Cetrilev
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETRILEV (CETRILEV)
Composition:
Active substance: levocetirizine;
1 tablet contains 5 mg of levocetirizine dihydrochloride;
Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, talc, magnesium stearate, hypromellose, colloidal anhydrous silicon dioxide, povidone K-30, titanium dioxide (E171), polyethylene glycol 400, quinoline yellow lake (E104).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: yellow, round, biconvex, film-coated tablets, smooth on both sides.
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 action 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 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, antipruritic, and anti-inflammatory effects, with almost no anticholinergic or anti-serotonin activity. At therapeutic doses, it has minimal sedative effect.
Pharmacokinetics.
Pharmacokinetic parameters of levocetirizine show linear dependence and are independent of dose and time, as well as demonstrate low variability among different patients. The pharmacokinetic profile after 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; however, the maximum concentration (Cmax) is reduced and reached later when taken with food. Bioavailability reaches 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. Cmax in blood plasma is achieved within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is reached after two days of daily dosing. Cmax is 270 ng/mL after a single dose and 308 ng/mL after repeated administration of a 5 mg dose, respectively.
Distribution. There is no available information regarding the distribution of the drug in human tissues 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 tissues of the central nervous system. 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 is primarily mediated by cytochrome CYP3A4, while oxidation involves multiple 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 an oral 5 mg dose. Due to the low extent of metabolism and lack of inhibitory potential, drug interactions involving levocetirizine (and vice versa) are unlikely.
Excretion. The drug is eliminated via two pathways: glomerular filtration and active tubular secretion. The elimination half-life (T1/2) of the drug in plasma in adults is 7.9 ± 1.9 hours. The half-life is shorter in young children. Total body clearance in adults is 0.63 mL/min/kg. Elimination of levocetirizine and its metabolites occurs mainly via urine (on average, 85.4% of the administered dose is excreted). Only 12.9% of the administered dose is excreted in feces.
Special populations
Renal impairment
The apparent total body clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing interval should be adjusted according to creatinine clearance. In anuria due to 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 < 10%.
Clinical characteristics.
Indications.
Symptomatic treatment of seasonal allergic rhinitis (including perennial allergic rhinitis) and chronic idiopathic urticaria.
Contraindications.
Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, to any other piperazine derivatives, or to any of the excipients of the medicinal product.
Rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Patients with end-stage renal disease with a calculated glomerular filtration rate (eGFR) below 15 mL/min (requiring dialysis treatment).
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 racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse interactions. In a multiple-dose study, concomitant administration with theophylline (400 mg daily) resulted in a slight reduction (by 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%) during concomitant cetirizine administration.
There are no data regarding potentiation of the effect of sedatives when used at therapeutic doses. However, the use of sedatives should be avoided during treatment with this medicinal product.
Food intake does not affect the extent of absorption of the medicinal product, but concomitant food intake 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 reduction in alertness and ability to perform tasks.
Special precautions for use
The drug should be used with caution in patients with chronic renal insufficiency (dose adjustment is required) and in elderly patients with renal impairment (possible reduction in glomerular filtration rate). Alcohol consumption should be avoided during treatment (see section "Interaction with other medicinal products and other forms of interaction").
Caution is advised 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 increased seizure activity.
Antihistamines suppress skin allergic reactions; therefore, the drug should be discontinued at least 3 days prior to skin testing (elimination period).
Pruritus may occur after discontinuation of levocetirizine, even if such symptoms were not present prior to the start of treatment. Symptoms may resolve spontaneously. In some cases, symptoms may be severe and re-administration of the drug after discontinuation may be required. Treatment may be restarted only after complete resolution of symptoms.
The tablet form of the drug is not recommended for children under 6 years of age, as appropriate dose adjustment cannot be achieved with this dosage form. This patient group should be prescribed levocetirizine in a dosage form suitable for pediatric use.
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), indicate no evidence of malformative or fetal/neonatal toxicity. Animal studies have not shown 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 necessary.
Breastfeeding
Cetirizine, the racemate of levocetirizine, is excreted in human milk. Therefore, excretion of levocetirizine into 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 shown no evidence that levocetirizine, at the recommended dose, impairs mental alertness, reaction ability, or the ability to drive vehicles or operate machinery.
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 drug.
Method of administration and doses.
The drug is intended for adults and children aged 12 years and older.
Recommended doses:
Adults and adolescents aged 12 years and older: the 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 impairment").
