Cetrilev neo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETRILEV NEO (CETRILEVNEO)

Composition:

Active substance: levocetirizine;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, lactose monohydrate, magnesium stearate, Opadry White YS-1-7003 (hypromellose (E 464), titanium dioxide (E 171), polysorbate, polyethylene glycol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, round-shaped, biconvex, with a score line, marked with "N" on one side and "161" 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 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 reaction development, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and suppresses the progression of allergic reactions, exerts anti-exudative, antipruritic, and anti-inflammatory effects, and has almost no anticholinergic or anti-serotonergic activity.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine exhibit linear kinetics and are independent of dose and time, showing low variability among different patients. The pharmacokinetic profile following administration of a single enantiomer is the same as that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

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

Therapeutic effect develops within 12 minutes after a single dose in 50% of patients and within 0.5–1 hour in 95% of patients. In adults, peak plasma concentration (Cmax) is achieved within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is reached after 2 days of daily administration. Cmax is 207 ng/mL after a single dose and 308 ng/mL after repeated administration of 5 mg once daily.

Distribution. There is no available information regarding tissue distribution of the drug in humans or its penetration through the blood-brain barrier. In animal studies, the highest concentrations were observed in the liver and kidneys, while the lowest were found in central nervous system tissues. The distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg. Plasma protein binding in humans is 90%.

Metabolism. In humans, the extent of metabolism is less than 14% of the administered dose of levocetirizine, suggesting that differences due to genetic polymorphism or concomitant use of enzyme inhibitors are likely to be minimal. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by cytochrome CYP3A4, whereas aromatic 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 the maximum levels achieved after a 5 mg oral dose. Due to its low extent of metabolism and lack of inhibitory potential, drug interactions involving levocetirizine (either as a perpetrator or victim) are unlikely.

Elimination. The drug is eliminated via two pathways: glomerular filtration and active tubular secretion. The elimination half-life (T₁/₂) in plasma is 7.9 ± 1.9 hours in adults. The T₁/₂ is shorter in younger children. The mean apparent total clearance in adults is 0.63 mL/min/kg. Elimination of levocetirizine and its metabolites occurs primarily via urine (on average, 85.4% of the administered dose is excreted renally). Only 12.9% of the administered dose is excreted in feces.

Special populations

Renal impairment

The apparent clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing interval should be adjusted based on creatinine clearance. In anuric patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to individuals with normal renal function. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is less than 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 of the excipients of the medicinal product.

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

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

Interaction with other medicinal products and other forms of interaction.

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

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

Food intake does not affect the extent of drug absorption, but co-ingestion with food reduces the rate of 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.

Use with caution in patients with chronic renal impairment (dose adjustment 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 (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the medicinal product to patients with factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), it should be borne in mind that 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 seizures.

Antihistamines suppress the response to skin allergy tests; therefore, treatment with the medicinal product should be discontinued 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-initiation of treatment. The symptom should resolve upon resuming treatment.

The tablet formulation of the medicinal product 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 dosage form suitable for pediatric use.

Use during pregnancy or breastfeeding.

Levocetirizine is contraindicated during pregnancy. Cetirizine is excreted in breast milk; therefore, breastfeeding should be discontinued if treatment with the 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 potentially hazardous machinery during treatment with this medicinal product.

Dosage and Administration

The medicine is intended for 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

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 function impairment (creatinine clearance) as shown in the table (see table below).

To do this, determine the patient's creatinine clearance (CrCl) in mL/min from serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment of the drug for patients with impaired renal function

For children with impaired kidney function, 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 the use of the drug in children with impaired kidney function.

Hepatic impairment

Dosage adjustment is not required in patients with hepatic impairment. In patients with both hepatic and renal impairment, dosage should be adjusted 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 the film-coated tablet formulation. It is recommended to prescribe levocetirizine in a dosage form suitable for paediatric use.

Method of administration

The tablet should be taken orally, independently of food intake. The tablet must be swallowed whole with a small amount of water. The daily dose is recommended to 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 course of the disease and medical history: treatment may be discontinued if symptoms resolve and resumed again upon recurrence of symptoms. For persistent allergic rhinitis (duration of symptoms more than 4 days per week or more than 4 weeks per year), continuous therapy may be recommended during the period of allergen exposure. There is clinical experience with the use of levocetirizine for at least a 6-month treatment period. In chronic conditions (chronic allergic rhinitis, chronic urticaria), the treatment duration may extend up to 1 year (data available from clinical studies using the racemate).

Children.

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. For this patient group, levocetirizine in a dosage form suitable for paediatric use is recommended.

Overdose.

Symptoms. Symptoms of overdose in adults may include somnolence. In children, initial excitation and increased irritability may occur, followed by somnolence.

Treatment. There is no specific antidote for levocetirizine. In case of overdose symptoms, symptomatic and supportive therapy is recommended. Gastric lavage may be considered shortly after drug intake. Hemodialysis is not effective for removing levocetirizine from the body.

Adverse Reactions

Immune system disorders: hypersensitivity, including anaphylaxis.

Nutrition and metabolism disorders: increased appetite.

Nervous system disorders: somnolence, headache, fatigue, weakness, asthenia, seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Psychiatric disorders: sleep disorders, 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.

Respiratory, thoracic and mediastinal disorders: dyspnoea.

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

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

General disorders: oedema.

Investigations: 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 medicine authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

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

Supply category. Over-the-counter.

Manufacturer.

Hetero Labs Limited, India.

Manufacturer's address and place of business.

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