Alzerin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALE RZIN (ALERZIN®)

Composition:

Active substance: levocetirizine dihydrochloride;

1 ml contains 5 mg of levocetirizine dihydrochloride (equivalent to 4.21 mg of levocetirizine);

Excipients: glycerol 85%, propylene glycol, sodium saccharin, sodium acetate trihydrate, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), glacial acetic acid, purified water.

Pharmaceutical form. Oral drops, solution.

Main physicochemical properties: colorless or almost colorless sweet liquid without sediment, with a slight odor of acetic acid.

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

Pharmacological properties.

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the group of competitive histamine antagonists.

The pharmacological effect is due to blockade of H1-histamine receptors.

Levocetirizine has a 2-fold higher affinity for H1-histamine receptors than cetirizine. It affects the histamine-dependent phase of allergic reaction development, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and alleviates the course of allergic reactions, exerts anti-exudative, antipruritic, and anti-inflammatory effects, and has minimal anticholinergic and anti-serotonin activity. At therapeutic doses, it has almost no sedative effect.

Pharmacokinetics.

Pharmacokinetic parameters of levocetirizine are linear and differ little from those of cetirizine.

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

In 50% of patients, the effect of the drug develops within 12 minutes after a single dose, and in 95% – within 0.5–1 hour. Cmax in blood plasma is achieved within 50 minutes after a single therapeutic dose and is maintained for up to 2 days. Cmax is 270 ng/mL after a single dose and 308 ng/mL after repeated administration of a 5 mg dose.

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 studies, the highest concentrations were observed in the liver and kidneys, and the lowest – in tissues of the central nervous system. The volume of distribution is 0.4 L/kg. Plasma protein binding is 90%.

Metabolism. Approximately 14% of levocetirizine undergoes metabolism in the human body. The metabolic process includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation occurs primarily via cytochrome CYP3A4, while 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 maximum levels after a 5 mg oral dose. Due to the low extent of metabolism and lack of inhibitory potential, drug interactions with levocetirizine (and vice versa) are unlikely.

Excretion. Elimination of the drug occurs mainly via 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 young children. 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.

Special populations

Renal impairment.

The apparent systemic 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 anuria at the end-stage of renal disease, total systemic clearance in patients is reduced by approximately 80% compared to individuals without such impairment. The amount of levocetirizine removed during a standard 4-hour hemodialysis session was < 10%.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to levocetirizine or to any other component of this medicinal form, or to any derivatives of piperazine.

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

Interaction with other medicinal products and other forms of interaction.

Studies on levocetirizine regarding interaction (including studies with CYP3A4 inducers) have not been conducted. Studies with cetirizine (the racemate compound) showed that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. Concomitant administration with theophylline (400 mg per day) reduces the total clearance of levocetirizine by 16% (the kinetics of theophylline are not altered). In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg once daily), the extent of exposure to cetirizine increased by approximately 40%, while the distribution of ritonavir was slightly altered (-11%) during concurrent administration of cetirizine.

There are no data on the potentiation of sedative effects when used at therapeutic doses. However, concomitant use of sedatives should be avoided during treatment with this medicinal product.

Levocetirizine does not enhance the effect of alcohol; however, in sensitive patients, concomitant use of Alzerin and alcohol or other agents that depress central nervous system function may affect central nervous system function.

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

Special precautions for use.

Use with caution in patients with chronic renal insufficiency (dose regimen adjustment is required) and in elderly patients (possible reduction in glomerular filtration rate). The drug should be used cautiously when taken concomitantly with alcohol (see section "Interaction with other medicinal products and other types of interactions").

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

Caution is advised when prescribing the drug to patients with certain factors predisposing to urinary retention (e.g., spinal cord injuries, benign prostatic hyperplasia), as levocetirizine may increase the risk of urinary retention.

Methylparahydroxybenzoate and propylparahydroxybenzoate contained in oral drops may cause allergic reactions (possibly delayed).

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

Pruritus may occur after discontinuation of levocetirizine, even if these symptoms were not present before treatment initiation. Symptoms may resolve spontaneously. In some cases, symptoms may be severe and re-initiation of treatment after discontinuation may be necessary. Re-treatment may only be started once symptoms have resolved.

Use during pregnancy or breastfeeding.

Levocetirizine is contraindicated during pregnancy. Levocetirizine is excreted in breast milk; therefore, breastfeeding should be discontinued if use of the drug is necessary.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery while taking this drug.

Method of Administration and Dosage

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 (20 drops) once daily.

Elderly patients

In elderly patients with normal renal function, dose adjustment of the medication is not required.

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

Renal Insufficiency

In elderly patients with normal renal function, dose adjustment of the medication is not required.

For patients with impaired renal function, dosage must be calculated based on creatinine clearance (CrCl) according to the table below.

To use this dosing table, it is necessary to estimate the patient's creatinine clearance (CrCl) in milliliters per minute (mL/min). CrCl is estimated from 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 use in children with renal impairment.

Hepatic insufficiency

Dose adjustment is not required in patients with hepatic insufficiency. In patients with both hepatic and renal insufficiency, adjust the dosage regimen according to the table above.

Pediatric population

Recommended doses:

• Children aged 2 to 6 years: the recommended daily dose is 2.5 mg (10 drops). This dose should be administered as 1.25 mg (5 drops) twice daily;
• Children aged 6 to 12 years: the recommended daily dose is 5 mg (20 drops) once daily.

Method of administration

The drops should be dispensed into a spoon or diluted in a small amount of water and taken orally. When diluting the drops, it should be taken into account (especially when administering to children) that the volume of water to which the drops are added should correspond to the amount of liquid the patient can swallow. The diluted solution should be taken immediately.

When counting drops, the bottle should be held vertically (upside down). If there is no drop flow (if the required number of drops has not been obtained), the bottle should be inverted into a vertical position and then turned back upside down, and the drop counting continued.

The drug may be taken independently of food intake.

Duration of use

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

Children

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

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

Overdose

Symptoms: overdose symptoms may include drowsiness in adults and initial excitation with 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 ineffective for removing levocetirizine from the body.

Adverse reactions.

Central nervous system: somnolence, headache, increased fatigue, weakness, asthenia, seizures, paresthesia, dizziness, fainting, tremor, dysgeusia.

Psychiatric disorders: sleep disorders, excitement, hallucinations, depression, aggression, insomnia, suicidal thoughts.

Cardiac disorders: palpitations, tachycardia.

Eye disorders: visual disturbances, blurred vision.

Ear and labyrinthine disorders: vertigo.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

Immune system disorders: hypersensitivity, including anaphylaxis.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Gastrointestinal disorders: diarrhea, vomiting, constipation, dry mouth, nausea, abdominal pain.

Skin and subcutaneous tissue disorders: angioneurotic edema, persistent drug rash, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Investigations: increased body weight, deviations in liver function tests from normal values.

Metabolism and nutrition disorders: increased appetite.

General disorders: edema.

The medication should be discontinued if any of the above adverse effects occur and when the cause of their development cannot be clearly established.

Methylparahydroxybenzoate and propylparahydroxybenzoate contained in the oral drops may cause allergic reactions (possibly delayed).

Description of individual adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after approval of the medicinal product is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system.

Shelf life. 4 years.

After opening the bottle, store for no more than 6 weeks.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Do not freeze!

Packaging.

20 ml of solution in brown glass bottles with a polyethylene dropper;

1 bottle per cardboard box.

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

Manufacturer. EGIS Pharmaceuticals Plc., Hungary.

Manufacturer's address and place of business.

65 Matyas Kiraly Street, Kermend, 9900, Hungary.