Patients with renal impairment
Dosing intervals should be individually selected based on 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
| Renal function group |
eGFR, mL/min |
Dosage and frequency |
| Normal renal function |
≥ 90 |
1 tablet once daily |
| Mild impairment |
60 – < 90 |
1 tablet once daily |
| Moderate impairment |
30 – < 60 |
1 tablet every 2 days |
| Severe renal impairment |
15 – < 30 (not requiring dialysis) |
1 tablet every 3 days |
| End-stage renal disease |
< 15 (dialysis required) |
Contraindicated |
For children with renal impairment, the dose of the drug should be individually adjusted according to the patient's renal clearance and body weight.
There are no specific data regarding the use of the drug in children with renal impairment.
Patients with hepatic impairment
Dose adjustment is not required in patients with hepatic impairment. In patients with both hepatic and renal impairment, dosage regimen 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 tablet).
For children aged 2 to 6 years, dose adjustment is not feasible with this pharmaceutical form. It is recommended to use levocetirizine in a pharmaceutical form suitable for paediatric use.
Method of administration
The drug is taken orally, independent of food intake. The tablet should 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 may be 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), continuous therapy may be offered during allergen exposure periods. There is clinical experience with the use of levocetirizine for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), the treatment duration may last up to 1 year (data available from clinical studies using cetirizine (racemate)).
Children.
The use of the drug in tablet form 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, levocetirizine in another pharmaceutical form suitable for paediatric use is recommended.
Overdose.
Symptoms. Overdose symptoms may include somnolence in adults and nervous excitation and restlessness in children, alternating with drowsiness.
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
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 discontinuation due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.
Therapeutic clinical studies with levocetirizine included 935 patients who received the drug at the recommended dose of 5 mg once daily. In this population, the following adverse reactions occurred at an incidence of 1% or greater (common: ≥1/100 to <1/10) during treatment with levocetirizine 5 mg or placebo:
| Adverse reaction |
Placebo (n =771) |
Levocetirizine 5 mg (n = 935) |
| Headache |
25 (3.2%) |
24 (2.6%) |
| Somnolence |
11 (1.4%) |
49 (5.2%) |
| Dry mouth |
12 (1.6%) |
24 (2.6%) |
| Increased fatigue |
9 (1.2%) |
23 (2.5%) |
Uncommon (≥ 1/1,000, < 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%).
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 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.
| Organ systems and adverse reactions |
Placebo (n=83) |
Levocetirizine (n=159) |
| Gastrointestinal disorders |
||
| Diarrhea |
0 |
3 (1.9%) |
| Vomiting |
1 (1.2%) |
1 (0.6%) |
| Constipation |
0 |
2 (1.3%) |
| Nervous system disorders |
||
| Somnolence |
2 (2.4%) |
3 (1.9%) |
| Psychiatric disorders |
||
| Sleep disorders |
0 |
2 (1.3%) |
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 durations ranging from less than 1 week to 13 weeks. The following adverse reactions were reported with an incidence of 1% or more for levocetirizine or placebo.
Adverse reactions |
Placebo (n=240) |
Levocetirizine 5mg (n=243) |
| headache |
5(2.1%) |
2(0.8%) |
| sleepiness |
1(0.4%) |
7(2.9%) |
Post-marketing experience
The frequency is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).
Immune system disorders: frequency not known: hypersensitivity, including anaphylaxis.
Nutritional and metabolism disorders: frequency not known: increased appetite.
Nervous system disorders: frequency not known: somnolence, headache, fatigue, weakness, asthenia, convulsions, paraesthesia, dizziness, fainting, tremor, dysgeusia.
Psychiatric disorders: frequency not known: sleep disorders, 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, constipation, dry mouth, nausea, abdominal pain.
Skin and subcutaneous tissue disorders: frequency not known: angioedema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal and connective tissue disorders: frequency not known: myalgia, arthralgia.
Investigations: frequency not known: weight increased, abnormal liver function tests.
General disorders and administration site conditions: frequency not known: swelling.
Description of selected adverse reactions
Pruritus has been reported after discontinuation of levocetirizine.
Shelf life.
2 years.
Storage conditions.
Store at temperatures not above 30 °C. Keep out of the reach and sight of children.
Packaging.
10 tablets in a blister; 1, 3 or 10 blisters in a cardboard box.
10 tablets in a blister; 1 blister in a cardboard box, 10 cardboard boxes in an outer cardboard box №100 (10x1x10).
The blister has a holographic strip with the name of the manufacturing plant.
Classification. Over-the-counter.
Manufacturer. FDS Limited.
Manufacturer's address and site of manufacturing.
L-121B, Phase III/A, Verna Industrial Estate, Verna, Salcete, Goa - 403 722, India.