L-cet®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT L-ЦЕТÒ (L-CET®)

Composition:

Active substance: levocetirizine dihydrochloride;

2.5 mg of levocetirizine dihydrochloride in 5 ml of syrup;

Excipients: glycerin, propylene glycol, sodium methylparahydroxybenzoate (E 219), sodium propylparahydroxybenzoate (E 217), sucrose, glacial acetic acid, sodium acetate trihydrate, peppermint flavoring, banana flavoring, purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: colorless transparent viscous liquid with a characteristic odor.

Pharmacotherapeutic group.

Antihistamines for systemic use. Piperazine derivatives.

ATC code R06AE09.

Pharmacological Properties.

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the group of competitive antagonists of peripheral H1-histamine receptors. Its pharmacological action is due to blockade of H1-histamine receptors. Binding studies have demonstrated that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). The affinity of levocetirizine is twice that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115±38 minutes. After single administration, receptor binding of levocetirizine was 90% at 4 hours and 57% at 24 hours. Pharmacodynamic studies in healthy volunteers have shown that half the dose of levocetirizine has comparable activity to cetirizine both in skin and nasal responses.

Pharmacokinetics.

The pharmacokinetics of levocetirizine are linear, dose- and time-independent, and exhibit low inter-patient variability. The pharmacokinetic profile after administration of a single enantiomer is identical to that of cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption. Levocetirizine is rapidly and extensively absorbed after oral administration. Maximum plasma concentration is reached within 0.9 hours after intake. Steady-state is achieved within 2 days. Maximum concentration (Cmax) typically reaches 270 ng/mL and 308 ng/mL after single and multiple doses, respectively, of the 5 mg once-daily regimen. The extent of absorption is independent of dose. Food does not affect the overall extent of absorption, but reduces the Cmax and delays its time to peak.

Distribution. There are no data available on the distribution of the drug in human tissues or on the passage of levocetirizine across the blood-brain barrier. In animal studies, the highest concentrations were observed in the liver and kidneys, while the lowest were found in central nervous system tissues. The distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg. Plasma protein binding in humans is 90%.

Metabolism. In humans, less than 14% of the dose undergoes metabolism, suggesting minimal impact from genetic polymorphisms or concomitant use of hepatic enzyme inhibitors. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by CYP3A4, while aromatic oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 at concentrations significantly exceeding the maximum plasma levels achieved after a 5 mg oral dose. Due to its low metabolic rate and lack of inhibitory potential, drug interactions involving levocetirizine (either as victim or perpetrator) are unlikely.

Excretion. The drug is eliminated via two pathways: glomerular filtration and active tubular secretion. The elimination half-life (T1/2) in plasma of adults is 7.9±1.9 hours. The half-life is shorter in younger children. Mean apparent total clearance in adults is 0.63 mL/min/kg. The majority of levocetirizine and its metabolites are excreted in urine (on average, 85.4% of the administered dose). Only 12.9% of the administered dose is excreted in feces.

Special Populations

Renal Impairment.

Apparent total clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing interval should be adjusted according to creatinine clearance. In anuric patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to individuals without such impairment. Less than 10% of levocetirizine is removed during a standard 4-hour hemodialysis session.

Children.

A comparative cross-over study of a single 5 mg oral dose of levocetirizine showed that Cmax and AUC values in 14 children aged 6 to 11 years (body weight 20–40 kg) were approximately twice those observed in healthy adult patients. The mean body-weight-normalized Cmax, reached at approximately 1.2 hours, was 450 ng/mL. Total clearance was 30% higher and elimination half-life 24% shorter in the pediatric population compared to adults. Specific pharmacokinetic studies in children under 6 years of age have not been conducted. A retrospective population pharmacokinetic analysis was performed in 323 patients (181 children aged 1 to 5 years, 18 children aged 6 to 11 years, and 124 adults aged 18 to 55 years) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data from this analysis indicate that administration of 1.25 mg levocetirizine once daily in children aged 6 months to 5 years is expected to result in plasma concentrations similar to those in adults receiving 5 mg levocetirizine once daily.

Elderly Patients.

Pharmacokinetic data in elderly patients are limited. After repeated oral administration of 30 mg levocetirizine once daily for 6 days in 9 elderly subjects (aged 65–74 years), total clearance was approximately 33% lower than in younger adults. It has been shown that the disposition of racemic cetirizine depends on renal function rather than age. This conclusion also applies to levocetirizine, as both levocetirizine and cetirizine are predominantly excreted in urine. Therefore, in elderly patients, the dose of levocetirizine should be adjusted according to renal function.

