L-may

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT L-MAI (L-MAI)

Composition:

Active substance: levocetirizine dihydrochloride;

1 ml (20 drops) contains levocetirizine dihydrochloride 5 mg;

Excipients: methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), sodium acetate trihydrate, glacial acetic acid, propylene glycol, glycerol, sodium saccharin, purified water.

Pharmaceutical form. Oral drops.

Main physicochemical properties: clear, colourless solution with a weak specific odour.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06AE09.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the class of competitive histamine antagonists. Its pharmacological effect is due to blockade of H1-histamine receptors.

Binding studies have shown 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 manifestations.

Pharmacodynamic properties

The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials.

In a comparative study of the effect of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced skin reactions characterized by wheal and flare, treatment with levocetirizine resulted in a significant reduction in wheal and flare formation, with the effect being highest during the first 12 hours and lasting for 24 hours (p < 0.001) compared to placebo and desloratadine.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms was observed within 1 hour after drug intake in placebo-controlled allergen challenge chamber model studies.

In vitro studies (Boyden chamber and cell monolayer methods) show that levocetirizine inhibits eotaxin-induced transendothelial migration of eosinophils through skin and lung cells. A pharmacodynamic in vivo experimental study (skin chamber technique) demonstrated three main inhibitory effects of a 5 mg dose of levocetirizine on allergen-induced reactions within the first 6 hours compared to placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability, and reduction in eosinophil recruitment.

Clinical efficacy and safety

The safety and efficacy of levocetirizine have been demonstrated in several double-blind, placebo-controlled clinical trials involving adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or chronic allergic rhinitis. Levocetirizine has been shown to significantly reduce allergic rhinitis symptoms, including nasal congestion in some studies.

A six-month clinical study in 551 adult patients (including 276 patients receiving levocetirizine) suffering from perennial allergic rhinitis (symptoms present 4 days per week for at least 4 consecutive weeks) and sensitized to house dust mites showed that levocetirizine 5 mg was clinically and statistically significantly more effective than placebo in reducing the total allergic rhinitis symptom score throughout the study duration, with no evidence of tachyphylaxis. Throughout the study period, levocetirizine significantly improved patients' quality of life.

In a placebo-controlled clinical trial involving 166 patients with chronic idiopathic urticaria, 85 patients received placebo and 81 patients received levocetirizine 5 mg once daily for six weeks.

Treatment with levocetirizine led to a significant reduction in pruritus intensity during the first week and throughout the entire treatment period compared to placebo. Levocetirizine also resulted in a significant improvement in health-related quality of life, as assessed by the Dermatology Life Quality Index, compared to placebo.

Chronic idiopathic urticaria was studied as a model for urticaria. Since histamine release is a causative factor in urticaria, levocetirizine is expected to be effective in providing symptomatic relief in other associated conditions accompanying chronic idiopathic urticaria.

Electrocardiographic studies did not demonstrate any effect of levocetirizine on the QT interval.

Paediatric population

The safety and efficacy of levocetirizine in children were studied in two placebo-controlled clinical trials, including patients aged 6 to 12 years with seasonal and perennial allergic rhinitis, respectively. In both studies, levocetirizine significantly improved symptoms and health-related quality of life.

In children under 6 years of age, clinical safety has been established through several short- or long-term therapeutic studies:

• one clinical study in which 29 children aged 2 to 6 years with allergic rhinitis received levocetirizine 1.25 mg twice daily for 4 weeks;
• one clinical study in which 114 children aged 1 to 5 years with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg twice daily for 2 weeks;
• one clinical study in which 45 children aged 6 to 11 months with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg once daily for 2 weeks;
• one long-term (18 months) clinical study of levocetirizine including 255 patients with atopy aged 12 to 24 months.

The safety profile was similar to that observed in short-term studies conducted in children aged 1 to 5 years.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine are linear, dose- and time-independent, and show low variability across different patients. The pharmacokinetic profile after administration of levocetirizine is the same as that of cetirizine. No chiral inversion occurs during absorption or elimination.

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

Distribution. There is no information on tissue distribution of the drug in humans or on penetration of levocetirizine across the blood-brain barrier. In animal studies with the original levocetirizine, the highest concentrations were recorded in the liver and kidneys, and the lowest 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%.

