Lazin

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

Composition:

Active substance: levocetirizine;

1 tablet contains 5 mg of levocetirizine dihydrochloride;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, lactose monohydrate, magnesium stearate, Opadry White YS-1-7003 (hypromellose (E 464), titanium dioxide (E 171), polysorbate, polyethylene glycol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white, round, biconvex, film-coated tablets with a score line, marked with "H" on one side and "161" on the other.

Pharmacotherapeutic group.

Antihistamines for systemic use. Piperazine derivatives.

ATC code R06A E09.

Pharmacological properties.

Pharmacodynamics.

Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Its pharmacological action is due to blockade of H1-histamine receptors. After single administration, levocetirizine occupies 90% of receptors within 4 hours and 57% after 24 hours. The affinity of levocetirizine for H1-histamine receptors is twice higher than that of cetirizine. It affects the histamine-dependent phase of allergic reaction, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and alleviates the course of allergic reactions, exerting anti-exudative, anti-pruritic, and anti-inflammatory effects, with minimal anticholinergic and anti-serotonin activity. At therapeutic doses, it has almost no sedative effect.

Pharmacokinetics.

The pharmacokinetics of levocetirizine are linear, with low inter-subject variability independent of dose and time. The pharmacokinetic profile is identical whether administered as a single enantiomer or as cetirizine. Chiral inversion does not occur during absorption or elimination.

Absorption. Levocetirizine is rapidly and extensively absorbed after oral administration. In adults, maximum plasma concentration (Cmax) is reached within 0.9 hours after dosing. Steady state is achieved within two days. Cmax is typically 270 ng/mL and 308 ng/mL after single and repeated administration of 5 mg once daily, respectively. The extent of absorption is independent of dose and is not altered by food, although Cmax is reduced and delayed.

Distribution. There is no information available 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, and the lowest in central nervous system tissues. In humans, plasma protein binding of levocetirizine is 90%. Distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg.

Biotransformation. The extent of levocetirizine metabolism in humans is less than 14% of the dose; therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be negligible. The metabolic process includes aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation is primarily mediated by cytochrome CYP3A4, while aromatic oxidation involves multiple and/or unknown CYP isoforms. Levocetirizine does not affect the activity of cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding maximum levels after a 5 mg oral dose. Given the low degree of metabolism and lack of enhanced inhibitory effect, interactions between levocetirizine and other substances are unlikely.

Elimination. The elimination half-life of the drug from plasma in adults is 7.9 ± 1.9 hours. The elimination half-life is shorter in young children.

Mean total clearance in adults is 0.63 mL/min/kg. Levocetirizine and its metabolites are primarily excreted via urine (on average, 85.4% of the administered dose). Only 12.9% of the administered dose is excreted in feces. Levocetirizine is eliminated by both glomerular filtration and active tubular secretion.

Special populations

Renal impairment

Total clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted according to creatinine clearance. In cases of anuria at the end-stage of renal disease, total body clearance in patients is reduced by approximately 80% compared to individuals without such impairments. The amount of levocetirizine removed during a standard 4-hour hemodialysis session was < 10%.

Children

After administration of a single oral dose of 5 mg levocetirizine in children aged 6 to 11 years with body weight between 20 and 40 kg, Cmax and AUC values were approximately twice higher than those observed in healthy adult volunteers in a comparative study; total clearance was 30% higher and elimination half-life 24% shorter in this pediatric population compared to adults. Specific pharmacokinetic studies have not been conducted in pediatric patients under 6 years of age.

Elderly patients

Limited pharmacokinetic data are available in elderly individuals. After single daily oral administration of 30 mg levocetirizine for 6 days in elderly patients, 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 via urine. Therefore, the dose of levocetirizine should be adjusted according to renal function in elderly patients.

Sex

Pharmacokinetic results were evaluated for potential sex-related effects. Elimination half-life was slightly shorter in women than in men; however, oral clearance adjusted for body weight was comparable between women and men. The same daily doses and dosing intervals are recommended for men and women with normal renal function.

Race

The effect of race on levocetirizine has not been studied. Since levocetirizine is primarily eliminated by the kidneys and there are no significant racial differences in creatinine clearance, the pharmacokinetic characteristics of levocetirizine are not expected to differ among patients of different races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Hepatic impairment

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

Clinical characteristics.

Indications.

Symptomatic treatment of seasonal allergic rhinitis, including perennial allergic rhinitis, and chronic idiopathic urticaria in adults and children aged 6 years and older.

Contraindications.

Hypersensitivity to the active substance, cetirizine, hydroxyzine, or to any other piperazine derivatives, as well as to any excipient of the medicinal product;

end-stage renal disease with estimated glomerular filtration rate (eGFR) below 15 mL/min (requiring dialysis treatment).

Interaction with other medicinal products and other forms of interactions.

Studies on levocetirizine regarding interactions (including studies with CYP3A4 inducers) have not been conducted. Studies on cetirizine (racemate) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. When administered concomitantly with theophylline (400 mg/day), a slight reduction (by 16%) in total clearance of levocetirizine was observed (theophylline distribution remained unchanged).

