Lazin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAZIN (LAzine)

Composition:

Active substance: levocetirizine;

5 ml of solution contain levocetirizine dihydrochloride 2,5 mg;

Excipients: methylparaben (E 218), propylparaben (E 216), liquid maltitol, glycerol, sodium saccharin, sodium acetate trihydrate, glacial acetic acid, grape flavor ART Grape FL#10273, purified water.

Pharmaceutical form. Oral solution.

Main physico-chemical properties: clear, colorless liquid free from foreign particles and sediment, with a characteristic grape-like odor.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06A E09.

Pharmacological Properties.

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the class of competitive histamine antagonists. Its pharmacological effect is mediated by blockade of H1-histamine receptors. The affinity of levocetirizine for H1-histamine receptors is twice as high as that of cetirizine. It affects the histamine-dependent phase of allergic reactions, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and suppresses the progression of allergic reactions, exerting anti-exudative, anti-pruritic, and anti-inflammatory effects, with minimal anticholinergic and anti-serotonergic activity.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine exhibit linear kinetics and are independent of dose and time, showing low variability among different patients. The pharmacokinetic profile after administration of a single enantiomer is the same as that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption. The drug is rapidly and extensively absorbed after oral administration. The extent of absorption is independent of dose and is not altered by food intake; however, the maximum plasma concentration (Cmax) is reduced and reached later when taken with food. Bioavailability is 100%.

Therapeutic effect develops within 12 minutes after a single dose in 50% of patients, and within 0.5–1 hour in 95% of patients. In adults, Cmax in plasma is achieved within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is reached after 2 days of daily dosing. Cmax is 207 ng/mL after a single dose and 308 ng/mL after repeated administration of 5 mg once daily.

Distribution. There is no available information on the distribution of the drug in human tissues or on the penetration 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 tissues of the central nervous system. 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, the extent of metabolism is less than 14% of the administered dose; therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are likely to be minimal. The metabolic process includes aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by cytochrome CYP3A4, whereas aromatic oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding the maximum plasma levels achieved after a 5 mg oral dose. Due to the low extent of metabolism and lack of inhibitory effect on metabolic pathways, drug interactions between levocetirizine and other substances (and vice versa) are unlikely.

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

Special Populations

Renal Impairment

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

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, to any other piperazine derivatives, or to any excipients of the medicinal product.

Severe form of chronic renal insufficiency (creatinine clearance <10 mL/min).

Interaction with other medicinal products and other forms of interaction.

Studies on interactions of levocetirizine (including with CYP3A4 inducers) have not been conducted. Studies on interactions of cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse effects. In a multiple-dose study, concomitant administration with theophylline (400 mg per day) resulted in a slight reduction (by 16%) in cetirizine clearance (theophylline distribution was not altered).

In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg per day), exposure to cetirizine increased by approximately 40%, while ritonavir distribution was slightly altered (−11%) with concomitant cetirizine administration.

Food intake does not affect the extent of drug absorption, but co-ingestion of food reduces the rate of its absorption.

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

Special precautions for use

During the use of this medicinal product, alcohol consumption should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Levocetirizine should be used with caution in patients with epilepsy or those at risk of seizures, as its use may lead to an increased frequency or severity of seizures.

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.

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 this symptom was not present before treatment initiation. This symptom may resolve spontaneously. In some cases, the symptom may be intense and may require re-initiation of treatment. The symptom should resolve after restarting therapy.

The medicinal product contains liquid maltitol; therefore, if a patient has been diagnosed with intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

The medicinal product contains methylparaben and propylparaben, which may cause allergic reactions (possibly delayed).

This medicinal product contains less than 1 mmol of sodium (23 mg) per mL, i.e. it is essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There are no data or the amount of data is limited (fewer than 300 pregnancy outcomes) on the use of levocetirizine in pregnant women. However, extensive data (over 1000 pregnancy outcomes) on cetirizine, the racemate of levocetirizine, indicate no evidence of malformative or fetoneonatal toxicity.

Levocetirizine is contraindicated during pregnancy.

Breastfeeding period

Cetirizine, the racemate of levocetirizine, is known to be excreted in human milk. Therefore, levocetirizine is likely to pass into breast milk. Adverse reactions related to levocetirizine may occur in breastfed infants. Hence, if treatment with this medicinal product is necessary, breastfeeding should be discontinued.