Biotransformation. In humans, the extent of levocetirizine metabolism is less than 14% of the administered dose; therefore, differences due to genetic polymorphism or concomitant use of drugs that inhibit enzymatic systems are expected to be minimal. The metabolic process includes aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation occurs primarily via cytochrome CYP3A4, while aromatic oxidation involves multiple and/or undefined cytochrome isoforms. Studies with the original levocetirizine showed no effect on the activity of cytochrome isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at concentrations significantly exceeding maximum levels after oral administration of 5 mg. Given the low extent of metabolism and lack of inhibitory potential on enzymatic systems, drug interactions between levocetirizine and other substances (and vice versa) are unlikely.

Elimination. Drug excretion occurs via glomerular filtration and active tubular secretion. The elimination half-life of levocetirizine in plasma in adults is 7.9 ± 1.9 hours. The half-life is shorter in young children. The mean apparent total clearance in adults is 0.63 mL/min/kg. Levocetirizine and its metabolites are primarily excreted in urine (on average, 85.4% of the administered dose is excreted). Only 12.9% of the administered dose is excreted in feces.

Special populations

Patients with renal impairment. Apparent clearance of levocetirizine correlates with creatinine clearance. Therefore, for patients with moderate and severe renal impairment, the dosing intervals of levocetirizine should be adjusted according to creatinine clearance. In anuria due to end-stage renal disease, the total clearance of levocetirizine in patients is reduced by approximately 80% compared to individuals without renal insufficiency. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is < 10%.

Children. Pharmacokinetic data from a study in 14 children aged 6 to 11 years with body weight between 20 kg and 40 kg receiving a single oral dose of levocetirizine 5 mg show that Cmax and area under the plasma concentration-time curve (AUC) are approximately twice higher than those observed in healthy adult volunteers in a crossover study. The mean Cmax was 450 ng/mL at 1.2 hours; normalized weight, total clearance was 30% higher, and elimination half-life was 24% shorter in this pediatric population compared to adults. Specialized 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 levocetirizine 1.25 mg 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 once daily.

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

Gender. Pharmacokinetic results from 77 patients (40 males, 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), but the normalized oral clearance in females (0.67 ± 0.16 mL/min/kg) is 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 apply.

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

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

Pharmacokinetic/pharmacodynamic interactions. The effect on histamine-induced skin reactions does not correlate with plasma concentration.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity following exposure to levocetirizine.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria.

Contraindications.

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

Patients with end-stage renal disease with glomerular filtration rate (GFR) below 15 ml/min requiring dialysis treatment.

Interaction with other medicinal products and other forms of interaction.

Interaction studies with levocetirizine (including studies with CYP3A4 inducers) have not been conducted. Studies with the original cetirizine (racemic compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse interactions. When administered concomitantly with theophylline (400 mg daily), multiple dosing resulted in a slight reduction (by 16%) in total clearance of levocetirizine (theophylline distribution was not altered). In a multiple-dose study with ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir exposure slightly decreased (–11%) after co-administration with cetirizine.

There are no data on potentiation of sedative effects when used at therapeutic doses; however, concomitant use of sedatives should be avoided during levocetirizine treatment.

Food intake does not affect the extent of drug absorption but reduces the rate of its absorption.

Concomitant use of cetirizine or levocetirizine with alcohol or other medicinal products that depress the central nervous system in sensitive patients may lead to additional reduction in alertness and ability to perform tasks.

Special precautions for use

Use with caution in patients with chronic renal insufficiency (dose adjustment required) and in elderly patients (possible reduction in glomerular filtration rate). The medicinal product should be used with caution when consuming alcohol (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the drug to patients with certain conditions that provoke urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), it should be borne in mind that levocetirizine increases this risk.

The medicinal product should be used with caution in patients with epilepsy or at risk of seizures, as its use may lead to exacerbation of seizures.

Antihistamines suppress the response to skin allergy tests; therefore, administration of the drug should be discontinued at least 3 days before testing (elimination period of levocetirizine).

Pruritus may occur after discontinuation of levocetirizine, even if such symptoms were not present prior to treatment initiation. This may resolve spontaneously. In some cases, symptoms may be severe, and resumption of the drug may be necessary. Symptoms should resolve after resuming treatment.

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.

Methylparahydroxybenzoate and propylparahydroxybenzoate contained in the medicinal product may cause allergic reactions (possibly delayed).

