Aleron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALEON (ALERON)

Composition:

Active substance: levocetirizine;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: maize starch, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: Opadry White 1185 F 18378 (partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, smooth on both sides.

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

Pharmacological Properties

Pharmacodynamics

Levocetirizine is the (R) enantiomer of cetirizine, a potent and selective antagonist of peripheral H1-receptors.

Binding studies have shown that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). Levocetirizine has twice the affinity compared to cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 minutes. After a single dose, levocetirizine demonstrates 90% receptor occupancy at 4 hours and 57% at 24 hours. Pharmacodynamic studies in healthy volunteers have shown that at half the dose, levocetirizine has comparable activity to cetirizine both in the skin and nasal mucosa.

Pharmacokinetics

The pharmacokinetics of levocetirizine are linear, independent of dose and time, with low inter-individual variability. The pharmacokinetic profile is identical whether administered as a single enantiomer or as cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed after oral administration. In adults, maximum plasma concentration is reached within 0.9 hours after intake. Steady state is achieved within two days. Peak concentrations typically reach 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 unaffected by food intake; however, peak concentration is reduced and delayed when taken with food.

Distribution

There are no data available on tissue distribution in humans or on the ability of levocetirizine to cross the blood-brain barrier. In rats and dogs, the highest tissue levels were found in the liver and kidneys, and the lowest in CNS regions.

In humans, levocetirizine is 90% bound to plasma proteins. Distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg.

Metabolism

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 minimal. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation pathways are primarily mediated by CYP3A4, while aromatic oxidation involves multiple and/or unidentified CYP isoforms. Levocetirizine did not affect the activity of CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly higher than peak plasma concentrations achieved after oral administration of 5 mg.

Due to low metabolism and lack of inhibitory potential, drug interactions involving levocetirizine are unlikely.

Elimination

The elimination half-life in adults is 7.9 ± 1.9 hours; in young children, the half-life is shorter. Mean apparent total clearance in adults is 0.63 mL/min/kg. The primary route of elimination of levocetirizine and its metabolites (averaging 85.4% of the dose) is via urine. Fecal excretion accounts for only 12.9% of the dose. Levocetirizine is eliminated by both glomerular filtration and active tubular secretion.

Special Populations

Renal Impairment

Apparent systemic clearance of levocetirizine correlates with creatinine clearance. Therefore, dosage intervals should be adjusted in patients with moderate to severe renal impairment. In patients with anuric end-stage renal disease, total clearance is reduced by approximately 80% compared to healthy volunteers. The amount of levocetirizine removed during a standard 4-hour hemodialysis session was < 10%.

Pediatric Population

Pharmacokinetic data from a study administering a single 5 mg oral dose of levocetirizine to 14 children aged 6 to 11 years with body weights between 20 and 40 kg showed that Cmax and AUC values were approximately twice those observed in healthy adult volunteers in a cross-over study. Mean body weight-normalized Cmax was 450 ng/mL, reached on average within 1.2 hours; total clearance was 30% higher and elimination half-life 24% shorter in this 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 volunteers (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 suggest that administration of 1.25 mg once daily to 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

Limited pharmacokinetic data are available for elderly patients. After repeated daily oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years), total drug clearance was approximately 33% lower than in younger subjects. 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 primarily excreted in urine. Therefore, levocetirizine dosage 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. Elimination half-life was slightly shorter in females (7.08 ± 1.72 hours) than in males (8.62 ± 1.84 hours); however, body weight-adjusted oral clearance 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 are recommended.

Race

The effect of race on levocetirizine use has not been studied. Since levocetirizine is primarily eliminated by the kidneys and there are no significant racial differences in creatinine clearance, no differences in the pharmacokinetic characteristics of levocetirizine are expected among racial groups. No racial 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. In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) who received a single dose of 10 or 20 mg of racemic cetirizine, elimination half-life increased by 50% and clearance decreased by 40% compared to healthy subjects.

Pharmacokinetic/Pharmacodynamic Relationship

The effect on histamine-induced skin reactions is independent of plasma concentration.

Clinical characteristics.

Indications.

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

Contraindications.

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

Patients with end-stage renal disease with a calculated glomerular filtration rate (cGFR) < 15 mL/min (who require dialysis).

Interaction with other medicinal products and other forms of interaction.

Interaction studies with levocetirizine have not been conducted (including with CYP3A4 inducers). Studies with the racemic compound cetirizine have shown that concomitant administration with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, or diazepam does not result in clinically significant adverse interactions.

A slight decrease in cetirizine clearance (by 16%) was observed in a multiple-dose study with theophylline (400 mg/day); however, the pharmacokinetics of theophylline were not altered when co-administered with cetirizine.

In a multiple-dose study with ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, whereas the distribution of ritonavir was slightly altered (-11%) compared to ritonavir administration alone.

In sensitive patients, concomitant intake of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may lead to additional reduction in alertness and impaired performance.

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

Special precautions for use

During administration of the drug, caution is recommended when consuming alcohol simultaneously. Caution should be exercised in patients predisposed to urinary retention (e.g., spinal cord lesions, benign prostatic hyperplasia), as levocetirizine may increase the risk of urinary retention.

