Cetirizine-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETIRIZINE-ASTRAPHARM (CETIRIZINE-ASTRAPHARM)

Composition:

Active substance: cetirizine;

One tablet contains 10 mg of cetirizine dihydrochloride calculated as 100% substance;

Excipients: microcrystalline cellulose; lactose monohydrate; magnesium stearate; crospovidone; colloidal anhydrous silicon dioxide; coating "Selacoat™" (hypromellose, polyethylene glycol (macrogol) 6000, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets. A two-layer cross-section is visible upon breaking.

Pharmacotherapeutic group.

Antihistamines for systemic use. Piperazine derivatives. ATC code R06AE07.

Pharmacological Properties

Pharmacodynamics

Cetirizine, a human metabolite of hydroxyzine, is a potent, selective antagonist of peripheral H1-receptors. In vitro binding studies have shown 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, in the skin and conjunctiva of individuals challenged with antigen. At a daily dose of 30 mg, it inhibits eosinophil influx in bronchoalveolar lavage 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 administration of kallikrein 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.

Cetirizine at doses of 5 and 10 mg has been reported to inhibit histamine-induced wheal and flare reactions in the skin, even at very high histamine concentrations. The onset of action after a single 10 mg dose occurs within 20 minutes to 1 hour. The effect lasts at least 24 hours after a single dose. In children aged 5 to 12 years, no tachyphylaxis to the antihistaminic effect of cetirizine (inhibition of wheal and flare) has been observed. When cetirizine treatment is discontinued after repeated administration, normal skin reactivity to histamine is restored within 3 days.

In patients with allergic rhinitis and concomitant mild to moderate bronchial asthma, administration of cetirizine 10 mg once daily improved rhinitis symptoms without affecting 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 does not cause statistically significant QT interval prolongation.

When administered at recommended doses, cetirizine improves symptoms in patients with perennial and seasonal allergic rhinitis.

Pharmacokinetics

The steady-state peak plasma concentration is approximately 300 ng/mL, reached within 1±0.5 hours. No accumulation of cetirizine was observed after administration of 10 mg daily for 10 days. The distribution of pharmacokinetic parameters such as peak concentration and area under the concentration-time curve is consistent among healthy volunteers.

The extent of cetirizine absorption is not reduced when taken with food, although the rate of absorption is decreased. The bioavailability is similar when cetirizine is administered as a solution, capsules, or tablets. The apparent volume of distribution is 0.5 L/kg. Plasma protein binding of cetirizine is 93±0.3%. Cetirizine does not affect the protein binding of warfarin.

Cetirizine undergoes minimal first-pass metabolism. Approximately two-thirds of the dose is excreted unchanged in urine. The terminal elimination half-life is approximately 10 hours. Cetirizine exhibits linear kinetics over the dose range of 5 to 60 mg.

Special Patient Groups

Elderly patients: After a single 10 mg oral dose, the elimination half-life increased by nearly 50%, and clearance decreased by approximately 40% in elderly subjects compared to younger individuals. The reduced clearance of cetirizine in elderly volunteers was associated with impaired renal function.

Children: The elimination half-life of cetirizine is approximately 6 hours in children aged 6–12 years and 5 hours in children aged 2–6 years. In children aged 6 to 24 months, the half-life is shortened to 3.1 hours.

Patients with renal impairment: The pharmacokinetics 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, the elimination half-life increased threefold and clearance decreased by 70% compared to healthy volunteers. In patients undergoing hemodialysis (creatinine clearance 7 mL/min), after a single 10 mg oral dose of cetirizine, the elimination half-life increased threefold and clearance decreased by 70% compared to healthy volunteers. Cetirizine is poorly removed by hemodialysis. Dose adjustment is required for patients with moderate to severe renal impairment.

Patients with hepatic impairment: In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis), following a single 10 or 20 mg dose of cetirizine, the elimination half-life increased by 50% and clearance decreased by 40% compared to healthy volunteers. Dose adjustment in patients with hepatic impairment is required only if they also have concomitant renal impairment.

Clinical characteristics.

Indications.

Cetirizine is indicated in adults and children aged 6 years and older:

• for relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis,
• for relief of symptoms of chronic idiopathic urticaria.

Contraindications.

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

End-stage renal disease with a calculated glomerular filtration rate (cGFR) below 15 mL/min.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take cetirizine in the form of coated tablets.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interaction studies have been conducted with cetirizine and antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, and azithromycin – no pharmacokinetic interactions were observed. In a multiple-dose study of theophylline (400 mg once daily) and cetirizine, a slight (16%) reduction in cetirizine clearance was observed, while the disposition of theophylline was not affected by concomitant administration of cetirizine.

Studies on the concomitant use of cetirizine with cimetidine, glipizide, diazepam, and pseudoephedrine showed no evidence of adverse pharmacodynamic interactions.

Studies on the use of cetirizine with antipyrine, azithromycin, erythromycin, ketoconazole, theophylline, and pseudoephedrine showed no evidence of adverse clinical interactions. Furthermore, concomitant administration of cetirizine with macrolides or ketoconazole has never led to clinically significant changes in ECG.

In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir disposition was slightly reduced (–11%) with concomitant cetirizine administration.

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

There are no data on enhanced sedative effects when cetirizine is used concomitantly with sedatives at therapeutic doses. However, concomitant use of sedatives should be avoided during treatment with this medicinal product.

