Contrahist allergy®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KONTRAHIST ALLERGY® (CONTRAHIST ALLERGY)

Composition:

Active substance: levocetirizine;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: microcrystalline cellulose, lactose monohydrate, magnesium stearate;

coating mixture: hypromellose (E 464), macrogol 400, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: film-coated tablets, white in color, biconvex, elongated (length 8 mm, width 4.5 mm), with engraving 'ᶺ 11' on one side, without visible impurities or contaminants.

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 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 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 produces almost no sedative effect.

Pharmacokinetics

The pharmacokinetic parameters of levocetirizine are linear and differ little from those of cetirizine.

Absorption

After oral administration, the drug is rapidly and extensively absorbed. The extent of absorption is independent of dose and is not altered by food intake; however, the maximum 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% of patients within 0.5–1 hour. The peak plasma concentration (Cmax) is achieved within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is reached after 2 days of regular dosing. Cmax is 270 ng/mL after a single dose and 308 ng/mL after repeated dosing at 5 mg, respectively.

Distribution

There is no available information on the distribution of the drug in human tissues or on the penetration of levocetirizine across 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%.

Biotransformation

Approximately 14% of levocetirizine is metabolized in the human body. The metabolic process includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation primarily involves cytochrome CYP3A4, whereas 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 extent of metabolism and lack of inhibitory potential, drug interactions involving levocetirizine are unlikely.

Elimination

Excretion of the drug occurs primarily via glomerular filtration and active tubular secretion. The elimination half-life (T1/2) in adults is 7.9 ± 1.9 hours. The T1/2 of the drug is shorter in young children. Total body clearance in adults is 0.63 mL/min/kg. The primary route of elimination of levocetirizine and its metabolites is via the urine (on average, 85.4% of the administered dose is excreted). Only 12.9% of the administered dose is excreted in feces.

The mean total body clearance is 0.63 mL/min/kg. Therefore, in 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 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.

Symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria.

Contraindications.

Hypersensitivity to levocetirizine or to any other component of the medicinal product, as well as to any piperazine derivatives.

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

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

Interaction with other medicinal products and other types of interactions.

Studies on levocetirizine regarding interactions (including studies with CYP3A4 inducers) have not been conducted. Studies with cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. When administered concomitantly with theophylline (400 mg per day), a slight decrease (by 16%) in total clearance of levocetirizine was observed (theophylline distribution remained unchanged). 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 distribution was slightly altered (-11%) during concomitant cetirizine administration.

There are no data on enhanced effects of sedatives 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 absorption of the drug, but co-administration with food reduces the rate of its absorption.

Concomitant use of cetirizine or levocetirizine and alcohol or other central nervous system depressants in susceptible patients may lead to additional impairment of 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 (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the drug, attention should be paid to the presence of certain factors provoking 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 the response to skin allergy tests; therefore, the drug should be discontinued at least 3 days prior to testing (elimination period).

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

Use during pregnancy or breastfeeding.

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

Fertility

There are no clinical data (including animal studies) on the effect of levocetirizine on fertility.

Ability to influence 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 ability, or the ability to drive vehicles.

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 medicinal product.

Method of Administration and Dosage

The medication is intended for adults and children aged 6 years and older.

Recommended Dosages

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

To apply this dosing table, the patient's creatinine clearance (CLcr) in mL/min must be estimated. CLcr (mL/min) can be estimated from serum creatinine concentration (mg/mL) using the following formula:

Dose adjustment of the medication for patients with impaired renal function

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

Dose adjustment is not required for patients with hepatic impairment. For patients with both hepatic and renal impairment, adjust the dosage regimen according to the table above.

Pediatric 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 administer levocetirizine in a pharmaceutical form suitable for pediatric use.

Administration

Take the tablet orally, independent of food intake. The tablet should be swallowed whole with a small amount of water. The daily dose should preferably be taken as a single dose.

Duration of treatment: Patients with intermittent allergic rhinitis (disease symptoms lasting < 4 days per week or < 4 weeks) should be treated according to the condition and medical history; treatment may be discontinued if symptoms resolve and restarted upon recurrence. For persistent allergic rhinitis (disease symptoms lasting > 4 days per week and > 4 weeks), continuous therapy may be considered during allergen exposure periods. For chronic conditions (chronic allergic rhinitis, chronic urticaria), the treatment duration may last up to 1 year (data available from clinical trials 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. This patient group should be given levocetirizine in a pharmaceutical form suitable for pediatric use.

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

Adverse Reactions

The following adverse reactions were 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 were also reported uncommonly (≥ 1/1000, < 1/100).

The following adverse reactions were 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: diarrhea, vomiting, constipation;

Nervous system disorders: somnolence;

Psychiatric disorders: sleep disorders.

The following adverse reactions were 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 categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

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

Nutritional and metabolic disorders: frequency not known: increased appetite.

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

Psychiatric disorders: frequency not known: sleep disorders, restlessness, 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: dyspnea.

Gastrointestinal disorders: frequency not known: nausea, diarrhea, 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: edema.

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

Description of selected adverse reactions

Pruritus after discontinuation of levocetirizine has been reported.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of the reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister; 1 blister in a cardboard box.

7 tablets in a blister; 1 blister in a cardboard box.

Pharmaceutical category. Over-the-counter.

Manufacturer.

Adamed Pharma S.A., Poland.

Manufacturer's address and place of business.

5 J. Pilsudskiego Marsh. Street, 95-200 Pabianice, Poland.