Gender

Pharmacokinetic results from 77 patients (40 males and 37 females) were evaluated for potential gender effects. The elimination half-life was slightly shorter in females (7.08 ± 1.72 hours) than in males (8.62 ± 1.84 hours); however, oral clearance normalized to body weight in females (0.67 ± 0.16 mL/min/kg) was comparable to that in males (0.59 ± 0.12 mL/min/kg). For males and females with normal renal function, the same daily doses and dosing intervals can be used.

Race

The effect of race on levocetirizine has not been studied. Since levocetirizine is primarily renally excreted and significant racial differences in creatinine clearance are not expected, pharmacokinetic characteristics of levocetirizine are not anticipated to differ by race. No racial differences have been observed in the kinetics of racemic cetirizine.

Hepatic Impairment

The pharmacokinetics of levocetirizine in patients with hepatic impairment have not been studied. In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) who received a single dose of 10 or 20 mg of racemic cetirizine, an increase in elimination half-life by 50% and a 40% reduction in clearance were observed compared to healthy subjects.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria in adults and children aged 2 years and older.

Contraindications.

Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, or to any other piperazine derivatives, as well as to any of the excipients of the medicinal product.

Severe form of chronic renal insufficiency (creatinine clearance < 15 mL/min) (requiring dialysis).

Interaction with other medicinal products and other forms of interaction.

Interaction studies with levocetirizine have not been conducted (including studies on interactions with CYP3A4 inducers); studies with the cetirizine racemate showed absence of clinically significant adverse interactions (with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, and pseudoephedrine). A slight reduction in cetirizine clearance (16%) was observed in a multiple-dose study with concomitant theophylline administration (400 mg once daily); theophylline distribution was not altered when co-administered with cetirizine.

In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by 40%, while ritonavir exposure changed insignificantly (-11%).

The extent of levocetirizine absorption is not reduced when taken with food, although the rate of absorption is decreased.

Concomitant use of cetirizine or levocetirizine with alcohol or other central nervous system depressants in susceptible patients may result in additional impairment of alertness and ability to perform tasks.

Special precautions for use

During levocetirizine therapy, alcohol consumption should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the medicinal product to patients with factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), it should be taken into account that levocetirizine may increase the risk of urinary retention.

Caution should be exercised when prescribing the medicinal product to patients with epilepsy or those at risk of seizures, as levocetirizine may exacerbate seizures.

Antihistamines suppress the response to skin allergy tests; therefore, administration of the medicinal product should be discontinued 3 days prior to testing (elimination period).

Pruritus may occur after discontinuation of levocetirizine, even if these symptoms were not present before treatment initiation. These symptoms may resolve spontaneously. In some cases, symptom severity may be significant, requiring resumption of the medicinal product. After resuming treatment, symptoms should resolve.

Paediatric population

Available clinical data on the use of levocetirizine in children aged 6 months to 12 years are insufficient to support its use in infants and children under 2 years of age.

Excipients

The medicinal product contains sucrose; therefore, if you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

The medicinal product contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). However, extensive data on cetirizine, the racemate of levocetirizine (more than 1000 pregnancy outcomes), indicate no evidence of malformative or fetal/neonatal toxicity. Animal studies have not shown any direct or indirect harmful effects of levocetirizine on pregnancy, embryonic/fetal development, delivery, or postnatal development.

Levocetirizine may be considered for use during pregnancy, if necessary.

Breastfeeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human milk. Therefore, excretion of levocetirizine into breast milk is likely. Adverse reactions related to levocetirizine may occur in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to breastfeeding women.

Fertility

There are no clinical data on the effect of levocetirizine on fertility.

Ability to affect reaction speed when driving or operating machinery

Comparative clinical trials have not demonstrated any evidence that levocetirizine at the recommended dose impairs mental alertness, reaction ability, or the ability to drive vehicles or operate machinery.

However, some patients may experience somnolence, fatigue, or asthenia during levocetirizine treatment. Therefore, patients intending to drive, engage in potentially hazardous activities, or operate machinery should consider their individual response to the medicinal product.

Method of Administration and Dosage.

The medication should be administered orally to adults and children aged 2 years and older, regardless of food intake.

Dosage

Adults and children aged 12 years and older.

The daily dose is 5 mg (10 ml of syrup) once daily.

Elderly patients.

Dosage adjustment is recommended for elderly patients with moderate to severe renal impairment (see section "Renal Insufficiency").

Renal Insufficiency.

Dosing intervals should be individually adjusted according to renal function (eGFR – estimated glomerular filtration rate). Refer to the table below and adjust the dose as indicated.

Table. Dose adjustment for patients with impaired renal function.

For children with impaired renal function, the dose should be individually adjusted according to the patient's renal clearance and body weight.

There are no specific data available on the use of the drug in children with impaired renal function.