In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) prior to 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 and alcohol or other central nervous system depressants in susceptible patients may cause additional reduction in alertness and ability to perform tasks.

Special precautions for use

During the use of this medicinal product, alcohol consumption should be avoided.

When prescribing the medicinal product, attention should be paid to the presence of certain factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), as levocetirizine may increase the risk of urinary retention.

The medicinal product should be administered with caution in patients with epilepsy and in patients at risk of seizures, as levocetirizine may lead to seizure exacerbation.

Skin allergy test responses are suppressed by antihistamines; therefore, a washout period (3 days) is required prior to testing.

Patients with rare hereditary forms of galactose intolerance, total lactase deficiency (Lapp lactase deficiency), or glucose-galactose malabsorption should not take this medicinal product.

Pruritus may occur upon discontinuation of levocetirizine, even if it was not present prior to the start of treatment. Symptoms may appear spontaneously. In some cases, symptoms may be severe and require resumption of treatment. Symptoms should resolve upon resumption of therapy.

Paediatric population

The tablet formulation is not recommended for children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. Use of levocetirizine in a formulation suitable for paediatric use is recommended.

Use during pregnancy or breastfeeding

Pregnancy

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

If necessary, the use of levocetirizine during pregnancy may be considered.

Breastfeeding

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

Fertility

Clinical data on the effects of levocetirizine on fertility are lacking.

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 capacity to drive vehicles.

However, some patients may experience somnolence, fatigue, or asthenia during treatment with levocetirizine. 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

Recommended Dosages

The medication is prescribed for adults and children aged 6 years and older at a daily dose of 5 mg once daily.

Elderly Patients

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

Renal Insufficiency

Dosing intervals should be individualized according to renal function (eGFR – estimated glomerular filtration rate) (see Table 1 and adjust dosage as indicated).

Table 1

Dosage Adjustment for Patients with Renal Impairment

In children with impaired renal function, the dose should be individually adjusted according to creatinine clearance and body weight. There are no specific data available for children with renal impairment.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment. In patients with both hepatic and renal impairment, dosage regimen should be adjusted according to Table 1.

Paediatric population

Children aged 6 to 12 years: the recommended daily dose is 5 mg (1 tablet).

The tablet formulation should not be used in children aged 2 to 6 years, as this dosage form does not allow appropriate dose adjustment. For this patient group, levocetirizine in a formulation suitable for paediatric use is recommended.

Method of administration

The tablet should be taken orally, swallowed whole with liquid, regardless of food intake. The recommended daily dose should be administered once daily.

Duration of treatment. Patients with intermittent allergic rhinitis (disease symptoms lasting less than 4 days per week or less than 4 weeks) should be treated according to the disease and medical history; treatment may be discontinued if symptoms resolve and restarted upon recurrence. In cases of persistent allergic rhinitis (disease symptoms lasting more than 4 days per week or more than 4 weeks) during allergen exposure periods, continuous therapy may be considered. For chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year (data available from clinical trials using the racemate).

Children.

The tablet formulation should not be administered to children under 6 years of age, as this dosage form does not allow appropriate dose adjustment. For this patient group, levocetirizine in a formulation suitable for paediatric use is recommended.

Overdose.

Symptoms of overdose: may include somnolence in adults; in children, initial excitation and restlessness may occur, followed by somnolence.

Treatment. In case of overdose symptoms, symptomatic and supportive therapy is recommended. Gastric lavage should be considered shortly after drug intake. There is no specific antidote. Haemodialysis is not effective for elimination of levocetirizine from the body.

Adverse reactions.

Clinical studies

Adults and children aged 12 years and older

In therapeutic studies involving women and men aged 12 to 71 years, 15.1% of patients in the group receiving levocetirizine 5 mg 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 intensity.

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.

Therapeutic clinical studies of levocetirizine included 935 patients who received the medicinal product at the recommended dose of 5 mg once daily. In these studies, the adverse reactions listed below occurred at a frequency of 1% or greater (common: ≥ 1/100 to < 1/10) with levocetirizine 5 mg or placebo (see Table 2).

Table 2

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

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

Paediatric population

In two placebo-controlled studies involving paediatric patients aged 6 to 11 months and aged 1 to 6 years, 159 patients received levocetirizine 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The incidence of adverse reactions with levocetirizine or placebo was 1% or higher (see Table 3).

Table 3

Double-blind, placebo-controlled studies involving children aged 6 to 12 years were conducted, in which 243 children received 5 mg of levocetirizine once daily for various durations ranging from less than 1 week to 13 weeks. The adverse reactions listed below were reported with an incidence of 1% or higher during treatment with levocetirizine or placebo (see Table 4).

Table 4

Post-marketing experience

The frequency is classified as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated from the available data).

Immune system disorders: hypersensitivity, including anaphylaxis.

Nutritional 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: visual disturbance, 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 and bone disorders: myalgia, arthralgia.

General disorders and administration site conditions: oedema.

Investigations: weight increased, liver function test abnormalities.

Description of selected adverse reactions

Pruritus has been reported following discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister pack, 1 or 3 blisters in a cardboard box.

Classification. Over-the-counter.

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.

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