Fertility

Clinical data on levocetirizine with respect to fertility are lacking.

Ability to influence reaction speed when driving or operating machinery

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

Nevertheless, during levocetirizine therapy, somnolence, fatigue, and asthenia may occur in some patients. Therefore, patients intending to drive, engage in potentially hazardous activities, or operate machinery should take into account their individual response to the medicinal product.

Method of administration and dosing.

The medication is intended for adults and children aged 2 years and older.

Recommended doses:

Adults and adolescents aged 12 years and older: the recommended daily dose is 5 mg (10 mL) once daily.

Elderly patients

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

Renal impairment

For patients with impaired renal function, the dose should be calculated according to the degree of renal impairment (creatinine clearance) as specified in the table (see table below).

To do this, determine the patient's creatinine clearance (CLcr) in mL/min based on serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment of the drug for patients with renal function impairment

For children with renal impairment, the dose of the drug should be individually adjusted based on the patient's renal clearance and body weight.

There are no specific data regarding the use of the drug in children with renal impairment.

Hepatic impairment

Patients with hepatic impairment alone do not require dose adjustment. Patients with both hepatic and renal impairment should have their dosing regimen adjusted according to the table above.

Paediatric population

Recommended doses:

― children aged 6 to 12 years: the recommended daily dose is 5 mg (10 ml) once daily;

• children aged 2 to 6 years: the recommended daily dose is 2.5 mg (5 ml); this dose should be administered as 1.25 mg (2.5 ml) twice daily;

Although some clinical data are available for children aged 6 months to 12 years (see section "Adverse reactions"), these data are insufficient to support the use of levocetirizine in infants and children under 2 years of age.

Method of administration

The drug may be taken independently of food intake.

The appropriate volume of oral solution can be measured using a teaspoon (1 teaspoon contains 5 ml).

Duration of treatment

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

Children.

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

The drug should be administered to 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 therapy is recommended. Gastric lavage may be considered shortly after drug intake. Hemodialysis is not effective for elimination of levocetirizine from the body.

Adverse Reactions

Clinical Studies

Adults and Adolescents aged 12 years and older

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 with 11.3% in the placebo group. 91.6% of these adverse reactions were mild to moderate in severity.

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

Clinical therapeutic trials of levocetirizine included 935 individuals exposed to the drug at the recommended dose of 5 mg daily. In this population, the following drug-related adverse reactions occurred at a frequency of 1% or greater (common: ≥ 1/100 to < 1/10) during treatment with either levocetirizine 5 mg or placebo:

Also observed were uncommon adverse reactions (uncommon: ≥ 1/1000 to < 1/100), such as asthenia or abdominal pain.

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

Pediatric population

In two placebo-controlled studies in children aged 6 to 11 months and children aged 1 to less than 6 years, 159 subjects received levocetirizine at a dose of 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The following adverse reactions were reported with an incidence of 1% or more during treatment with levocetirizine or placebo.

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.

As stated in the section "Dosage and Administration", please note that even though clinical data presented in this section are available for children aged from 6 months to 12 years, there are insufficient data to confirm the use of the product in infants and toddlers under 2 years of age.

Post-marketing experience

Adverse reactions reported from post-marketing experience are listed by system organ class and frequency. Frequency is 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); not known (cannot be estimated from available data). The frequency of the adverse reactions listed below is not known.

Immune system disorders: Hypersensitivity, including anaphylaxis.

Nutrition and metabolism disorders: Increased appetite.

Psychiatric disorders: Aggression, agitation, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

Nervous system disorders: Seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Ear and labyrinth disorders: Vertigo.

Eye disorders: Vision disorders, blurred vision, nystagmus.

Cardiac disorders: Palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Nausea, vomiting, diarrhoea.

Hepatobiliary disorders: Hepatitis.

Renal and urinary disorders: Dysuria, urinary retention.

Skin and subcutaneous tissue disorders: Angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

General disorders: Oedema.

Investigations: Increased body weight, abnormal liver function tests.

Methylparaben and propylparaben may cause allergic reactions (possibly delayed).

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization 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, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After first opening of the bottle – 30 days.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

148 ml in a bottle, 1 bottle in a cardboard box.

Authorization category. Over-the-counter (without prescription).

Manufacturer.

Hetero Labs Limited, India.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.