Cetrin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETRINE (CETRINE)

Composition:

Active substance: levocetirizine dihydrochloride;

5 ml of syrup contain levocetirizine dihydrochloride 2.5 mg;

Excipients: sugar; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); disodium edetate; sodium citrate; citric acid anhydrous; sorbitol solution, non-crystallizing (E 420); glycerol; sunset yellow FCF (E 110); orange flavor RS 15215; purified water.

Pharmaceutical form. Syrup.

Main physico-chemical properties: orange-colored syrup with a pleasant odor, sweet to taste, free from sediment.

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 antagonists of peripheral H1-histamine receptors. Its pharmacological effect is due to the blockade of H1-histamine receptors. Binding studies have demonstrated that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). The affinity of levocetirizine is twice as high as that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 minutes. After a single dose, receptor binding of levocetirizine was 90% at 4 hours and 57% at 24 hours. Pharmacodynamic studies in healthy volunteers showed that half the dose of levocetirizine has comparable activity to cetirizine in terms of both cutaneous and nasal responses.

Pharmacodynamic Effects

The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials:

In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and flare, treatment with levocetirizine resulted in a significant reduction in wheal and flare formation, with the maximum effect observed within the first 12 hours and lasting for 24 hours (p<0.001) compared to placebo and desloratadine.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms was observed within 1 hour after dosing in placebo-controlled allergen challenge chamber studies.

In vitro studies (Boyden chambers and transcellular layer techniques) show that levocetirizine inhibits eotaxin-induced transendothelial migration of eosinophils through skin and lung cells. A pharmacodynamic in vivo experimental study (skin chamber method) demonstrated three main inhibitory effects of levocetirizine 5 mg during the first 6 hours of pollen response compared to placebo in 14 adult patients: suppression of VCAM-1 release, modulation of vascular permeability, and reduction in eosinophil recruitment.

Pharmacokinetics

The pharmacokinetic parameters of levocetirizine are linear and nearly identical to those of cetirizine. The pharmacokinetic profile is the same whether administered as a single enantiomer or as 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 dose and is not altered by food intake; however, the maximum plasma concentration (Cmax) is reduced and reached later. Bioavailability reaches 100%.

In 50% of patients, the effect of the drug develops within 12 minutes after a single dose, and in 95% within 0.5–1 hour. Cmax in plasma is achieved within 50 minutes after a single therapeutic dose and remains sustained for up to 2 days. Cmax is 270 ng/mL after a single dose and 308 ng/mL after repeated administration of 5 mg, respectively.

Distribution. There is no available information on tissue distribution in humans or on the penetration of levocetirizine across the blood-brain barrier. In 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. In humans, the extent of metabolism is less than 14% of the levocetirizine dose. The metabolic process includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by cytochrome CYP3A4, while 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 degree of metabolism and lack of inhibitory potential, drug interactions (either as a perpetrator or victim) are unlikely.

Excretion. Drug excretion 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. The elimination half-life is shorter in young children. Total clearance in adults is 0.63 mL/min/kg. Levocetirizine and its metabolites are primarily excreted in urine (on average, 85.4% of the administered dose). Only 12.9% of the administered dose is excreted in feces.

Special Populations

Renal Impairment

The apparent systemic clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted according to creatinine clearance. In anuric patients with end-stage renal disease, total systemic 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 < 10%.

Pediatric Population

A comparative cross-over study of a single 5 mg oral dose of levocetirizine showed that Cmax and AUC values in 14 children aged 6 to 11 years with body weight between 20 and 40 kg were approximately twice those observed in healthy adult patients. The mean body weight-normalized Cmax, achieved on average within 1.2 hours, was 450 ng/mL. Total clearance was 30% higher, and elimination half-life was 24% shorter in the pediatric population compared to adults. Specific pharmacokinetic studies in children under 6 years of age have not been conducted. A retrospective population pharmacokinetic analysis was performed in 323 patients (181 children aged 1 to 5 years, 18 children aged 6 to 11 years, and 124 adults aged 18 to 55 years) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data from this analysis suggest that administration of 1.25 mg levocetirizine once daily in children aged 6 months to 5 years is expected to result in plasma concentrations similar to those in adults receiving 5 mg levocetirizine once daily.

Elderly Patients

Pharmacokinetic data in elderly patients are limited. After repeated oral administration of 30 mg levocetirizine once daily for 6 days in 9 elderly subjects (aged 65–74 years), total clearance was approximately 33% lower than in younger adult patients. It has been shown that the disposition of racemic cetirizine depends on renal function rather than age. This conclusion also applies to levocetirizine, as both levocetirizine and cetirizine are predominantly excreted in urine. Therefore, in elderly patients, the dose of levocetirizine should be adjusted according to renal function.

Gender

Pharmacokinetic results from 77 patients (40 males and 37 females) were evaluated for potential gender effects. The elimination half-life was slightly shorter in females (7.08 ± 1.72 hours) than in males (8.62 ± 1.84 hours); however, oral clearance adjusted for body weight in females (0.67 ± 0.16 mL/min/kg) is comparable to that in males (0.59 ± 0.12 mL/min/kg). For males and females with normal renal function, the same daily doses and dosing intervals can be used.

Race

The effect of race on levocetirizine has not been studied. Since levocetirizine is primarily renally excreted and significant racial differences in creatinine clearance are absent, no differences in the pharmacokinetic characteristics of levocetirizine based on race are expected. No racial differences in the kinetics of racemic cetirizine have been observed.

