CETIRIZINE

INSTRUCTIONS FOR MEDICINAL USE OF CETIRIZINE

Composition:

Active substance: cetirizine dihydrochloride;

1 tablet contains 10 mg of cetirizine dihydrochloride;

Excipients: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E 171), polyethylene glycol (macrogol) 6000, propylene glycol (1,2-propanediol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round-shaped, biconvex tablets with a score line on one side, coated with a film.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives.

ATC code R06A E07.

Pharmacological Properties

Pharmacodynamics

Cetirizine, a metabolite of hydroxyzine formed in the human body, is a potent selective antagonist of peripheral H1-receptors. In vitro binding studies showed no affinity for receptors other than H1-receptors. In addition to its H1-receptor antagonistic activity, cetirizine exerts anti-allergic effects: administration of 10 mg once or twice daily inhibits the late-phase recruitment of inflammatory cells, particularly eosinophils, into the skin and conjunctiva of individuals exposed to allergens. At a daily dose of 30 mg, it inhibits eosinophil influx into bronchoalveolar fluid during the late-phase bronchoconstriction induced by inhaled allergens in patients with bronchial asthma. Furthermore, cetirizine inhibits the late-phase inflammatory response induced by intradermal kallikrein administration in patients with chronic urticaria. It also reduces the expression of adhesion molecules such as ICAM-1 and VCAM-1, which are markers of allergic inflammation.

It has been reported that cetirizine at doses of 5 and 10 mg inhibits the development of wheal and flare reactions induced by high concentrations of histamine in the skin. Onset of action after a single 10 mg dose occurs within 20 minutes to 1 hour. The effect lasts for at least 24 hours after a single dose. In children aged 5 to 12 years, no tolerance to the antihistaminic effect of cetirizine (suppression of wheal and flare reactions) was observed. When cetirizine treatment is discontinued after repeated administration, normal skin reactivity to histamine recovers within 3 days.

In patients with allergic rhinitis and concomitant bronchial asthma (mild to moderate severity), administration of cetirizine 10 mg once daily improved rhinitis symptoms and had no effect on lung function. This confirms the safety of cetirizine use in patients with mild to moderate bronchial asthma.

It has been reported that administration of cetirizine at a high daily dose of 60 mg did not cause statistically significant QT interval prolongation.

When administered at recommended doses, cetirizine improves the condition of patients with perennial and seasonal allergic rhinitis.

Pharmacokinetics

Peak plasma concentration at steady state is approximately 300 ng/mL and is reached within 1.0 ± 0.5 hours. After administration of 10 mg daily for 10 days, no accumulation was observed. The distribution of pharmacokinetic parameters such as maximum plasma concentration (Cmax) and area under the pharmacokinetic curve (AUC) is consistent among volunteers.

The extent of cetirizine absorption is not reduced when taken with food, although the rate of absorption is slowed. The bioavailability of cetirizine in solution, capsule, or tablet form is similar.

The apparent volume of distribution is 0.50 L/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not affect warfarin binding to plasma proteins.

Cetirizine undergoes minimal first-pass metabolism. Approximately two-thirds of the drug is excreted unchanged in urine. The terminal elimination half-life is approximately 10 hours.

Over the dose range of 5 to 60 mg, the pharmacokinetics of cetirizine are linear.

Special patient populations

Elderly patients: after a single 10 mg oral dose, elimination half-life increased by approximately 50% and clearance decreased by 40% in 16 elderly patients compared to healthy adults. The reduced clearance in these elderly volunteers is likely related to decreased renal function.

Children, infants, and young children: elimination half-life of cetirizine is approximately 6 hours in children aged 6 to 12 years, and 5 hours in children aged 2 to 6 years. In infants and young children (6 to 24 months), this value is reduced to 3.1 hours.

Patients with renal impairment: pharmacokinetic parameters of the drug were similar in patients with mild renal impairment (creatinine clearance >40 mL/min) and healthy volunteers. In patients with moderate renal impairment, elimination half-life increased threefold and clearance decreased by 70% compared to healthy volunteers.

