Glentset

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLENCEt (GLENCET)

Composition:

Active substance: levocetirizine;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry white (Opadry Y 1-7000): titanium dioxide (E 171), polyethylene glycol, hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, oval, biconvex, film-coated tablets with a break line on one side and a smooth surface on the other, marked with the letter "G" on both sides of the break line.

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 class 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, anti-pruritic, and anti-inflammatory effects, with virtually no anticholinergic or anti-serotonin activity.

Pharmacokinetics

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

Absorption. The drug is rapidly absorbed after oral administration. Food intake does not affect the extent of absorption but reduces its rate. Bioavailability reaches 100%. In 50% of patients, the effect develops within 12 minutes after a single dose, and in 95% – within 0.5–1 hour. Maximum 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 dosing. Cmax is 207 ng/mL after a single dose and 308 ng/mL after repeated administration of 5 mg, respectively.

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

Metabolism. In humans, the extent of metabolism is less than 14% of the administered dose of levocetirizine. Therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be minimal. The metabolic process includes aromatic oxidation, N- and O-dealkylation, and conjugation with taurine.

Dealkylation occurs primarily via cytochrome CYP3A4, whereas aromatic oxidation involves multiple cytochrome isoforms. Levocetirizine does not affect the activity of cytochrome isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations even exceeding peak levels after a 5 mg oral dose. Given the low degree of metabolism and lack of significant inhibitory effects, drug interactions (either with levocetirizine or by other drugs affecting levocetirizine) are unlikely.

Elimination. The drug is primarily eliminated via glomerular filtration and active tubular secretion. The elimination half-life from plasma (T_1/2) is 7.9 ± 1.9 hours. T_1/2 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 mainly through urine (on average, 85.4% of the administered dose is excreted). Only 12.9% of the administered dose is excreted in feces.

Special Populations

Patients with Renal Impairment

The apparent clearance of levocetirizine correlates with creatinine clearance (CL_cr). Therefore, in patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted based on CL_cr. In anuric patients with end-stage renal disease, total clearance decreases by approximately 80% compared to patients without such impairment. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is less than 10%.

Excreted in breast milk.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis, including perennial allergic rhinitis, and urticaria.

Contraindications.

Hypersensitivity to levocetirizine or to any other component of this medicinal formulation, or to any piperazine derivative.

End-stage renal disease (glomerular filtration rate (GFR) < 15 ml/min) requiring dialysis.

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

Interaction with other medicinal products and other forms of interaction.

Studies on interactions of levocetirizine (including with CYP3A4 inducers) have not been conducted. Studies with cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, or diazepam does not result in clinically significant adverse interactions. Concomitant use with theophylline (400 mg daily) reduces total clearance of cetirizine by 16%, while the kinetics of theophylline remain unchanged. In a study of multiple dosing of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, whereas ritonavir disposition was slightly altered (-11%) during 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 of food reduces the rate of absorption.

Concomitant administration of cetirizine or levocetirizine with alcohol or other central nervous system depressants in sensitive 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 (possible reduction in glomerular filtration rate). Alcohol consumption should be avoided during treatment with this drug.

Caution is necessary 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.

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

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).

This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Pruritus may occur after discontinuation of levocetirizine, even if this symptom was not present before treatment initiation. The pruritus may resolve spontaneously. In some cases, it may be intense and require re-initiation of treatment. The pruritus should resolve after resuming treatment.

Levocetirizine in tablet form 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 pharmaceutical form suitable for pediatric use.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (<300 pregnancy cases). However, extensive data on cetirizine, the racemate of levocetirizine (over 1000 pregnancy cases), indicate no evidence of fetal/neonatal developmental abnormalities or 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 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. The medicinal product should be used with caution during breastfeeding.

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

Comparative clinical trials have not demonstrated any evidence that levocetirizine at the recommended dose impairs attention, reaction speed, or ability to drive vehicles or operate machinery.

However, some patients may experience somnolence, fatigue, or asthenia during treatment with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities, or operate machinery should take into account their individual response to the drug.

Dosage and Administration

The medicinal product is intended for oral administration.

The tablet should be swallowed whole with a small amount of water, regardless of food intake.

Adults and children aged 12 years and older

The recommended daily dose is 5 mg (1 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 "Patients with Renal Impairment").

Patients with Renal Impairment

Dosage should be individually adjusted according to renal function (eGFR [estimated glomerular filtration rate]) as specified in the table below.

Dosage adjustment for patients with impaired renal function

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

There are no specific data regarding the use of levocetirizine in children with impaired renal function.

Patients with hepatic impairment

In patients with hepatic impairment alone, dosage adjustment is not required. In patients with both hepatic and renal impairment, dosage should be adjusted according to the table above.

Paediatric 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 in tablet form is not recommended for 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.

Duration of treatment

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

Children

The tablet formulation of the drug is not recommended for 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: Overdose symptoms 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 treatment is recommended. Gastric lavage should be considered shortly after drug intake. Haemodialysis is not effective in removing levocetirizine from the body.

Side effects

The following adverse reactions have been reported during clinical trials of levocetirizine in at least 1 % of patients aged 12 to 71 years (common (≥1/100, <1/10)):

Nervous system disorders: headache, somnolence;

Gastrointestinal disorders: dry mouth;

General disorders and administration site conditions: fatigue.

Infrequently (≥1/1000, <1/100), asthenia and abdominal pain were also reported.

The following adverse reactions have been reported during clinical trials of levocetirizine in at least 1 % of infants aged 6–11 months and children aged 1 to 6 years:

Gastrointestinal disorders: diarrhoea, vomiting, constipation;

Nervous system disorders: somnolence;

Psychiatric disorders: sleep disturbance.

The following adverse reactions have been reported during clinical trials of levocetirizine in at least 1 % of children aged 6 to 12 years:

Nervous system disorders: headache, somnolence.

The following adverse reactions have also been reported in the post-marketing period. Adverse reactions are listed by system organ class 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.

Metabolism and nutrition disorders:

Frequency not known – increased appetite.

Psychiatric disorders:

Frequency not known – aggression, agitation, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

Nervous system disorders:

Frequency not known – seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Ear and labyrinth disorders:

Frequency not known – vertigo.

Eye disorders:

Frequency not known – visual disturbance, blurred vision, nystagmus.

Cardiac disorders:

Frequency not known – palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders:

Frequency not known – dyspnoea.

Gastrointestinal disorders:

Frequency not known – diarrhoea, vomiting, constipation, dry mouth, nausea, abdominal pain.

Hepatobiliary disorders:

Frequency not known – hepatitis.

Renal and urinary disorders:

Frequency not known – dysuria, urinary retention.

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.

General disorders and administration site conditions:

Frequency not known – oedema.

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

Description of selected adverse reactions

Pruritus after discontinuation of levocetirizine has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 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 in a blister; 1, 3, or 10 blisters in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Glenmark Pharmaceuticals Ltd. / Glenmark Pharmaceuticals Ltd.

Manufacturer's address.

Plot No. C-7, Kolval Industrial Estate, Kolval, Bardez, Goa – 403 513, India.