Hepatic Impairment

The pharmacokinetics of levocetirizine in patients with hepatic impairment have not been studied. In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) who received a single dose of 10 or 20 mg of racemic cetirizine, an increase in elimination half-life by 50% and a 40% reduction in clearance were observed compared to healthy subjects.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria in adults and children aged 2 years and older.

Contraindications.

Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, to any other piperazine derivatives, or to any of the excipients of the medicinal product.

Severe renal impairment (creatinine clearance < 10 mL/min).

Interaction with other medicinal products and other forms of interaction.

Interaction studies with levocetirizine (including studies with CYP3A4 inducers) have not been conducted. Interaction studies with cetirizine (the racemic compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. When co-administered with theophylline (400 mg daily), a slight decrease (by 16%) in total clearance of levocetirizine was observed (theophylline distribution was not altered).

In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir exposure was slightly altered (-11%) during concomitant cetirizine administration.

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 susceptible patients may cause additional impairment of alertness and ability to perform tasks.

Special precautions for use

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

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

When prescribing the drug to patients with certain 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.

Antihistamines suppress the response to skin allergy tests; therefore, administration of the drug 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 starting treatment. The symptom may resolve spontaneously. In some cases, it may be intense and may require re-treatment. The symptom should resolve after re-initiation of therapy.

Paediatric population

Although there are some clinical data on the use of levocetirizine in children aged 6 months to 12 years, these data are insufficient to support its use in infants and children under 2 years of age.

Excipients

Methylparahydroxybenzoate and propylparahydroxybenzoate contained in the medicinal product may cause allergic reactions (possibly delayed).

The product contains sugar; therefore, it should be used with caution in patients with diabetes mellitus.

Since the product contains sorbitol solution, patients with rare hereditary fructose intolerance should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). However, extensive data (more than 1000 pregnancy outcomes) on cetirizine, the racemate of levocetirizine, indicate no malformations or fetal/neonatal toxicity. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Levocetirizine may be considered for use during pregnancy if clinically needed.

Breastfeeding period

It has been established 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 (including animal studies) on the effect of levocetirizine on fertility.

Ability to affect 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 ability to drive vehicles.

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.

Dosage and Administration

The medication can be taken regardless of food intake.

Recommended doses:

Adults and adolescents aged 12 years and older

The recommended daily dose is 5 mg (10 mL) once daily.

Elderly patients

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 based on renal function (eGFR – estimated glomerular filtration rate). Refer to the table below and adjust the dose as indicated.

Dose adjustment for patients with impaired renal function:

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

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

Patients with hepatic impairment

Dose adjustment is not required in patients with hepatic insufficiency. Patients with both hepatic and renal insufficiency require dose adjustment according to the table provided above.

Children

Recommended doses:

• children aged 2 to 6 years: the recommended daily dose is 2.5 mg (5 mL). This dose should be administered as 1.25 mg (2.5 mL) twice daily;
• children aged 6 to 12 years: the recommended daily dose is 5 mg (10 mL) once daily.

Although there are some clinical data on the use of levocetirizine in children aged 6 months to 12 years, these data are insufficient to support the use of levocetirizine in infants and children under 2 years of age.

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 restarted upon recurrence of symptoms. In cases of persistent allergic rhinitis (duration of symptoms more than 4 days per week or more than 4 weeks per year) during periods of allergen exposure, continuous therapy may be recommended. Clinical experience supports the use of levocetirizine for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), the duration of treatment may extend up to 1 year (data are available from clinical studies using cetirizine (racemate)).

Children

The use of levocetirizine in children under 2 years of age is not recommended due to limited data in this age group.

The medicinal product is indicated for use in children aged 2 years and older.

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 therapy is recommended. Gastric lavage should be considered shortly after drug ingestion. Hemodialysis is not effective for removing levocetirizine from the body.

Adverse reactions.

Clinical studies

Adults and adolescents over 12 years of age.

In therapeutic studies 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 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.

Clinical therapeutic studies of levocetirizine included 935 patients who received the medicinal product at the recommended dose of 5 mg once daily. In this population, the following adverse reactions occurred at a frequency 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 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 more for either levocetirizine or placebo.

As stated in sections "Dosage and Administration" and "Special Warnings and Precautions for Use", please note that even though clinical data presented in this section are available for children aged 6 months to 12 years, we do not have sufficient data to support the use of the medicinal product in infants and children under 2 years of age.

Post-marketing experience

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

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

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

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

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

Cardiac disorders: frequency not known: palpitations, tachycardia.

Eye disorders: frequency not known: 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.

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: angioedema, fixed drug eruptions, pruritus, rash, urticaria.

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

General disorders: frequency not known: swelling.

Investigations: frequency not known: weight gain, abnormal liver function tests.

Methyl parahydroxybenzoate and propyl parahydroxybenzoate contained in the syrup may cause allergic reactions (possibly delayed).

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 product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 2 years.

After opening the bottle, use within 3 months.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging. 30 ml, 50 ml or 100 ml of syrup in a bottle; 1 bottle with a measuring cap in a cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer. FDC Limited.

Manufacturer's address and location of operations.

Plot No. B-8, MIDC, Industrial Area, Waluj, 431 136, Dist. Aurangabad, India.