Cesera

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEZERA® (CEZERA®)

Composition:

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

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry White 33G28707 (containing hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets with beveled edges.

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

Pharmacological Properties

Pharmacodynamics

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the group of competitive histamine antagonists. Its pharmacological effect is due to blockade of H1-histamine receptors. The affinity of levocetirizine for H1-histamine receptors is twice as high as that of cetirizine. It affects the histamine-dependent phase of allergic reactions, 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 minimal anticholinergic and anti-serotonergic activity. At therapeutic doses, it has virtually no sedative effect.

Pharmacokinetics

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

Absorption

The drug is rapidly absorbed after oral administration. Food does not affect the extent of absorption but reduces its rate. Bioavailability reaches 100%. In 50% of patients, the effect of the drug develops within 12 minutes after a single dose, and in 95% of patients – within 0.5–1 hour. Maximum plasma concentration (Cmax) is achieved within 50 minutes after a single oral therapeutic dose and is maintained for up to 2 days. Cmax is 207 ng/ml after a single dose and 308 ng/ml after repeated dosing of 5 mg, respectively.

Distribution

There is no available information on tissue distribution or on the ability of levocetirizine to cross the blood-brain barrier.

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, while oxidation involves multiple cytochrome isoforms. Levocetirizine does not affect the activity of cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4, even at concentrations exceeding peak levels after a 5 mg oral dose. Due to the low extent of metabolism and lack of enzyme inhibition enhancement, drug interactions (either as perpetrator or victim) are unlikely.

Excretion

Elimination of the drug occurs mainly via glomerular filtration and active tubular secretion. The elimination half-life (T1/2) is 7.9 ± 1.9 hours, and total clearance is 0.63 ml/min/kg. The drug does not accumulate and is completely eliminated from the body within 96 hours. 85.4% of the administered dose is excreted unchanged in urine, and approximately 12.9% in feces.

Renal Impairment

In patients with impaired renal function (creatinine clearance < 40 ml/min), drug clearance is reduced and T1/2 is prolonged (in patients undergoing hemodialysis, total clearance is reduced by 80%), necessitating appropriate dose adjustment. During a standard 4-hour hemodialysis session, only a small fraction (less than 10%) of levocetirizine is removed. Levocetirizine is excreted into breast milk.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to levocetirizine, other piperazine derivatives, or to any other component of the medicinal product.
• Patients with end-stage renal disease with a calculated glomerular filtration rate (cGFR) below 15 mL/min (requiring dialysis).
• Rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Interaction with other medicinal products and other forms of interaction.

Studies on interaction with levocetirizine (including with CYP3A4 inducers) have not been conducted. Studies with cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse effects. In a multiple-dose study, concomitant administration with theophylline (400 mg daily) resulted in a slight reduction (by 16%) in cetirizine clearance (theophylline distribution was not altered). In another multiple-dose study, coadministration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily) increased cetirizine exposure by approximately 40%, while ritonavir distribution was slightly altered (-11%) with concomitant cetirizine use.

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

Concomitant use of cetirizine or levocetirizine with alcohol or other central nervous system depressants in sensitive patients may cause additional impairment of attention and ability to perform tasks.

Special precautions for use

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

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

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

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

Pruritus may occur after discontinuation of levocetirizine, even if this symptom was not present before treatment initiation. The symptom may resolve spontaneously. In some cases, it may be intense and require re-initiation of treatment. The symptom should resolve after restarting therapy.

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 prescribed levocetirizine in a pharmaceutical form suitable for pediatric use.

There are no data on enhanced effects of sedatives when levocetirizine is used at therapeutic doses. However, concomitant use of sedatives during treatment should be avoided.

Since the product contains lactose, it is not recommended for patients with rare hereditary problems such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Levocetirizine is contraindicated during pregnancy. Cetirizine passes into breast milk; therefore, breastfeeding should be discontinued if use of the drug 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

Comparative clinical studies have not shown any evidence that levocetirizine, at recommended doses, impairs attention, reaction speed, or the ability to drive a car or operate machinery. However, some patients may experience drowsiness, 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.

Dosage and Administration.

The drug is intended for administration to adults and children aged 6 years and older at a daily dose of 5 mg once daily. The tablet should be taken regardless of food intake. The tablet must be swallowed whole with a small amount of water.

Elderly Patients

Elderly patients with normal renal function do not require dose adjustment.

Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see section “Renal Impairment*”* ).

Renal Impairment

For patients with renal function impairment, dosage must be calculated according to the degree of renal impairment (creatinine clearance) as specified in the table below.

To apply this dosing table, the patient's creatinine clearance (CrCl) in mL/min must be estimated. CrCl (mL/min) should be estimated from serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment of the drug for patients with impaired renal function

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 available regarding use in children with renal impairment.

Hepatic impairment

Dose adjustment is not required in patients with severe hepatic impairment. For patients with both hepatic and renal impairment, adjust the dosage regimen according to the table provided 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 this pharmaceutical form (film-coated tablets). It is recommended to prescribe levocetirizine in a pharmaceutical form suitable for paediatric use.

Duration of treatment: Patients with intermittent allergic rhinitis (duration of symptoms < 4 days per week or for less than 4 weeks) should be treated according to the disease and medical history; treatment may be discontinued if symptoms resolve and may be restarted upon recurrence of symptoms. For persistent allergic rhinitis (duration of symptoms > 4 days per week and for more than 4 weeks) during allergen exposure periods, continuous therapy may be considered. In chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may last up to 1 year (data are available from clinical studies using the racemate).

Children.

The tablet formulation of the drug should not be used in children under 6 years of age, as this pharmaceutical form does not allow for appropriate dose adjustment. This patient group is recommended to receive levocetirizine in a pharmaceutical form suitable for paediatric use.

Overdose.

Symptoms: Symptoms of overdose may include somnolence in adults and initial excitation and increased irritability followed by somnolence 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 intake. Haemodialysis is not effective in removing levocetirizine from the body.

Side effects

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders

Not known: increased hypersensitivity, including anaphylaxis.

Nutritional and metabolism disorders

Not known: increased appetite.

Psychiatric disorders

Not known: somnolence, sleep disturbances, excitement, aggression, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

Nervous system disorders

Not known: headache, increased fatigue, weakness, asthenia, seizures, paraesthesia, dizziness, syncope, tremor, dysgeusia.

Ear and labyrinth disorders

Not known: vertigo.

Eye disorders

Not known: visual disturbances, blurred vision, nystagmus.

Cardiac disorders

Not known: palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders

Not known: dyspnoea.

Gastrointestinal disorders

Not known: nausea, vomiting, constipation, dry mouth, diarrhoea, abdominal pain.

Hepatobiliary disorders

Not known: hepatitis.

Renal and urinary disorders

Not known: dysuria, urinary retention.

Skin and subcutaneous tissue disorders

Not known: angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders

Not known: myalgia, arthralgia.

General disorders and administration site conditions

Not known: oedema.

Investigations

Not known: weight gain, abnormal liver function tests.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of the reach and sight of children.

Packaging.

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

Pharmaceutical category.

Over-the-counter (without prescription).

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.