In patients undergoing hemodialysis (creatinine clearance <7 mL/min), a single 10 mg oral dose of cetirizine resulted in a threefold increase in elimination half-life and a 70% reduction in clearance compared to healthy subjects. Cetirizine is poorly removed by hemodialysis. Dose adjustment is required for patients with moderate to severe renal impairment (see section "Dosage and Administration").

Patients with hepatic impairment: in patients with chronic liver disease (hepatocellular, cholestatic disorders, or biliary cirrhosis) who received a single 10 or 20 mg dose of cetirizine, elimination half-life increased by 50% and clearance decreased by 40% compared to healthy subjects. Dose adjustment in patients with hepatic impairment is necessary only if there is concomitant renal impairment.

Clinical characteristics.

Indications. The medicinal product is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria in adults and children over 6 years of age.

Contraindications. Hypersensitivity to the active substance or to any of the excipients of the medicinal product, to hydroxyzine, or to any piperazine derivative.

Severe renal impairment with creatinine clearance less than 10 ml/min.

Interaction with other medicinal products and other types of interactions. Due to the pharmacokinetics, pharmacodynamics, and tolerability profile of cetirizine, the occurrence of any type of interaction when taking this antihistamine is unlikely. In particular, drug interaction studies have shown neither pharmacodynamic nor any clinically significant pharmacokinetic interaction when administered concomitantly with pseudoephedrine or theophylline (400 mg/day).

In sensitive patients, concomitant intake of alcohol or other central nervous system depressants may lead to additional reduction in alertness and impaired performance, although cetirizine does not potentiate the effect of alcohol (blood concentration of 0.5 g/l).

Special precautions for use.

Alcohol. No clinically significant interactions with alcohol (at blood alcohol levels of 0.5 g/L) have been observed when the drug is used at therapeutic doses. However, caution should be exercised when using this medicinal product concomitantly with alcohol.

Increased risk of urinary retention. Caution should be exercised when administering the drug to patients predisposed to urinary retention (e.g., in spinal cord lesions, benign prostatic hyperplasia), as cetirizine increases the risk of urinary retention.

Skin reactions. Pruritus and/or urticaria may occur after discontinuation of cetirizine, even if these symptoms were not present before initiation of treatment. In some cases, symptoms may be severe and may require resumption of treatment after discontinuation. These symptoms usually resolve upon resumption of treatment.

Patients at risk of seizures. The drug should be prescribed with caution in patients with epilepsy or those prone to seizures.

Skin allergy tests. The use of antihistamines may influence the results of skin allergy tests; therefore, a washout period of at least three days should be observed before conducting such tests.

Food intake. Food does not affect the extent of cetirizine absorption, but it reduces the rate of absorption.

Excipients. The medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy. Prospective data on the effects of cetirizine during pregnancy do not indicate a potential toxicity for mother or embryo/fetus above background levels. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Nevertheless, caution should be exercised when prescribing cetirizine to pregnant women.

Breastfeeding period. Cetirizine passes into breast milk. The risk of adverse effects in breastfed infants cannot be excluded. Cetirizine concentrations in breast milk range from 25–90% of plasma concentrations, depending on the time interval after drug administration. Therefore, cetirizine should be used with caution in breastfeeding women.

Fertility. Data on fertility in humans are limited; however, no safety concerns have been identified. Animal studies have shown no risks to human reproductive function.

Ability to influence reaction speed when driving or operating machinery. Objective assessments of the ability to drive, operate machinery, and degree of drowsiness have shown no clinically significant impairment when the drug is used at the recommended dose of 10 mg. However, patients who experience drowsiness should refrain from driving, operating machinery, or engaging in other potentially hazardous activities. Patients should not exceed the recommended doses and should consider their individual response to the drug.

Method of Administration and Dosage

Children aged 6 to 12 years: 5 mg twice daily (½ tablet twice daily).

