Allergofree

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALLEGROFREE (ALLERGOFREE)

Composition:

Active substance: levocetirizine;

1 tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: microcrystalline cellulose, maize starch, povidone (K-30), crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: oval tablets, white to almost white in color.

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 effect 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 the allergic reaction, 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. It has virtually no anticholinergic or anti-serotonergic activity. At therapeutic doses, it has practically no sedative effect.

Pharmacokinetics.

Pharmacokinetic parameters of levocetirizine show linear dependence and are almost identical to those of cetirizine.

Absorption. The drug is rapidly absorbed after oral administration; food intake does not affect the extent of absorption but reduces its rate. Bioavailability is 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. Maximum serum concentration (C_max) is reached within 50 minutes after a single oral therapeutic dose and remains sustained for up to 2 days. C_max 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. Volume of distribution is 0.4 L/kg. Plasma protein binding is 90%.

Metabolism. 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, while oxidation involves numerous 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 maximum levels achieved after a 5 mg oral dose. Due to the low extent of metabolism and lack of inhibitory effect on metabolic pathways, drug interactions between levocetirizine and other substances (and vice versa) are unlikely.

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

The apparent clearance of levocetirizine correlates with creatinine clearance. 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 at the terminal stage of renal disease, total clearance is reduced by approximately 80% compared to normal renal function. The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.

Clinical Characteristics.

Indications.

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

Contraindications.

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

Severe form of chronic renal insufficiency (creatinine clearance < 15 mL/min). Requirement for hemodialysis.

Interaction with other medicinal products and other types of interactions.

Studies on levocetirizine regarding interactions (including studies on CYP3A4 enzymes) have not been conducted. Studies on 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. Concomitant use with theophylline (400 mg per day) reduces total cetirizine clearance by 16%, while the kinetics of theophylline remain unchanged. In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg per day), the extent of exposure to cetirizine increased by approximately 40%, whereas the disposition of ritonavir was slightly altered (-11%) with concomitant cetirizine administration.

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 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 required) and in elderly patients with renal impairment (possible reduction in glomerular filtration rate). During treatment with the drug, alcohol consumption should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

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.

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

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 these symptoms were not present prior to the start of treatment. Symptoms may resolve spontaneously. In some cases, symptoms may be severe and re-initiation of treatment after discontinuation may be required. Symptoms should resolve upon resumption of treatment.

Pediatric population

The use of the drug in tablet form is not recommended in children under 6 years of age, as this dosage form does not allow appropriate dose adjustment. This patient group should be treated with levocetirizine in a pharmaceutical form suitable for pediatric use.

Use during pregnancy or breastfeeding

Pregnancy

There are no or only limited data (fewer than 300 pregnancy outcomes) on the use of levocetirizine in pregnant women. However, extensive data from use of cetirizine, the racemate of levocetirizine, in pregnant women (over 1000 pregnancy outcomes) indicate no malformations or fetal/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects of levocetirizine on pregnancy, embryonal/fetal development, parturition, or postnatal development.

If necessary, levocetirizine may be considered during pregnancy.

Breastfeeding

Cetirizine, the racemate of levocetirizine, is excreted into breast milk. Therefore, levocetirizine may also be excreted into breast milk. Adverse reactions related to levocetirizine may occur in breastfed infants. Thus, levocetirizine should be used with caution in women during breastfeeding.

Fertility

There are no clinical data on the effect of levocetirizine on fertility.

Ability to influence reaction speed when driving vehicles or operating machinery

Comparative clinical studies have not demonstrated any evidence that levocetirizine at the recommended dose impairs mental alertness, reaction ability, 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.

Method of administration and dosage.

The drug should be administered orally once daily at a dose of 5 mg to adults and children aged 6 years and older. Tablets should be taken independently of food intake. The tablet should be swallowed whole with a small amount of water.

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 calculation should be based on creatinine clearance (CrCl, mL/min) according to the table provided below.

Creatinine clearance (CrCl, mL/min) should be estimated from serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment of the drug for patients with impaired renal function

In children with renal function impairment, the dose of the drug should be individually adjusted according to creatinine clearance and body weight. There are no specific data on the use of the drug in children with renal impairment.

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment alone. 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: recommended daily dose – 5 mg (1 tablet).

For children aged 2 to 6 years, dose adjustment is not feasible with this pharmaceutical form (tablets). It is recommended to prescribe levocetirizine in a pharmaceutical form suitable for paediatric use.

Duration of treatment. Patients with intermittent allergic rhinitis (duration of symptoms < 4 days per week or for less than 4 weeks) should be treated according to the disease and medical history; treatment may be discontinued if symptoms resolve and restarted upon recurrence.

In cases of persistent allergic rhinitis (duration of symptoms > 4 days per week and for more than 4 weeks) during allergen exposure periods, continuous therapy may be considered. For chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year (data available from clinical trials using the racemate).

Children.

The tablet form of the drug is not recommended for children under 6 years of age, as this pharmaceutical form does not allow appropriate dose adjustment. This patient group should be prescribed levocetirizine in a pharmaceutical form suitable for paediatric use.

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 therapy is recommended. Gastric lavage should be considered shortly after drug ingestion. Haemodialysis is not effective in eliminating 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.

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 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.

The following adverse reactions have also been reported during the post-marketing period. Adverse reactions are listed by system organ class and 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 the 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, syncope, tremor, dysgeusia.

Ear and labyrinth disorders:

frequency not known – vertigo.

Eye disorders:

frequency not known – vision disorders, 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 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 increased, 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 authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard pack.

Supply category. Over-the-counter.

Manufacturer.

Simpex Pharma Pvt. Ltd.

Manufacturer's address and place of business.

C7 to C13 and C59 to C64, Sigaddi Development Centre (SIDCUL), Sigaddi, Kotdwar-246149 Distt. Pauri Garhwal, Uttarakhand, India.