Cetlo®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETLO® (CETLO®)

Composition:

Active substance: levocetirizine;

One film-coated tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: sodium croscarmellose, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate; film coating Opadry white (03K58884): hypromellose, titanium dioxide (E 171), triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: almost white to white, oval, biconvex, film-coated tablets.

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 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 reduces the symptoms of allergic reactions, exerts anti-edematous, antipruritic, and anti-inflammatory effects, and has almost no anticholinergic or anti-serotonin activity.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine are linear and are almost identical to those of cetirizine.

Absorption.

The drug is rapidly absorbed after oral administration. The extent of absorption is independent of dose and is not altered by food intake; however, the rate of absorption is reduced, and the time to maximum concentration (Cₘₐₓ) is delayed. Steady-state plasma concentration is achieved after 2 days of continuous administration. Cₘₐₓ in plasma is reached within 50 minutes and amounts to 270 ng/mL after a single dose and 308 ng/mL after repeated administration at a dose of 5 mg per day. In 50% of patients, the effect of the drug begins within 12 minutes after a single dose, and in 95% of patients, within 0.5–1 hour. Bioavailability is approximately 100%.

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 animal studies, the highest concentrations were observed in the liver and kidneys, and the lowest in central nervous system tissues. 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 the cytochrome CYP3A4, whereas 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 the low extent of metabolism and lack of inhibitory potential on other metabolic pathways, drug interactions with levocetirizine (and vice versa) are unlikely.

Elimination.

Elimination of the drug occurs mainly via glomerular filtration and active tubular secretion. The elimination half-life (T₁/₂) in plasma in adults is 7.9 ± 1.9 hours. Total body clearance in adults is 0.63 mL/min/kg. The majority of levocetirizine and its metabolites are excreted in urine (on average, 85.4% of the administered dose). Only 12.9% of the administered dose is excreted in feces.

Levocetirizine clearance correlates with creatinine clearance. Therefore, dosage regimens of levocetirizine should be adjusted according to creatinine clearance in patients with moderate to severe renal impairment. In cases of anuria at end-stage renal disease, total body clearance is reduced by approximately 80% compared to individuals without such impairment. 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, or to any 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 treatment).

Interaction with other medicinal products and other forms of interaction.

Studies on levocetirizine interaction with other drugs (including CYP3A4 inducers) have not been conducted. Studies on cetirizine racemate have shown that concomitant administration with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, or diazepam does not cause clinically significant adverse interactions.

Concomitant use with theophylline (400 mg per day) reduces total clearance of cetirizine by 16% (the pharmacokinetics of theophylline remain unchanged). In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) when co-administered with cetirizine.

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

There are no data on the potentiation of sedative effects when used at therapeutic doses. However, the use of sedatives should be avoided during treatment with this medicinal product.

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

Special precautions for use.

Use with caution in patients with chronic renal insufficiency (dose adjustment is required) and in elderly patients with renal impairment (due to possible reduction in glomerular filtration rate).

Alcohol consumption should be avoided during treatment with this medication.

When prescribing the drug, attention should be paid to the presence of certain factors in patients that may provoke urinary retention (such as spinal cord injuries, benign prostatic hyperplasia), since levocetirizine increases the risk of urinary retention.

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

Antihistamines suppress the response to skin allergy tests; therefore, the use of 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. Pruritus may resolve spontaneously. In some cases, it may be intense and require re-treatment. Pruritus should resolve after re-initiation of treatment.

Levocetirizine in tablet form 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.

This medicinal product contains less than 1 mmol/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (less than 300 pregnancy outcomes). However, extensive data on cetirizine, the racemate of levocetirizine (over 1000 pregnancy outcomes) do not indicate any malformative or fetal/neonatal toxicity. Animal studies have shown no direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development.

Levocetirizine may be considered for use during pregnancy if clinically needed.

Breastfeeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human milk. Therefore, excretion of levocetirizine in breast milk is likely. Adverse reactions related to levocetirizine may occur in breastfed infants. Thus, caution should be exercised when prescribing levocetirizine to breastfeeding women.

Fertility

There are no clinical data on the effect of levocetirizine on fertility.

Ability to influence reaction speed when driving vehicles or operating machinery.

Comparative clinical studies have not shown any evidence that levocetirizine, at the recommended dose, impairs mental alertness, reaction ability, or the ability to drive vehicles.

Nevertheless, some patients may experience somnolence, fatigue, or asthenia during levocetirizine therapy. Therefore, patients intending to drive, engage in potentially hazardous activities, or operate machinery should take into account their individual response to the medicinal product.

Method of administration and dosage.

The medicinal product is intended for oral administration.

Take independently of food intake; swallow the tablet whole with a small amount of water without chewing.

