (see section “Drug Interactions”);
• Children under 1 year of age;
• Pregnancy;
• Period of breastfeeding.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of cetirizine during pregnancy are limited (300-1000 pregnancy outcomes). However, no cases of malformations, fetal and neonatal toxicity with a clear causal relationship have been identified. Experimental animal studies have not revealed any direct or indirect adverse effects of cetirizine on the developing fetus (including in the postnatal period), the course of pregnancy and postnatal development.

During pregnancy, cetirizine may be prescribed after consultation with a doctor, if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Cetirizine is excreted in breast milk. Cetirizine is excreted in breast milk in an amount of 25-90% of the plasma concentration, depending on the time of sampling after drug intake. Adverse reactions associated with cetirizine may be observed in breastfed infants.

During breastfeeding, the drug should be used with caution, if the expected benefit to the mother outweighs the potential risk to the child.

Fertility

Available data on the effect on human fertility are limited, however, no negative effect on fertility was identified in animal studies.

Use in Hepatic Impairment

Dose adjustment is necessary only if a patient with hepatic impairment also has concomitant renal impairment.

Use in Renal Impairment

The use of the drug is contraindicated in patients with end-stage renal disease (CrCl <10 ml/min).

The drug should be prescribed with caution in chronic renal failure (CrCl >10 ml/min, dose adjustment required).

Pediatric Use

The drug is contraindicated for use in children under 6 months of age. Zodac^® drops should be prescribed with caution to children under 1 year of age.

Geriatric Use

Due to the possible decrease in renal function in elderly patients, the dosage regimen of the drug should be adjusted.

Special Precautions

Due to the potential depressant effect on the CNS, caution should be exercised when prescribing Zodac^® to children aged 6 months to 1 year in the presence of the following risk factors for sudden infant death syndrome, such as (but not limited to this list)

• Sleep apnea syndrome or sudden infant death syndrome in a sibling;
• Maternal drug abuse or smoking during pregnancy;
• Young maternal age (19 years and younger);
• Smoking abuse by the nurse caring for the child (1 pack of cigarettes per day or more);
• Children who regularly fall asleep face down and are not placed on their back;
• Premature (gestational age less than 37 weeks) or children born with low birth weight (below the 10th percentile for gestational age);
• Concomitant use of drugs that have a depressant effect on the CNS.

In patients with spinal cord injury, prostatic hyperplasia, as well as in the presence of other predisposing factors for urinary retention, caution is required, as Cetirizine may increase the risk of urinary retention.

In patients with renal impairment, the dosage regimen of the drug should be adjusted (see section “Dosage and Administration”).

Due to the possible decrease in renal function in elderly patients, the dosage regimen of the drug should be adjusted (see section “Dosage and Administration”).

It is recommended to exercise caution when using cetirizine concomitantly with alcohol or drugs that depress the CNS, as Cetirizine may lead to increased drowsiness.

Caution should be exercised in patients with epilepsy and increased seizure predisposition.

A three-day “washout” period is recommended before prescribing allergy tests due to the fact that histamine H₁-receptor blockers inhibit the development of skin allergic reactions.

Excipients

The drug contains the excipients methylparaben and propylparaben, which may cause allergic reactions, including delayed-type reactions.

Effect on ability to drive and operate machinery

Cetirizine may lead to increased drowsiness, therefore, the drug Zodac^® may affect the ability to drive vehicles and operate machinery.

Overdose

Symptoms observed after obvious drug overdose were due to its effect on the CNS or were associated with a possible anticholinergic effect.

Symptoms that were observed after taking at least five times the recommended daily dose included the following: confusion, diarrhea, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, urinary retention.

Treatment There is no specific antidote. In case of overdose, symptomatic or supportive treatment is recommended. Gastric lavage and/or administration of activated charcoal may be effective if the overdose occurred recently. Cetirizine is partially removed by dialysis.

Drug Interactions

Concomitant use with azithromycin, cimetidine, erythromycin, ketoconazole or pseudoephedrine does not affect the pharmacokinetic parameters of cetirizine. No pharmacokinetic interaction was observed. According to in vitro tests, Cetirizine does not affect the plasma protein binding of warfarin.

Concomitant administration of azithromycin, erythromycin, ketoconazole, theophylline and pseudoephedrine did not reveal significant changes in clinical laboratory parameters, vital functions and ECG.

In a study with concomitant administration of theophylline (400 mg/day) and cetirizine (20 mg/day), a slight but statistically significant increase in 24-hour AUC by 19% for cetirizine and by 11% for theophylline was found. In addition, maximum plasma concentrations increased by up to 7.7% and 6.4% for cetirizine and theophylline, respectively. At the same time, the clearance of cetirizine decreased by -16%, and by -10% in the case of theophylline, when Cetirizine was taken by patients who had previously received theophylline treatment. However, pretreatment with cetirizine did not have a significant effect on the pharmacokinetic parameters of theophylline.

After a single dose of cetirizine 10 mg, the effect of alcohol (0.8‰) was not significantly enhanced; a statistically significant interaction with 5 mg diazepam was demonstrated in one out of 16 psychometric tests.

Concomitant administration of cetirizine 10 mg/day with glipizide resulted in a slight decrease in glucose concentration. This effect was not clinically significant. Nevertheless, separate administration is recommended: glipizide – in the morning, Cetirizine – in the evening.

The extent of absorption of cetirizine is not reduced when taken with food, although absorption is delayed by 1 hour.

In a study with multiple doses of ritonavir (600 mg twice daily) and cetirizine (10 mg/day), the extent of exposure to cetirizine was increased by approximately 40%, while the exposure to ritonavir changed slightly (-11%) due to concomitant administration of cetirizine.

If the patient is taking the above or other medications (including over-the-counter), a doctor should be consulted before using Zodac^®.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is available without a 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.