Zenaro^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

ATC Code

R06AE09 (Levocetirizine)

Active Substance

Levocetirizine (Rec.INN registered by WHO)

Dosage Form

Zenaro®

Film-coated tablets, 5 mg: 7, 20, or 28 pcs.

Dosage Form, Packaging, and Composition

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Histamine H₁-receptor blocker. Antiallergic drug

Pharmacotherapeutic Group

Antiallergic agent – H₁-histamine receptor blocker

Pharmacological Action

Levocetirizine, the (R)-enantiomer of cetirizine, is an inhibitor of peripheral H₁-histamine receptors, with an affinity two times higher than that of cetirizine. After a single dose of levocetirizine, 90% binding of H₁-histamine receptors was observed after 4 hours and 57% after 24 hours.

It affects the histamine-dependent stage of allergic reactions; reduces eosinophil migration, reduces vascular permeability, and limits the release of inflammatory mediators.

It prevents the development and alleviates the course of allergic reactions, has an anti-exudative, antipruritic effect; it has practically no anticholinergic or antiserotonin action. In therapeutic doses, it has practically no sedative effect.

The effect begins within 12 minutes after a single dose in 50% of patients, within 1 hour in 95% of patients, and lasts for 24 hours.

It does not affect the QT interval on the ECG.

Pharmacokinetics

The pharmacokinetics are linear, independent of dose and time, and vary slightly among individuals.

Absorption

After oral administration, levocetirizine is absorbed rapidly and extensively. The maximum plasma concentration is reached 0.9 hours after drug intake. The equilibrium concentration is established after 2 days. The maximum plasma concentration after a single 5 mg dose of levocetirizine is 270 ng/ml, and after repeated administration of a 5 mg dose, it is 308 ng/ml. The extent of absorption is dose-dependent and is not impaired by food intake, but when taken with food, the maximum concentration decreases and its attainment is delayed.

Distribution

Levocetirizine is 90% bound to plasma proteins. The volume of distribution is 0.4 l/kg. Data on the distribution of levocetirizine in tissues and its penetration through the blood-brain barrier in humans are not available. Levocetirizine penetrates into breast milk.

Metabolism

In humans, less than 14% of the levocetirizine dose is metabolized, as the presumed differences in the pharmacokinetic profile of levocetirizine due to genetic polymorphism or concurrent administration of enzyme inhibitors are insignificant. Metabolic transformations involve oxidation of the aromatic ring, N- and O-dealkylation, and conjugation with taurine. The dealkylation process is mainly carried out by the CYP3A4 isoenzyme, while the oxidation of the aromatic ring occurs via many and/or unidentified CYP isoforms. Levocetirizine, when taken orally at a dose of 5 mg and/or at plasma concentrations exceeding the maximum, does not affect the activity of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4.

Due to limited metabolism and lack of metabolic inhibitory activity, interaction of levocetirizine at the metabolic level with other substances is unlikely.

Excretion

T_1/2 in adults is 7.9 ± 1.9 hours. The mean observed total clearance is 0.63 ml/min/kg. Levocetirizine is predominantly excreted in the urine, on average about 85.4% of the administered dose, via glomerular filtration and active tubular secretion. Excretion through the intestine (with feces) is only 12.9% of the administered dose.

Patients with renal impairment

The total clearance of levocetirizine depends on creatinine clearance (CrCl). Therefore, patients with moderate and severe renal impairment are recommended to increase the intervals between drug doses according to CrCl. In patients with anuria and end-stage renal failure, the total clearance of levocetirizine is reduced by approximately 80% compared to healthy individuals. The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure is less than 10%.

Indications

• Treatment of symptoms of perennial (persistent) and seasonal (intermittent) allergic rhinitis and allergic conjunctivitis, such as itching, sneezing, nasal congestion, rhinorrhea, lacrimation, conjunctival hyperemia;
• Hay fever;
• Urticaria, including chronic idiopathic urticaria;
• Angioedema (as an adjunctive therapy);
• Other allergic dermatoses accompanied by itching and rashes.

ICD codes

Dosage Regimen

The tablet should be taken orally, without chewing, with liquid, regardless of meals. It is recommended to take the daily dose in a single intake.

Adults, adolescents, and children over 6 years

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

Elderly patients

In elderly patients with moderate and severe renal impairment, dose adjustment is recommended (see “Patients with renal impairment” below).

