Levzirin

INSTRUCTIONS for medical use of the medicinal product LEVZIRIN (LevZirin)

Composition:

Active substance: levocetirizine;

One tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, coating: Opadry white YS-1-7003: titanium dioxide (E 171), hypromellose, polyethylene glycol, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in colour, round-shaped, biconvex, with a break line on one side and an engraving «Н», and an engraving «161» on the other side.

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 class 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 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. It has virtually no anticholinergic or anti-serotonin activity. At therapeutic doses, it exhibits almost no sedative effect.

Pharmacokinetics

The pharmacokinetic parameters of levocetirizine are linear and do not differ significantly from those of cetirizine.

Absorption. The drug is rapidly absorbed after oral administration. Food intake does not affect the extent of absorption but reduces its rate. Bioavailability is 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 reached within 50 minutes after a single oral therapeutic dose and is maintained for up to 2 days. Maximum concentration (Cmax) is 207 ng/mL after a single dose and 308 ng/mL after repeated dosing at 5 mg, respectively.

Distribution. There is no available information regarding tissue distribution or penetration of levocetirizine across the blood-brain barrier.

Biotransformation. 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 a range of cytochrome isoenzymes are involved in oxidation. Levocetirizine does not affect the activity of cytochrome isoenzymes 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 with levocetirizine are unlikely.

Elimination. The drug is primarily excreted via glomerular filtration and active tubular secretion. The elimination half-life (T1/2) is 7.9±1.9 hours, and total body 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.

In patients with impaired renal function (creatinine clearance < 40 mL/min), drug clearance is reduced and T1/2 is prolonged (for example, 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. The drug penetrates 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.
• Severe form of chronic renal insufficiency (creatinine clearance < 10 ml/min).

Interaction with other medicinal products and other forms of interaction.

Interaction studies 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 per day) resulted in a slight decrease (by 16%) in cetirizine clearance (theophylline distribution was not altered). In another multiple-dose study, co-administration of ritonavir (600 mg twice daily) and cetirizine (10 mg once 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 (CNS) depressants in sensitive patients may result in 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 adjustment is required) and in elderly patients with renal insufficiency (possible reduction in glomerular filtration rate). Alcohol consumption must be avoided during treatment with this medicinal product.

Caution is necessary 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.

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

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, the symptom may be intense and may necessitate re-treatment. The symptom should resolve upon resumption of treatment.

The tablet formulation should not be administered to 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 indicating enhancement of the effect 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 conditions 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) regarding the effect of levocetirizine on fertility.

Ability to influence reaction rate when driving or operating machinery.

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

Dosage and Administration.

The drug should be administered orally to adults and children aged 6 years and older at a daily dose of 5 mg once daily. The tablet should be taken with food or on an empty stomach, without chewing, and swallowed 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 impairment, dosage must be adjusted according to the degree of renal dysfunction (creatinine clearance) as specified in the table below.

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

In patients 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

No dosage adjustment is required in patients with hepatic impairment alone. For patients with both hepatic and renal impairment, adjust the dosage regimen 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, it is not possible to adjust the dose of the drug in 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 (disease symptoms lasting < 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 restarted upon recurrence. In cases of persistent allergic rhinitis (disease symptoms lasting > 4 days per week and for more than 4 weeks) during allergen exposure periods, continuous therapy may be considered. For chronic conditions (chronic allergic rhinitis, chronic urticaria), the duration of treatment may last up to 1 year (data available from clinical trials using the racemate).

Children.

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

Overdose.

Symptoms: Symptoms of overdose may include somnolence in adult patients and initial excitation, 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 for removing levocetirizine from the body.

Adverse Reactions

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

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

Cardiac disorders: palpitations, tachycardia.

Eye disorders: visual 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 and administration site conditions: edema.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister, 1 or 3 blisters per cardboard box.

Supply category. Over-the-counter.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and place of business.

Unit III, Formulation Plot No. 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.

Marketing authorization holder.

Mega Lifesciences (Australia) Pty Ltd.

Address of the marketing authorization holder.

60, National Avenue, Pakenham, Victoria 3810, Australia.