Cetrimak

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

Composition:

Active substance: levocetirizine dihydrochloride;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, lactose monohydrate, colloidal anhydrous silicon dioxide, magnesium stearate, coating Instacoat Universal White A05G10679: hypromellose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of white to almost white color, with imprint "M" and "17" separated by a break line on one side and a break line on the other side.

Pharmacotherapeutic group.

Antihistamines for systemic use. Piperazine derivatives. Levocetirizine.

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 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 alleviates the course of allergic reactions, exerting anti-exudative, anti-pruritic, and anti-inflammatory effects, with almost no anticholinergic or anti-serotonin activity.

Pharmacokinetics

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

Absorption

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

The onset of action occurs within 12 minutes after a single dose in 50% of patients, and within 0.5–1 hour in 95% of patients. In adults, peak plasma concentration (Cmax) is achieved approximately 50 minutes after oral administration of a tablet. Steady-state plasma concentration is reached after 2 days of daily dosing. Cmax is typically 270 ng/ml and 308 ng/ml after single and repeated administration of 5 mg once daily, respectively.

Distribution

There is no available data on tissue distribution of the drug in humans or on the ability of levocetirizine to cross 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 (CNS). Distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg. Plasma protein binding in humans 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 is mediated by multiple and/or undefined CYP isoenzymes. Levocetirizine does not affect the activity of cytochrome isoenzymes 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 its low extent of metabolism and lack of inhibitory effect on metabolic enzymes, drug interactions involving levocetirizine (and vice versa) are unlikely.

Excretion

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

In patients with impaired renal function (creatinine clearance < 40 ml/min), drug clearance is reduced and T1/2 is prolonged (in patients undergoing hemodialysis, total clearance is reduced by 80%), necessitating appropriate dose adjustment. 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 or to any other component of the medicinal product, or to any piperazine derivatives.

Severe form of chronic renal insufficiency (creatinine clearance < 10 ml/min). Requirement for hemodialysis.

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

Interaction with other medicinal products and other forms of interaction.

Studies on levocetirizine regarding interaction (including studies with CYP3A4 enzymes) have not been conducted.

Studies with racemic cetirizine have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions.

A reduction (~16%) in cetirizine clearance has been observed with concomitant administration of 400 mg theophylline. It is quite possible that higher doses of theophylline may have a greater effect.

In a study of multiple dosing of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of cetirizine exposure increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) with concomitant cetirizine administration.

The extent of levocetirizine absorption is not reduced by food, although the rate of absorption is decreased.

Concomitant administration of cetirizine or levocetirizine and alcohol or other CNS depressants in susceptible patients may cause additional reduction in alertness and ability to perform tasks.

Special precautions for use

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

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

When prescribing the drug, one should take into account the presence of certain factors in patients that may provoke urinary retention (such as spinal cord injuries, benign prostatic hyperplasia), since levocetirizine may increase the risk of urinary retention.

Levocetirizine should be used with caution in patients with epilepsy and those at risk of seizures, as its use may lead to exacerbation of seizures.

Antihistamines suppress the response to skin allergy tests; therefore, the drug should be discontinued at least 3 days before 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, it may be intense and require resumption of treatment. The symptom should resolve after restarting therapy.

The tablet form 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 formulation suitable for pediatric use is recommended.

Since the drug contains lactose, it is not recommended for patients with diagnosed intolerance to certain sugars. Consult a physician before taking this medicinal product.

This medicinal product contains 0.015 mmol (or 0.35 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Levocetirizine is contraindicated during pregnancy. Cetirizine is excreted in breast milk; therefore, if use of the drug is necessary during breastfeeding, breastfeeding should be discontinued.

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 studies have not shown evidence that levocetirizine at the recommended dose impairs mental alertness, reaction capability, or 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 consider their individual response to the drug.

Dosage and Administration

The drug is intended for use in adults and children aged 6 years and older.

Recommended Doses

Adults and children aged 12 years and older: the daily dose is 5 mg (1 film-coated tablet) once daily.

Elderly Patients

For elderly patients with normal renal function, dose adjustment is not required.

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

Renal Impairment

For patients with impaired renal function, dosage must be adjusted according to the degree of renal impairment (creatinine clearance) as specified in the table (see table below).

To do this, determine the patient's creatinine clearance (CrCl) in mL/min based on serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment of the drug for patients with impaired renal function

In children with impaired renal function, the dose of the medicinal product should be individually adjusted according to the patient's renal clearance and body weight.

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

Hepatic impairment

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

Paediatric population

Children aged 6 to 12 years: the recommended daily dose is 5 mg (1 film-coated tablet).

For children aged 2 to 6 years, dose adjustment is not feasible with the film-coated tablet formulation. It is recommended to prescribe levocetirizine in a dosage form suitable for paediatric use.

Method of administration

The tablet should be taken orally, independent of food intake. The tablet should be swallowed whole with a small amount of water. The daily dose should preferably be administered once daily.

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 when symptoms resolve and restarted upon recurrence. 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 considered during periods of allergen exposure. There is clinical experience with levocetirizine 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 derived from clinical studies using the racemate).

Children

The tablet formulation should not be administered to children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. For this patient group, levocetirizine in a formulation suitable for paediatric use is recommended.

Overdose

Symptoms: Overdose symptoms may include somnolence in adults and nervous excitability and restlessness in children, which may alternate with somnolence.

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.

Adverse reactions.

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.

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

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 disorders.

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.

Below is a summary of the main adverse reactions and their frequency, identified during clinical trials and/or based on post-marketing experience.

Frequency is defined 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.

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

Nervous system disorders: frequency not known – somnolence, headache, fatigue, asthenia, convulsions, paraesthesia, dizziness, syncope, tremor, dysgeusia.

Psychiatric disorders: frequency not known – sleep disorders, restlessness, hallucinations, depression, aggression, insomnia, suicidal ideation, 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, diarrhoea, vomiting, constipation, dry mouth, abdominal pain.

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 and administration site conditions: frequency not known – oedema.

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

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30°C in the original packaging.

Keep out of the reach of children.

Packaging.

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

Prescription status. Over-the-counter.

Manufacturer. MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address.

Village Theda, P.O. Lodhimary, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.