Adults and children aged 12 years and older

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

Elderly patients

Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see section "Renal insufficiency").

Dosing intervals should be individually adjusted according to renal function (eGFR – estimated glomerular filtration rate). Refer to the table and adjust the dose as indicated.

Dose adjustment of the drug in patients with impaired renal function

Dose adjustment in children with renal impairment should be individualized based on renal clearance and body weight.

There are no specific data available on the use of levocetirizine in children with renal impairment.

Patients with hepatic insufficiency do not require dose adjustment.

For patients with both hepatic and renal insufficiency, dosage regimen should be adjusted according to the table above.

Pediatric population

Children aged 6 to 12 years

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

Children aged 2 to 6 years

Levocetirizine tablets should not be administered to children under 6 years of age, as this pharmaceutical form does not allow appropriate dose adjustment. This patient group should be prescribed levocetirizine in a pharmaceutical form suitable for pediatric use.

Duration of treatment

For patients with intermittent allergic rhinitis (duration of symptoms < 4 days per week or less than 4 weeks), treatment should be administered according to the disease and medical history; therapy may be discontinued if symptoms resolve and restarted upon recurrence.

In cases of persistent allergic rhinitis (duration of symptoms > 4 days per week or more than 4 weeks), during allergen exposure periods, physicians may prescribe continuous therapy. Clinical experience supports the use of levocetirizine for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year.

Children

Levocetirizine tablets should not be used in children under 6 years of age, as this pharmaceutical form does not allow appropriate dose adjustment. This patient group should be prescribed levocetirizine in another pharmaceutical form suitable for pediatric use.

Overdose

Symptoms of overdose may include drowsiness in adults and initial excitation with increased irritability followed by drowsiness in children.

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

Adverse Reactions

Adverse reactions reported during clinical trials are described below.

Adults and adolescents aged 12 years and older

In therapeutic trials involving men and women aged 12 to 71 years, 15.1% of patients in the 5 mg levocetirizine group experienced at least one adverse reaction, compared with 11.3% in the placebo group. 91.6% of these adverse reactions were of mild to moderate intensity. In therapeutic trials, the discontinuation rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Therapeutic clinical trials of levocetirizine included 935 patients who received the drug at the recommended dose of 5 mg daily. In this population, the following adverse reactions were reported with an incidence of 1% or greater (common: ≥1/100 to <1/10) during treatment with levocetirizine 5 mg or placebo:

Uncommon (≥ 1/1000, < 1/100) asthenia and abdominal pain have also been reported.

The frequency of sedative adverse reactions such as somnolence, fatigue, and asthenia was generally higher (8.1%) with levocetirizine 5 mg than with placebo (3.1%).

Children

In two placebo-controlled studies involving pediatric patients aged 6 to 11 months and aged 1 to 6 years, 159 subjects received levocetirizine at a dose of 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The incidence of adverse reactions with levocetirizine or placebo was 1% or higher.

Double-blind, placebo-controlled studies were conducted in children aged 6 to 12 years, in which 243 children received 5 mg of levocetirizine once daily for various periods ranging from less than 1 week to 13 weeks.

The following adverse reactions were reported with an incidence of 1% or greater during treatment with levocetirizine or placebo.

In the post-marketing period, the following adverse reactions have also been reported. Adverse reactions are listed by system organ classes according to MedDRA and by frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from available data).

Immune system disorders: frequency not known – hypersensitivity, including anaphylaxis.

Nervous system disorders: frequency not known – convulsions, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Psychiatric disorders: frequency not known – sleep disorders, excitement, hallucinations, depression, aggression, insomnia, suicidal thoughts, nightmares.

Cardiac disorders: frequency not known – palpitations, tachycardia.

Eye disorders: visual disturbances, blurred vision, nystagmus.

Ear and labyrinth disorders: frequency not known – vertigo.

Hepatobiliary disorders: frequency not known – hepatitis.

Renal and urinary disorders: frequency not known – dysuria, urinary retention.

Immune system disorders: frequency not known – hypersensitivity, including anaphylaxis.

Respiratory, thoracic and mediastinal disorders: frequency not known – dyspnoea.

Gastrointestinal disorders: frequency not known – nausea, vomiting, diarrhoea.

Skin and subcutaneous tissue disorders: frequency not known – angioneurotic oedema, persistent drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: frequency not known – myalgia, arthralgia.

Investigations: weight increased, hepatic function test abnormal.

Metabolism and nutrition disorders: frequency not known – increased appetite.

General disorders: frequency not known – oedema.

Laboratory investigations: frequency not known – weight increased, hepatic function test abnormal.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

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 any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard pack.

Release category. Over-the-counter.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address and location of operations.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.