Adults and children aged 12 years and older: 10 mg once daily (1 tablet once daily).

Tablets should be swallowed with a glass of water.

Elderly patients: if renal function is normal, dosage reduction is not required.

Patients with moderate to severe renal impairment: data on the benefit-risk balance in patients with renal impairment are lacking. Since cetirizine is predominantly excreted by the kidneys (see section "Pharmacological properties"), when no alternative treatment method can be used, dosing intervals should be individually adjusted. Dose adjustment should be made according to the table below. To use this dosing table, the patient's creatinine clearance (CC) in mL/min must be calculated. It can be calculated using the formula, knowing the serum creatinine level in mg/dL:

Dosage adjustment of the drug for adult patients with renal function impairment

For children with impaired kidney function, the dose should be individually adjusted based on each patient's renal clearance value, as well as their age and body weight.

Patients with hepatic impairment: dose adjustment is not required for patients who have only hepatic impairment.

Patients with concomitant hepatic and renal impairment: dose adjustment is recommended (see above, "Patients with moderate to severe renal impairment").

The duration of treatment is determined individually by the physician, depending on the course of the disease.

Children. The medicinal product can be administered to children aged 6 years and older. The tablet with film coating is not recommended for children under 6 years of age, as this dosage form does not allow for appropriate dose selection.

Overdose.

Symptoms. Symptoms observed in cases of cetirizine overdose are mainly related to its effects on the central nervous system or manifestations resembling anticholinergic effects.

Adverse events reported after ingestion of doses at least five times higher than the recommended daily dose include: confusion, diarrhea, vertigo, increased fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedative effect, somnolence, stupor, tachycardia, tremor, and urinary retention.

Treatment. There is no known specific antidote for cetirizine. In case of overdose, symptomatic or supportive therapy is recommended. Gastric lavage should be performed as soon as possible. Removal of cetirizine by dialysis is ineffective.

Adverse Reactions

Clinical studies have shown that the use of cetirizine at recommended doses may cause minor undesirable effects on the central nervous system, including somnolence, increased fatigue, vertigo, and headache. In some cases, paradoxical stimulation of the central nervous system has been reported.

Although cetirizine is a selective antagonist of peripheral H₁-receptors without significant anticholinergic activity, isolated cases of urinary retention, accommodation disorders, and dry mouth have been reported.

Cases of hepatic function abnormalities with increased levels of liver enzymes in combination with elevated bilirubin levels have been reported. These symptoms mostly resolved after discontinuation of treatment with cetirizine dihydrochloride.

In double-blind, placebo-controlled clinical or pharmacokinetic studies comparing cetirizine with placebo or other antihistamines at recommended doses (10 mg cetirizine per day), with available quantitative safety data, more than 3,200 patients received cetirizine. In placebo-controlled studies, the following adverse reactions were observed with cetirizine 10 mg in at least 1.0% of patients:

Although somnolence occurred statistically more frequently than in the placebo group, in most cases its severity was mild or moderate. Other studies have shown that administration of the drug at the recommended daily doses did not impair daily performance in healthy young volunteers.

The following adverse drug reactions, with a frequency of 1% or higher, were observed in children aged 6 months to 12 years who participated in placebo-controlled clinical or pharmacokinetic studies:

Observations during the use of the medicinal product

In addition to adverse reactions reported during clinical trials, the following adverse reactions have been reported after the initiation of the medicinal product use.

Adverse reactions are listed by system organ class (according to MedDRA — Medical Dictionary for Regulatory Activities) and frequency of occurrence.

Frequency of occurrence is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be determined from the available data).

Description of individual adverse reactions

Pruritus (intense itching) and/or urticaria have been reported after discontinuation of cetirizine.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 10 tablets per blister, 2 or 3 blisters per carton.

Availability category. Over-the-counter.

Manufacturer. JSC "Lubnifarm".

Manufacturer's address and place of business. 16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.