The drug should be used with caution in patients with epilepsy and in patients at risk of seizures, as levocetirizine may lead to their exacerbation.

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

After discontinuation of levocetirizine, pruritus may occur, even if this symptom was not present before treatment initiation. Symptoms may resolve spontaneously. In some cases, symptoms may be severe and require resumption of treatment. Symptoms should resolve after resuming therapy.

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

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (less than 300 pregnancy outcomes). However, extensive data on cetirizine, the racemate of levocetirizine (over 1000 pregnancy outcomes) indicate no evidence of developmental malformations or fetal/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Levocetirizine may be considered during pregnancy if clinically necessary.

Breastfeeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human milk. Therefore, excretion of levocetirizine into human milk is likely. Adverse reactions related to levocetirizine may occur in breastfed infants. Thus, levocetirizine should be prescribed with caution to women who are breastfeeding.

Fertility

There are no clinical data available on levocetirizine and fertility.

Ability to affect reaction speed when driving or operating machinery.

Comparative clinical studies have not demonstrated evidence that levocetirizine at recommended doses impairs cognitive function, reactivity, or ability to drive a vehicle.

Nevertheless, 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 take into account their individual response to the medicinal product.

Method of administration and dosage.

Take the tablet regardless of food intake. The tablet should be swallowed whole with a small amount of water. It is recommended to take the daily dose as a single administration.

The drug is intended for adults and children aged 12 years and older at a daily dose of 5 mg (1 film-coated tablet) once daily.

For elderly patients with moderate and severe renal impairment, dose adjustment is recommended (see below).

Renal function impairment

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

Dose adjustment in patients with impaired renal function:

For children with impaired renal function, the dose of the drug must be individually adjusted based on the patient's renal clearance and body weight. There are no specific data available for children with renal insufficiency.

Patients with hepatic impairment alone do not require dose adjustment. For patients with both hepatic and renal insufficiency, dosage regimen should be adjusted according to the table provided above.

Pediatric population

Children aged 6 to 12 years

The recommended daily dose is 5 mg (1 film-coated tablet).

For children aged 2 to 6 years, dose adjustment using film-coated tablets is not feasible. It is recommended to use a formulation of levocetirizine suitable for pediatric use.

Duration of treatment: Patients with intermittent allergic rhinitis (disease symptoms lasting < 4 days per week or less than 4 weeks per year) should be treated according to the condition and medical history; treatment may be discontinued if symptoms resolve and resumed again upon recurrence of symptoms. For persistent allergic rhinitis (disease symptoms lasting > 4 days per week and more than 4 weeks per year), continuous therapy may be considered during allergen exposure periods.

There is clinical experience with levocetirizine use for treatment periods of at least 6 months. For chronic allergic rhinitis and chronic urticaria, there is clinical experience with cetirizine (racemate) use up to 1 year.

Children.

The tablet formulation should not be used in children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. This patient group should be treated with a levocetirizine formulation suitable for pediatric use.

Overdose.

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

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

Adverse reactions.

Adults and adolescents aged 12 years and older

In clinical trials involving male and female patients aged 12 to 71 years, at least one adverse reaction was observed in 15.1% of patients in the 5 mg levocetirizine group, compared with 11.3% in the placebo group. 91.6% of these adverse reactions were of mild to moderate severity.

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

Clinical therapeutic trials of levocetirizine included 935 individuals who received the medicinal product at the recommended dose of 5 mg once daily. In this cohort, the following adverse reactions were reported with an incidence of 1% or higher (common: ≥ 1/100 to < 1/10) during treatment with either 5 mg levocetirizine or placebo:

Also observed were less common adverse reactions (frequency ≥ 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 involving children aged 6–11 months and 1 to 6 years, 159 subjects received levocetirizine 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 higher during treatment with levocetirizine or placebo.

Double-blind, placebo-controlled studies were conducted in children aged 6–12 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 adverse reactions listed below were reported at a frequency of 1% or more with levocetirizine or placebo.

Post-marketing period

Adverse reactions reported during the post-marketing period 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); frequency not known (cannot be estimated from the available data).

Nervous system disorders: frequency not known – convulsions, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Psychiatric disorders: frequency not known – excitement, hallucinations, depression, aggression, insomnia, suicidal thoughts, night terrors.

Cardiac disorders: frequency not known – palpitations, tachycardia.

Eye disorders: frequency not known – visual disturbance, blurred vision, oculogyric crisis.

Ear and labyrinth disorders: frequency not known – vertigo.

Hepatobiliary disorders: frequency not known – hepatitis.

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

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

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

Gastrointestinal disorders: frequency not known – diarrhoea, nausea, vomiting.

Skin and subcutaneous tissue disorders: frequency not known – angioneurotic oedema, rash (including persistent drug-induced rash), pruritus, urticaria.

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

Investigations: frequency not known – weight increased, liver function test abnormalities.

Metabolism and nutrition disorders: frequency not known – increased appetite.

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

Description of selected adverse reactions. Pruritus has been reported following discontinuation of levocetirizine.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging.

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

Pharmaceutical category. Over-the-counter.

Manufacturer.

Emcure Pharmaceuticals Ltd.

Manufacturer's name and address of the place of business.

Plot No. P-1 and P-2, I.T.B.T. Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.