Cetrine^® (Tablets) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Contact Information

DR. REDDY’S LABORATORIES LTD. (India)

ATC Code

R06AE07 (Cetirizine)

Active Substance

Cetirizine (Rec.INN registered by WHO)

Dosage Form

Cetrine®

Film-coated tablets, 10 mg: 20 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with a score on one side; the core on the cross-section is white to almost white.

Excipients: lactose, corn starch, povidone (K-30), magnesium stearate.

Film coating composition: hypromellose (6 cps), macrogol 6000, titanium dioxide, talc, polysorbate 80, dimethicone.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Histamine H₁-receptor blocker. Antiallergic drug

Pharmacotherapeutic Group

Systemic antihistamines, piperazine derivatives

Pharmacological Action

Mechanism of action

Cetirizine – the active substance of the drug Cetrine^® – is a metabolite of hydroxyzine, has an antihistamine effect with 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 cross the BBB and, therefore, is almost unable to reach central histamine H₁-receptors.

Pharmacodynamic effects

In studies of the effect of histamine on the skin, the action of cetirizine at a dose of 10 mg began 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 once or twice daily 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.

Pharmacokinetics

Absorption

After oral administration, the drug is rapidly absorbed from the gastrointestinal tract. C_ss is reached after 3 days.

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.

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

Distribution

V_d after taking 10 mg is 35 L in adults, and binding to plasma proteins is 93%.

A small amount of cetirizine is excreted in breast milk.

Metabolism

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

Excretion

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 doses do not change the pharmacokinetic parameters. When taking the drug at a daily dose of 10 mg for 10 days, no accumulation of cetirizine was observed.

After the end of treatment, the plasma level of cetirizine quickly drops 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.

Special patient groups

Renal impairment

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

In patients with moderate renal impairment (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.

Hepatic impairment

In patients with chronic liver diseases (hepatocellular, cholestatic and biliary cirrhosis), after a single dose of the drug at a 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 impairment also has concomitant renal impairment.

Elderly patients

In 16 elderly individuals after a single dose of the drug at a 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 likely associated with reduced renal function in this category of patients.

Children

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 children after taking cetirizine at a dose of 5 mg, C_max in plasma is reached after 1 hour and is 275 ng/ml. In children, V_d after taking 5 mg is approximately 17 L.

In children from 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 from 6 to 12 years is 6 hours, from 2 to 6 years – 5 hours.

Indications

For adults and children 6 years 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.

ICD codes

Dosage Regimen

Adults

10 mg (1 tablet) once daily.

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 impairment” below).

Patients with renal impairment

Since Cetirizine is eliminated from the body mainly by the kidneys (see the “Pharmacokinetics” section), if alternative treatment is not possible, the dosage regimen of the drug should be adjusted in patients with renal failure depending on renal function (glomerular filtration rate [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 (ml/min) = [140 – age (years)] × body weight (kg)/72 × serum Cr (mg/dl)

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

Table 1. Dosing in adult patients with renal impairment

Patients with hepatic impairment

In patients with hepatic impairment only, no adjustment of the dosage regimen is required.

In patients with both hepatic and renal impairment, dose adjustment is recommended (see table above).

Children

Children under 6 years of age

Cetirizine in 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. If it is necessary to use cetirizine in children under 6 years of age, cetirizine preparations in the form of oral drops should be used.

Children from 6 to 12 years

10 mg (1 tablet) once daily. The duration of treatment should not exceed 4 weeks. Alternatively, the dose can be divided into two doses (1/2 tablet in the morning and evening).

Children over 12 years

10 mg (1 tablet) once daily.

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

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

Method of administration

Orally.

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

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

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

Adverse Reactions

Summary of the safety profile

Data from clinical studies

Results from clinical studies have demonstrated that the use of cetirizine at recommended doses leads to the development of minor undesirable effects on the CNS, including drowsiness, fatigue, dizziness and headache. In some cases, paradoxical stimulation of the CNS has been reported.

Although Cetirizine is a selective blocker of peripheral histamine H₁– receptors 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 levels of liver enzymes and bilirubin have been reported. In most cases, adverse events resolved after discontinuation of cetirizine.

Summary of adverse reactions

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

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 1.0% 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-marketing experience

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

The frequency of adverse events was determined as follows: very common (≥1/10); common (≥1/100, but <1/10); uncommon (≥1/1000, but <1/100); rare (≥1/10000, but <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Description of selected adverse reactions

After discontinuation of cetirizine, cases of itching (including intense itching) and/or urticaria have been noted.

Children

Data from clinical studies

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• hypersensitivity to cetirizine, hydroxyzine, or other piperazine derivatives, or to any of the excipients of the drug;
• end-stage renal failure (GFR <15 ml/min).

With caution

• chronic renal failure (dose adjustment is required for GFR ≥15 ml/min);
• elderly patients (possible decrease in glomerular filtration rate);
• epilepsy and patients with increased seizure predisposition;
• Patients with predisposing factors for urinary retention;
• With simultaneous use of alcohol or drugs that depress the CNS (see section “Drug Interactions”);
• pregnancy;
• breastfeeding period.

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, embryonic 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 childbirth.

The drug should be used with caution during pregnancy if the intended benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

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

The drug should be used with caution during breastfeeding if the intended 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

No dose adjustment is required for patients with impaired liver function and normal renal function.

Use in Renal Impairment

Contraindicated in end-stage renal failure (GFR < 15 ml/min).

Use with caution in chronic renal failure – dose adjustment is required for GFR ≥15 ml/min.

Pediatric Use

Contraindicated in children under 6 years of age (for this dosage form).

Geriatric Use

The drug should be prescribed with caution to elderly patients (due to age-related decrease in glomerular filtration).

Special Precautions

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

In patients with renal failure, the drug dosage regimen should be adjusted (see section “Dosage Regimen”).

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

It is recommended to exercise caution when using cetirizine simultaneously with alcohol or drugs that depress the CNS, because 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 because histamine H₁-receptor blockers inhibit the development of skin allergic reactions.

After discontinuation of cetirizine, itching and/or urticaria may appear, even if these symptoms were absent at the beginning of treatment. In some cases, the symptoms may be intense and require resumption of cetirizine intake. The symptoms disappear upon resumption of cetirizine intake.

Excipients

The drug contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and machinery

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

Overdose

Symptoms symptoms observed after obvious drug overdose were associated with an effect on the CNS or a possible anticholinergic effect.

Symptoms observed after taking at least five times the recommended daily dose included the following: confusion, diarrhea, fatigue, headache, malaise, mydriasis, itching, restlessness, sedation, drowsiness, 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 studies, Cetirizine does not affect the protein binding effect 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. Furthermore, C_max values in blood plasma increased by up to 7.7% and 6.4% for cetirizine and theophylline, respectively. Simultaneously, 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, prior treatment with cetirizine did not significantly affect 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 of 16 psychometric tests.

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

The extent of absorption of cetirizine is not reduced when taken concomitantly 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 cetirizine administration.

Storage Conditions

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

Shelf Life

Shelf life – 3 years.

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.