Patients with renal impairment

The interval between drug doses is determined individually, taking into account renal function. Information on dose adjustment is provided in the table below. To use it, the patient’s creatinine clearance (CrCl) must be calculated in ml/min based on serum creatinine concentration (mg/dl) using the following formula:

[140 – age)] × weight (kg)
———————————————————————————————=CrCl
72 × serum creatinine (mg/dl)

× 0.85 for women

Dose adjustment in patients with renal impairment

In children with renal impairment, the dose should be adjusted individually, taking into account creatinine clearance and body weight. There are no separate data on use in children with renal impairment.

Patients with hepatic impairment

In isolated hepatic impairment, no dose adjustment is required. In patients with hepatorenal impairment, dose adjustment is recommended (see “Patients with renal impairment” above).

Duration of treatment

Treatment of allergic rhinitis is carried out in accordance with the course of the disease; the drug can be discontinued when symptoms disappear and resumed upon relapse. In the case of chronic allergic rhinitis, long-term treatment may be prescribed during the period of allergen exposure. Currently, clinical experience with levocetirizine in the form of 5 mg film-coated tablets is limited to 6 months.

Adverse Reactions

Side effects of levocetirizine are divided by system-organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA) classification with an indication of their frequency of occurrence: common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); very rare (< 1/10000).

Immune system disorders

Very rare: hypersensitivity reactions, including anaphylactic reactions.

Nervous system disorders:

Common: headache.

Uncommon: drowsiness

Very rare: aggression, agitation, hallucinations, depression, convulsions.

Eye disorders

Very rare: visual disturbances.

Cardiac disorders

Very rare: palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders:

Very rare: dyspnea.

Gastrointestinal disorders:

Common: dry mouth.

Uncommon: abdominal pain.

Very rare: nausea, diarrhea.

Hepatobiliary disorders

Very rare: hepatitis.

Skin and subcutaneous tissue disorders

Very rare: angioedema, pruritus, rash, including drug rash, urticaria.

Musculoskeletal and connective tissue disorders:

Very rare: myalgia.

General disorders:

Common: fatigue.

Uncommon: asthenia

Investigations

Very rare: impaired liver function tests, increased body weight.

Contraindications

• Hypersensitivity to levocetirizine and other piperazine derivatives or to any of the auxiliary components of the drug;
• End-stage renal failure with CrCl less than 10 ml/min;
• Pregnancy;
• Children under 6 years of age (for this dosage form);
• Congenital galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (due to the lactose content in the drug).

With caution

• Caution should be exercised when taking concomitantly with alcohol (see section “Drug Interactions”);
• Chronic renal failure with CrCl greater than 10 ml/min but less than 50 ml/min (requires dosage regimen adjustment);
• Elderly age (possible decrease in glomerular filtration).

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated.

Levocetirizine is excreted in breast milk, therefore, if it is necessary to use the drug during lactation, it is recommended to discontinue breastfeeding.

Use in Hepatic Impairment

In isolated hepatic impairment, no dose adjustment is required. In patients with hepatorenal impairment, dose adjustment is recommended (see “Patients with renal impairment” above).

Use in Renal Impairment

The interval between drug doses is determined individually, taking into account renal function. Information on dose adjustment is provided in the table.

In children with renal impairment, the dose should be adjusted individually, taking into account creatinine clearance and body weight. There are no separate data on use in children with renal impairment.

Pediatric Use

Contraindicated in children under 6 years of age.

Geriatric Use

In elderly patients with moderate and severe renal impairment, dose adjustment is recommended (see “Patients with renal impairment” below).

Special Precautions

It is not recommended to take ethanol during treatment with the drug.

Effect on ability to drive vehicles or operate machinery

Levocetirizine, when taken in recommended doses, does not have a negative effect on attention and speed of psychomotor reactions and the ability to drive vehicles. Nevertheless, during the period of taking the drug, it is advisable to refrain from engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms

Overdose symptoms may include drowsiness in adults and agitation, as well as restlessness, alternating with drowsiness, in children.

Treatment

There are no specific antidotes for levocetirizine.

In case of overdose, symptomatic or supportive treatment is recommended. If little time has passed since drug intake, gastric lavage should be performed. Levocetirizine is practically not removed by hemodialysis.

Drug Interactions

No drug interaction studies have been conducted with levocetirizine, including studies with inducers of the CYP3A4 isoenzyme.

The extent of absorption of levocetirizine was not reduced under the influence of food, although the rate of absorption decreased.

In sensitive patients, the simultaneous use of levocetirizine and alcohol or other substances that have a depressant effect on the central nervous system (CNS) may enhance the effect on the CNS.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children. Shelf life – 2 years.

Dispensing Status

Over-the-counter.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.