Hepatic impairment.

Dose adjustment is not required in patients with isolated hepatic impairment. In patients with both hepatic and renal impairment, dosage adjustment should be performed according to the table above.

Children

Children aged 6 to 12 years: the recommended daily dose is 5 mg (10 mL of syrup) once daily.

Children aged 2 to 6 years: the recommended daily dose is 2.5 mg, divided into two doses of 1.25 mg (2.5 mL of syrup twice daily).

Duration of treatment.

For patients with intermittent allergic rhinitis (duration of symptoms less than 4 days per week or less than 4 weeks per year), treatment should be administered according to the course of the disease and medical history: treatment may be discontinued if symptoms resolve and restarted upon recurrence of symptoms. For persistent allergic rhinitis (duration of symptoms more than 4 days per week or more than 4 weeks per year) during periods of allergen exposure, continuous therapy may be considered. There is clinical experience with levocetirizine use for at least a 6-month treatment period. In chronic conditions (chronic allergic rhinitis, chronic urticaria), the treatment duration may extend up to 1 year (data are available from clinical studies using cetirizine (racemate)).

Children.

Use in children under 2 years of age is not recommended due to limited data in this age group.

The drug may be used in children aged 2 years and older.

Overdose.

Symptoms.

Symptoms of overdose in adults may include somnolence. In children, initial symptoms may include excitation and increased irritability, followed by somnolence.

Treatment.

There is no specific antidote for levocetirizine. In case of overdose symptoms, symptomatic and supportive treatment is recommended. Gastric lavage should be considered shortly after drug ingestion. Hemodialysis is not effective for removing levocetirizine from the body.

Adverse Reactions.

Clinical Studies

Adults and adolescents over 12 years of age.

In therapeutic studies involving men and women aged 12 to 71 years, 15.1% of patients in the 5 mg levocetirizine group experienced at least one adverse reaction compared to 11.3% in the placebo group. 91.6% of these adverse reactions were mild to moderate in intensity.

In therapeutic studies, the discontinuation rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Therapeutic clinical studies with levocetirizine included 935 patients who received the drug at the recommended dose of 5 mg once daily. In this population, the following adverse reactions occurred with an incidence of 1% or greater (common: ≥1/100 to <1/10) during treatment with levocetirizine 5 mg or placebo:

Uncommonly (≥ 1/1000, < 1/100), asthenia and abdominal pain have also been reported.

The frequency of sedative adverse reactions such as somnolence, fatigue, and asthenia was generally higher (8.1%) with levocetirizine 5 mg compared to placebo (3.1%).

Children

In two placebo-controlled studies involving pediatric patients aged 6 to 11 months and those aged 1 to 6 years, 159 subjects received levocetirizine 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. During treatment with levocetirizine or placebo, the incidence of adverse reactions was 1% or higher.

Double-blind, placebo-controlled studies were conducted in children aged 6 to 12 years, in which 243 children received 5 mg of levocetirizine once daily for variable periods ranging from less than 1 week to 13 weeks. The following adverse reactions were reported with an incidence of 1% or greater for either levocetirizine or placebo.

Post-marketing experience

The frequency is classified 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 the available data).

Immune system disorders: frequency not known: hypersensitivity, including anaphylaxis.

Nutritional and metabolism disorders: frequency not known: increased appetite.

Nervous system disorders: frequency not known: somnolence, headache, increased fatigue, weakness, asthenia, seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Psychiatric disorders: frequency not known: sleep disorders, excitation, hallucinations, depression, aggression, insomnia, suicidal thoughts, nightmares.

Ear and labyrinth disorders: frequency not known: vertigo.

Eye disorders: frequency not known: visual disturbances, blurred vision, nystagmus.

Cardiac disorders: frequency not known: palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: frequency not known: dyspnoea.

Gastrointestinal disorders: frequency not known: diarrhoea, vomiting, constipation, dry mouth, nausea, abdominal pain.

Hepatobiliary disorders: frequency not known: hepatitis.

Renal and urinary disorders: frequency not known: dysuria, urinary retention.

Skin and subcutaneous tissue disorders: frequency not known: angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: frequency not known: myalgia, arthralgia.

General disorders and administration site conditions: frequency not known: oedema.

Investigations: frequency not known: weight gain, abnormal liver function tests.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

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

Keep out of the reach of children.

After first opening of the bottle, store for no more than 4 weeks.

Packaging.

60 ml or 100 ml in polyethylene or glass bottles. Each bottle in a cardboard pack with a measuring spoon.

Classification of supply.

Over-the-counter.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its place of business.

40020, Ukraine, Sumy region, Sumy city, Skryabina Street, 54.

or

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of its place of business.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhorii Street, 54.