CETRILEV ODT

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETRILEV ODT (CETRILEV ODT)

Composition:

Active substance: levocetirizine dihydrochloride;

One orodispersible tablet contains 5 mg of levocetirizine dihydrochloride;

Excipients: potassium polacrilin; Pharmaburst B2 (mannitol (E 421), polyplasdone, sorbitol (E 420), silicified); lactose monohydrate; aspartame (E 951); colloidal anhydrous silicon dioxide; magnesium stearate; blackcurrant flavor.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties: round, white to almost white, flat tablets with beveled edges, smooth on both sides.

Pharmacotherapeutic group. Systemic antihistamines. Piperazine derivatives. ATC code R06AE09.

Pharmacological properties.

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine, belonging 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 the allergic reaction, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and suppresses the progression of allergic reactions, exerting anti-exudative, anti-pruritic, and anti-inflammatory effects, with minimal anticholinergic and 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

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

In 50% of patients, the drug's effect begins within 12 minutes after a single dose, and in 95% of patients, within 0.5–1 hour. The Cmax in blood plasma is reached within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is achieved after 2 days of continuous dosing. Cmax is 270 ng/mL after a single dose and 308 ng/mL after repeated administration of a 5 mg dose.

Distribution

There is no available data on the distribution of the drug in human tissues or on the penetration of levocetirizine through 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

The extent of levocetirizine metabolism in humans is approximately 14%. The metabolic process includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation primarily involves cytochrome CYP3A4, while oxidation involves numerous and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding the maximum levels achieved after oral administration of a 5 mg dose. Due to the low extent of metabolism and lack of inhibitory potential, drug interactions with other substances are unlikely.

Elimination

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

The mean total clearance is 0.63 mL/min/kg. Therefore, for patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted based on creatinine clearance. In cases of anuria due to end-stage renal disease, total body clearance in patients 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.

For 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.

End-stage renal disease with calculated glomerular filtration rate (GFR) below 15 ml/min requiring dialysis treatment.

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

Interaction with other medicinal products and other forms of interaction.

Studies on levocetirizine regarding interactions (including studies with CYP3A4 inducers) have not been conducted. Studies with the racemic compound cetirizine have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. When used concomitantly with theophylline (400 mg per day), a slight decrease (by 16%) in cetirizine clearance was observed (theophylline distribution was not altered). In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) when co-administered with cetirizine.

There are no data on 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 concomitant food intake reduces the rate of absorption.

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

During the use of the medicinal product, alcohol consumption should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the medicinal product to a patient, attention should be paid to the presence of certain factors provoking urinary retention (e.g. spinal cord injuries, benign prostatic hyperplasia), as levocetirizine increases the risk of urinary retention.

Levocetirizine should be used with caution in patients with epilepsy or a risk of seizures, as its use may lead to an exacerbation of seizures.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take levocetirizine.

Antihistamines suppress the response to skin allergy tests; therefore, 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 the start of treatment. The symptom may resolve spontaneously. In some cases, the symptom may be intense and re-treatment may be required. The symptom should resolve after re-initiation of treatment.

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 (more than 1000 pregnancy outcomes), do not indicate any malformative or fetal/neonatal toxicity. Animal studies have not demonstrated any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

If necessary, the use of levocetirizine during pregnancy may be considered.

Breastfeeding

It has been shown that cetirizine, the racemate of levocetirizine, is excreted in human milk. Therefore, excretion of levocetirizine in breast milk is likely. Adverse reactions related to levocetirizine may occur in breastfed infants. Therefore, 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 affect reaction speed when driving or operating machinery

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

However, 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 dosing.

Recommended doses

The medication is prescribed to adults and children aged 6 years and older. It is administered orally at a daily dose of 5 mg 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 insufficiency").

Renal insufficiency

Dosing intervals should be individually adjusted according to the patient's renal function (eGFR – estimated glomerular filtration rate); see Table 1 for dose adjustment.

Table 1

Dose adjustment of the medication for patients with renal impairment

For children with renal impairment, the dose of the drug should be adjusted individually based on renal clearance and body weight.

There are no specific data available regarding the use of the drug in children with renal impairment.

Patients with hepatic impairment

Patients with hepatic impairment alone do not require dosage adjustment. Patients with both hepatic and renal impairment should have their dosage regimen adjusted according to the information provided in Table 1.

Paediatric population

Children aged 6 to 12 years: the recommended daily dose is 5 mg (1 orally disintegrating tablet).

For children aged 2 to 6 years, dose adjustment is not feasible with the orally disintegrating tablet formulation. Levozetirizine in a formulation suitable for paediatric use is recommended.

Method of administration

The orally disintegrating tablet should be placed on the tongue and allowed to disintegrate without chewing. The resulting suspension should be swallowed with saliva. The orally disintegrating tablet may be taken with or without water, and with or without food. The recommended daily dose should be administered as a single dose.

Duration of treatment

Patients with intermittent allergic rhinitis (disease symptoms lasting < 4 days per week or < 4 weeks per year) should be treated according to the condition and medical history; treatment may be discontinued when symptoms resolve and restarted if symptoms recur. In cases of persistent allergic rhinitis (symptoms lasting > 4 days per week and > 4 weeks per year), continuous therapy may be considered during allergen exposure periods. There is clinical experience with levozetirizine use for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year (data available from clinical studies using cetirizine (racemate)).

Children

The drug is not recommended for children under 6 years of age, as this pharmaceutical form does not allow for appropriate dose adjustment. For this patient group, levozetirizine in a formulation suitable for paediatric use is recommended.

Overdose

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

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

Adverse Reactions

Clinical Studies

Adults and Children Aged 12 Years and Older

In therapeutic studies involving men and women aged 12 to 71 years, 15.1% of patients in the group receiving levocetirizine at a dose of 5 mg 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 severity.

In therapeutic studies, the rate of withdrawal due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Therapeutic clinical studies of levocetirizine included 935 patients who received the medicinal product at the recommended dose of 5 mg once daily. In these studies, the adverse reactions listed below occurred with a frequency of 1% or greater (common: ≥ 1/100 to < 1/10) during treatment with either levocetirizine 5 mg or placebo (see Table 2).

Table 2

Uncommon (≥ 1/1,000, < 1/100): asthenia and abdominal pain.

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

Pediatric population

In two placebo-controlled studies involving pediatric patients aged 6 to 11 months and aged 1 to 6 years, 159 subjects received levocetirizine 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The incidence of adverse reactions occurring at a frequency of 1% or higher with levocetirizine or placebo is presented in Table 3.

Table 3

Double-blind, placebo-controlled studies involving children aged 6 to 12 years were conducted, in which 243 children received 5 mg of levocetirizine daily for various durations ranging from less than 1 week to 13 weeks. The adverse reactions listed below were reported to occur at a frequency of 1% or more with either levocetirizine or placebo (see Table 4).

Table 4

Post-marketing experience

The frequency is classified as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated based on available data).

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

Nutrition and metabolism disorders: frequency not known: increased appetite.

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

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

Cardiac disorders: palpitations, tachycardia.

Eye disorders: frequency not known: visual disturbance, 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.

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

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

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

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

Investigations: frequency not known: weight increased, liver function test abnormal.

General disorders and administration site conditions: frequency not known: oedema.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration 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 of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of the reach of 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 №100 (10x1x10).

Supply category. Over-the-counter.

Manufacturer.

Athena Drug Delivery Solutions Pvt. Ltd.

Manufacturer's address and location of its business operations.

Plot A1-A5, MIDC, Chemical Zone, Ambernath (West), Maharashtra, 421 501, India.