Alzerin

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

Composition:

Active substance: levocetirizine dihydrochloride;

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

Excipients: microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose monohydrate, magnesium stearate;

coating composition: Opadry II 33G28523 white (hypromellose, titanium dioxide (E 171), polyethylene glycol 3350, triacetyl glycerin, lactose monohydrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, moderately biconvex, film-coated tablets, odorless or almost odorless, with a engraved stylized letter «E» on one side and the number «281» on the other.

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 class of competitive histamine antagonists. Its pharmacological action is due to blockade of H1-histamine receptors. 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 almost no anticholinergic or anti-serotonin activity.

Pharmacokinetics.

Pharmacokinetic parameters of levocetirizine are linear and are nearly identical to those of cetirizine.

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

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

Distribution. There is no available information 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, while the lowest were found 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 primarily involves cytochrome CYP3A4, whereas oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding the maximum levels achieved 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. The drug is primarily excreted 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. The main route of elimination of levocetirizine and its metabolites is via urine (on average, 85.4% of the administered dose is excreted). 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, for patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted according to creatinine clearance. In anuria associated with end-stage renal disease, total systemic clearance is reduced by approximately 80% compared to that in individuals without such impairment. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is < 10%.

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 excipients of the medicinal product.

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

Rare hereditary diseases of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Interaction with other medicinal products and other forms of interaction.

Interaction studies (including studies with CYP3A4 inducers) have not been conducted with levocetirizine.

Studies with cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. Concomitant use with theophylline (400 mg daily) reduces total levocetirizine clearance by 16% (theophylline kinetics remain unchanged). In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir disposition was slightly altered (-11%) following coadministration with cetirizine.

There are no data regarding potentiation of the effect of sedatives when used at therapeutic doses. However, concomitant use of sedatives during treatment should be avoided.

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

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

Special precautions for use

Use with caution in patients with chronic renal insufficiency (dose adjustment is required) and in elderly patients with renal impairment (possible reduction in glomerular filtration rate). Alcohol consumption should be avoided during treatment with this medicinal product.

In patients with certain factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), careful consideration should be given when determining the dosage, as levocetirizine may increase the risk of urinary retention.

Levocetirizine should be used with caution in patients with epilepsy or at risk of seizures, as its use may lead to increased seizure activity.

Antihistamines suppress the response to skin allergy tests; therefore, treatment with this medicinal product should be discontinued at least 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 may be required. Treatment may be restarted only after complete resolution of symptoms.

The tablet form of the medicinal product is not recommended for children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. Pediatric patients should be prescribed levocetirizine in a dosage form suitable for pediatric use.

Use during pregnancy or breastfeeding

Levocetirizine is contraindicated during pregnancy. Levocetirizine passes into breast milk; therefore, breastfeeding should be discontinued if treatment with this medicinal product is necessary.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

Patients should refrain from driving or operating machinery during treatment with this medicinal product.

Dosage and Administration

The drug is intended for use in adults and children aged 6 years and older.

Recommended doses:

Adults and children aged 12 years and older: the daily dose is 5 mg (1 film-coated tablet) once daily.

Elderly patients

Dose adjustment is not required in elderly patients with normal renal function. Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see section "Renal Insufficiency").

Renal Insufficiency

Dosage must be adjusted in patients with renal function impairment according to the creatinine clearance (CrCl) values presented in the table.

To use this dosing table, the patient's creatinine clearance (CrCl) in milliliters per minute must first be estimated. CrCl (mL/min) can be 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 renal clearance and body weight.

There are no specific data regarding use in children with renal impairment.

Hepatic impairment

Patients with hepatic impairment alone do not require dose adjustment. Patients with both hepatic and renal impairment should have their dosage regimen adjusted according to the table above.

Paediatric 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 is not feasible with the film-coated tablet formulation. It is recommended to administer levocetirizine in a dosage form suitable for paediatric use.

Method of administration

Take the tablet orally, regardless of food intake. The tablet should be swallowed whole with a small amount of water. The daily dose should preferably be taken as a single dose.

Duration of treatment.

Patients with intermittent allergic rhinitis (duration of symptoms 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. For persistent allergic rhinitis (symptoms lasting more than 4 days per week and for 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 treatment duration may extend up to 1 year (data available from clinical studies using cetirizine (racemate)).

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 administered levocetirizine in a dosage form suitable for paediatric 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 treatment is recommended. Gastric lavage should be considered shortly after drug ingestion. Haemodialysis is not effective for removing levocetirizine from the body.

Adverse Reactions

Nervous system disorders: drowsiness, headache, increased fatigue, weakness, asthenia, seizures, paresthesia, dizziness, fainting, tremor, dysgeusia.

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

Cardiac disorders: palpitations, tachycardia.

Eye disorders: vision disturbances, blurred vision, nystagmus.

Ear and labyrinth 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: angioedema, persistent drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Investigations: weight gain, abnormal liver function tests.

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.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 5 years.

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

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging.

7 tablets in a blister; 1 or 2 blisters in a cardboard box;

10 tablets in a blister; 1, 2, or 3 blisters in a cardboard box.

Dispensing category. Over-the-counter.

Manufacturer. EGIS Pharmaceuticals Ltd., Hungary.

Manufacturer's address and place of business.

1165 Budapest, Beketere 118-120, Hungary.