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

Film-coated tablets.

Basic physical and chemical properties: round, biconvex film-coated tablets
of green color.

active substance: levocetirizine dihydrochloride;

1 film-coated tablet contains 5 mg of levocetirizine dihydrochloride;

excipients: microcrystalline cellulose, croscarmellose sodium, magnesium stearate,
colloidal anhydrous silica, Opadry II 85G51300 green*;

*Opadry II 85G51300 green: polyvinyl alcohol, talc, titanium dioxide (E 171),
polyethylene glycol, lecithin, indigo carmine (E 132), quinoline yellow (E 104),
sunset yellow FCF (E 110)

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine, belonging to the group of competitive peripheral H1-histamine receptor antagonists. The affinity of levocetirizine for H1-histamine receptors is twice as high as that of cetirizine. It affects the histamine-dependent stage of the 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, providing anti-exudative, antipruritic, and anti-inflammatory effects, with almost no anticholinergic or antiserotonergic action.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine exhibit a linear dependence, are dose- and time-independent, and show low variability among different patients. The pharmacokinetic profile upon administration of the single enantiomer is identical to that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed after oral administration. The extent of absorption is dose-independent and unaffected by food intake, although the maximum concentration (Cmax) decreases and is reached later. Bioavailability is 100%.

In 50% of patients, the effect of levocetirizine develops 12 minutes after a single dose, and in 95% – within 0.5-1 hour. Maximum serum concentration (Cmax) is achieved 50 minutes after a single oral therapeutic dose. Steady-state concentration is reached after two days of administration. Cmax is 270 ng/ml after a single 5 mg dose and 308 ng/ml after repeated administration, respectively.

Distribution.

There is no information on the distribution of the drug in human tissues or the penetration of levocetirizine through the blood-brain barrier. In studies, the highest concentrations were recorded in the liver and kidneys, while the lowest were in central nervous system tissues. Distribution is limited, with a volume of distribution of 0.4 l/kg. Plasma protein binding is 90%.

Biotransformation.

In humans, the extent of metabolism is less than 14% of the dose; therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be negligible. Metabolic processes include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation is primarily mediated by cytochrome CYP 3A4, while multiple and/or unidentified CYP isoforms participate in aromatic oxidation. Levocetirizine did not affect the activity of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 at concentrations significantly exceeding those reached after a 5 mg oral dose. Given the low metabolism and lack of metabolic inhibition, interactions with other substances are unlikely.

Elimination.

Excretion occurs primarily via glomerular filtration and active tubular secretion. The plasma half-life (T1/2) 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. Excretion occurs mainly via urine (averaging 85.4% of the dose), with only 12.9% 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, dosing intervals should be adjusted based on creatinine clearance. In anuric patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to healthy individuals. Levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.

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

Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, any other piperazine derivatives, or any other excipient of the drug.

Severe chronic renal failure (creatinine clearance < 10 ml/min).

Interaction studies with levocetirizine (including studies with CYP3A4 inducers) have not been performed. Studies with cetirizine (the racemate compound) have shown that concomitant use with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse interactions. A small decrease in levocetirizine clearance (16%) was observed with concomitant administration of theophylline (400 mg/day), while the disposition of theophylline was not altered. In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) by concomitant cetirizine administration.

Food intake does not affect the extent of absorption of the drug, but it decreases the rate of its absorption.

In sensitive patients, the simultaneous administration of cetirizine or levocetirizine and alcohol or other central nervous system depressants may cause additional reduction in alertness and impairment of performance.

Use with caution in patients with chronic renal failure (dosage adjustment is required) and in elderly patients (glomerular filtration may be decreased). The drug should be used with caution when taken concurrently with alcohol (see section "Interaction with other medicinal products and other forms of interaction").

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

There is no evidence of potentiation of the effect of sedatives when used at therapeutic doses. However, the use of sedatives should be avoided during treatment with the drug.

As antihistamines may suppress the response to allergic skin tests, a washout period (of 3 days) is required before performing them.

Pruritus (itching) may occur after discontinuation of levocetirizine, even if these symptoms were not present before treatment. Pruritus may resolve spontaneously. In some cases, pruritus may be intense, which may lead to the resumption of treatment. After restarting levocetirizine, the pruritus usually disappears.

Excipients.

The drug contains the dye Sunset Yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or lactation.

Pregnancy

Levocetirizine is contraindicated for use during pregnancy.

Breastfeeding

Cetirizine is excreted in breast milk; therefore, if the use of the drug is necessary, breastfeeding should be discontinued.

Fertility

There are no clinical data (including animal studies) regarding the effect of levocetirizine on fertility.

Ability to affect the reaction speed when driving vehicles or operating other mechanisms.

Driving vehicles or operating other potentially dangerous mechanisms should be avoided during treatment with the drug.

The drug is prescribed to adults and children over 6 years of age orally at a daily dose of 5 mg (1 tablet) once a day, regardless of food intake. The tablet must be swallowed whole with a small amount of water.

Elderly patients with normal renal function: no dose adjustment is required.

For patients with impaired renal function, the dose calculation must be carried out taking into account the creatinine clearance in accordance with the table.

To use this dosing table, the patient's creatinine clearance (CLcr) in ml/min must be estimated. CLcr (ml/min) should be estimated from serum creatinine (mg/dl) using the appropriate formula.

Dose adjustment for patients with impaired renal function:

In children with impaired renal function, the dose must be adjusted individually taking into account the patient's renal clearance and body weight.

There are no specific data on use in children with impaired renal function.

Patients with hepatic impairment.

No dose adjustment is required in patients with solely hepatic impairment. In patients with both hepatic and renal impairment, the dose should be adjusted according to the table above.

Duration of use.

Patients with intermittent allergic rhinitis (symptoms lasting less than 4 days a week or less than 4 weeks a year) should be treated according to the course of the disease and history: treatment can be stopped when symptoms disappear and restarted when they reappear. In case of persistent allergic rhinitis (symptoms lasting more than 4 days a week or more than 4 weeks a year), continuous therapy can be offered during the period of contact with allergens. There is clinical experience with the use of levocetirizine for at least a 6-month treatment period. For chronic diseases (chronic allergic rhinitis, chronic urticaria), the duration of treatment is up to 1 year.

Children.

The drug is used in children from 6 years of age.