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

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 (over 1000 pregnancy outcomes), do not indicate any malformative or fetal/neonatal toxicity. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Levocetirizine may be considered for use during pregnancy if clinically needed.

Breastfeeding period

It has been shown that cetirizine, the racemate of levocetirizine, is excreted in human milk. Therefore, levocetirizine is likely to be excreted in breast milk as well. 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 influence reaction speed when driving or operating machinery

Comparative clinical studies have not shown any evidence that levocetirizine at the recommended dose impairs mental alertness, reaction ability, or the ability to drive vehicles.

However, some patients may experience somnolence, fatigue, or asthenia during levocetirizine therapy. 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 dosage.

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

For adults and adolescents aged 12 years and older, the recommended daily dose is 5 mg (20 drops) once daily.

Elderly patients

Elderly patients with normal renal function do not require dose adjustment. Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see section «Renal insufficiency» below).

Renal insufficiency

For patients with impaired renal function, dosage must be individually calculated based on the glomerular filtration rate (eGFR) according to the table below.

Dose adjustment of the drug in patients with impaired renal function depending on eGFR:

For children with impaired kidney function, the dose of the medicinal product should be individually adjusted based on renal clearance and body weight.

There are no specific data regarding the use of the medicinal product in children with impaired kidney function.

Hepatic impairment

There is no need to adjust the dosing regimen for patients with hepatic impairment. For patients with both hepatic and renal impairment, the dosing regimen should be adjusted according to the table above (see section «Renal impairment» above).

Use in children

Recommended single and daily doses for children according to age are presented in the table:

Administration

The drops should be administered into a spoon or diluted in a small amount of water and taken orally, regardless of food intake. If the drops are taken in a diluted form, it is important to consider, especially when administering to children, that the volume of water used for dilution should correspond to the amount of liquid the patient is able to swallow. The diluted solution should be taken immediately.

When counting drops, the bottle should be held vertically with the cap facing downwards. If there is no drop flow, or if the required number of drops has not been obtained due to interruption of flow, the bottle should be turned upright, then again inverted (cap down) and the counting of drops continued.

The medication can be taken regardless of food intake.

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 resumed again 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), continuous therapy may be recommended during periods of allergen exposure. There is clinical experience with the use of levocetirizine for at least a 6-month treatment period. In chronic conditions (chronic allergic rhinitis, chronic urticaria), the duration of treatment may last up to 1 year (data available from clinical studies using original cetirizine (racemic mixture)).

Children.

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

The medicinal product should be administered to children aged 2 years and older.

Overdose.

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

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 ingestion. Hemodialysis is ineffective for removing levocetirizine from the body.

Adverse Reactions

Clinical Trials

Adults and adolescents aged 12 years and older

In therapeutic trials 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 severity.

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

Therapeutic clinical trials of levocetirizine included 935 patients who received the medicinal product at the recommended dose of 5 mg once daily. In this population, the following adverse reactions occurred at a frequency of 1% or greater (common: ≥ 1/100 to < 1/10) with levocetirizine 5 mg or placebo:

It has also been reported that the following adverse reactions occurred at the following frequency (uncommon: ≥ 1/1,000, < 1/100): asthenia and 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%).

Paediatric population

In two placebo-controlled studies involving paediatric patients aged 6 to 11 months and patients aged 1 to 6 years, 159 patients received levocetirizine at a dose of 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.

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 durations ranging from less than 1 week to 13 weeks. The following adverse reactions were reported with an incidence of 1% or more during treatment with levocetirizine or placebo.

Post-marketing experience

Summary table of adverse reaction frequencies.

The frequency of adverse reactions is classified 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 (frequency cannot be estimated from the available data).

Description of individual adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

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

Shelf life.

3 years. Do not use the medicinal product after the expiry date stated on the packaging.

After opening the container, use within 3 months.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

20 ml in a container with a dropper cap, closed with a child-resistant cap, in a carton.

Availability classification.

Over-the-counter (without prescription).

Manufacturer.

Ukrainian-Spanish joint enterprise "Sperco Ukraine".

Manufacturer's address and location of business activity.

25, 600-richchia St., Vinnytsia, Ukraine, 21027.

Tel.: + 38(0432)52-30-36. E-mail: [email protected]

www.sperco.ua