Special precautions for use

In therapeutic doses, no clinically significant interaction with alcohol (at blood alcohol levels of 0.5 g/L) has been demonstrated. Nevertheless, caution is recommended when alcohol is consumed concomitantly.

Patients with risk factors for urinary retention (e.g., spinal cord lesions, benign prostatic hyperplasia) should be cautious, as cetirizine may increase the risk of urinary retention.

Caution is recommended in patients with epilepsy or those at risk of seizures.

Skin allergy tests are suppressed by antihistamines; therefore, a washout period (3 days) is required before testing.

Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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

Use during pregnancy or breastfeeding

Pregnancy. There is insufficient data on the effects of the drug during pregnancy. The drug should be prescribed to pregnant women only if, in the opinion of the physician, the benefit outweighs the potential risk to the fetus.

Breastfeeding period. Cetirizine passes into breast milk at concentrations ranging from 25–90% of plasma levels, depending on the time interval after drug administration. Therefore, the drug should be prescribed with caution to breastfeeding women.

Ability to influence reaction rate when driving or operating machinery

Objective assessments of driving ability, presence of hidden drowsiness, and performance on assembly-line work have shown no clinically significant effects with the recommended 10 mg dose of the drug.

Patients intending to drive, engage in potentially hazardous activities, or operate machinery should not exceed the recommended dose and should consider their individual response to the drug. In sensitive individuals, concomitant use of the drug with other central nervous system depressants may additionally impair concentration and reduce performance.

Method of administration and dosage.

Tablets should be swallowed with a glass of water.

Children aged 6 to 12 years: 5 mg* (half a tablet) twice daily.

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

Elderly patients: dose adjustment in elderly patients is not required provided normal renal function.

Patients with moderate to severe renal impairment: data on the benefit/risk ratio of cetirizine in patients with renal impairment are limited. Since cetirizine is primarily excreted by the kidneys, when alternative treatment options are not available, the dosing intervals must be individually adjusted. Dose adjustment should be made according to the table below. To use this dosing table, the patient's creatinine clearance (CCr) in mL/min must be calculated using the serum creatinine level (mg/dL) and the following formula:

CCr = [140 – age (years)] × body weight (kg) (×0.85 for women)

72 × serum creatinine (mg/dL)

Dose adjustment for adult patients with renal impairment

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

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

* administer cetirizine-containing drugs at the appropriate dosage.

Children

The use of the medicinal product in tablet form is not recommended for children under 6 years of age, as this pharmaceutical form does not allow for the necessary dose adjustment.

Overdose.

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

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

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

Adverse Reactions

Clinical studies have shown that cetirizine at the recommended dosage has minimal adverse effects on the central nervous system (CNS), including somnolence, fatigue, dizziness, and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H1-receptors and is relatively free of anticholinergic activity, isolated cases of urinary retention, disturbances of eye accommodation, and dry mouth have been reported.

Cases of hepatic function impairment with elevated liver enzymes, sometimes accompanied by increased bilirubin levels, have been reported. These effects are mostly reversible upon discontinuation of cetirizine dihydrochloride.

Double-blind, placebo-controlled clinical trials comparing cetirizine with placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), from which quantitative safety data are available, included over 3,200 subjects exposed to cetirizine.

In placebo-controlled studies, the following adverse reactions associated with cetirizine 10 mg were reported at an incidence rate of 1.0% or higher:


Note: The list of specific adverse reactions is implied to follow here based on the original structure.

Although statistically more frequent than with placebo, drowsiness was in most cases mild to moderate. Objective tests from other studies have shown that normal everyday activities are not affected at the recommended daily dose in healthy young volunteers.

Pediatric population

Adverse reactions with an incidence of 1% or higher in children aged 6 months to 12 years included in placebo-controlled clinical trials:

Post-marketing experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse effects have been reported in post-marketing experience.

Adverse effects are described according to MedDRA system organ class and approximate frequency based on post-marketing experience.

Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

• Blood and lymphatic system disorders

Very rare: thrombocytopenia

• Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactic shock

• Metabolism and nutrition disorders

Frequency not known: increased appetite

• Psychiatric disorders

Uncommon: excitement

Rare: aggression, confusion, depression, hallucinations, insomnia

Very rare: tics

Frequency not known: suicidal thoughts, nightmares

• Nervous system disorders

Uncommon: paraesthesia

Rare: convulsions

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia

Frequency not known: amnesia, memory impairment

• Eye disorders

Very rare: accommodation disorders, blurred vision, oculogyric crisis

• Ear and labyrinth disorders

Frequency not known: dizziness

• Cardiac disorders

Rare: tachycardia

• Gastrointestinal disorders

Uncommon: diarrhoea

• Hepatobiliary disorders

Rare: liver function abnormalities (increased levels of transaminases, alkaline phosphatase, γ-GT and bilirubin)

Frequency not known: hepatitis

• Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash

Rare: urticaria

Very rare: angioedema, fixed drug eruption

Frequency not known: acute generalized exanthematous pustulosis

• Musculoskeletal and connective tissue disorders

Frequency not known: arthralgia, myalgia

• Renal and urinary disorders

Very rare: dysuria, enuresis

Frequency not known: urinary retention

• General disorders and administration site conditions

Uncommon: asthenia, malaise

Rare: oedema

• Investigations

Rare: increased body weight.

Description of selected adverse reactions

After discontinuation of cetirizine, pruritus (intense itching) and/or urticaria have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 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 2 blisters in a carton.

Classification.

Over-the-counter (OTC).

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address and location of its operations.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Region, 08132, Ukraine.